Ahead of print articles
EFFECTIVENESS OF A META-COGNITIVE GROUP INTERVENTION FOR OLDER ADULTS WITH SUBJECTIVE COGNITIVE DECLINE OR MILD COGNITIVE IMPAIRMENT: THE ASPIRE RANDOMIZED CONTROLLED TRIAL
S. Rotenberg, N.D. Anderson, M.A. Binns, E.R. Skidmore, A.K. Troyer, J. Richardson, F. Xie, E. Nalder, Y. Bar, N. Davids-Brumer, A. Bernick, D.R. Dawson
Show summaryHide summary
BACKGROUND: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) can lead to functional and cognitive decline, increasing dementia risk. There is a pressing need for interventions that prevent this deterioration. The ASPIRE (Adult Strategies Put Into Real-world Environments) intervention was developed to improve performance of daily activities.
OBJECTIVES: The primary objective was to determine whether ASPIRE was more effective than a Brain Education control intervention in improving performance and satisfaction with daily life activities that were not specifically trained in the intervention. Secondary objectives were to explore: 1) whether ASPIRE was more effective in improving self-reported health and quality of life, and performance on cognitive tests; and 2) maintenance of change over six-months.
DESIGN: Double-blind, two-armed, parallel randomized controlled trial, with a six-month follow-up period.
SETTING: Community based, Greater Toronto Area.
PARTICIPANTS: Two-hundred sixty-four older adults (aged 70.8 ± 6.6 years) with SCD or MCI, randomized to ASPIRE (n=131) or a Brain Education active control arm (n= 133).
INTERVENTION: ASPIRE is a 10-week meta-cognitive group intervention focusing on strategy acquisition and application to improve performance of individualized daily activity identified by each participant as important. It involves setting goals, creating tailored plans, and iteratively modifying these plans with support from the group members and facilitator.
MEASUREMENTS: Performance of and satisfaction with daily activities was rated on a 10-point Likert scale using the Canadian Occupational Performance Measure (COPM). Secondary outcome were subjective cognition, depression, anxiety, self-efficacy, quality of life, and cognitive tests of memory and executive functions.
RESULTS: Post-intervention, clinically significant improvement of untrained activities (two points or more on the COPM) was found in 32.5% in ASPIRE; and 30.6% in the control arm, with no significant between group differences (Performance: (exp(β ̂) =0.96, z=-0.15, p=.879); Satisfaction: (exp(β ̂) =0.94, z=-0.29, p=.775). The improvements remained stable over six months in both arms. No significant group effects were found on the secondary outcomes, but improvements were found on subjective cognition and self-efficacy in both arms post intervention.
CONCLUSION: Both a meta-cognitive strategy approach and an adult learning activity resulted in positive changes in subjective cognition, self efficacy, and, to a certain extent, engagement in daily activities.
CITATION:
S. Rotenberg ; N.D. Anderson ; M.A. Binns ; E.R. Skidmore ; A.K. Troyer ; J. Richardson ; F. Xie ; E. Nalder ; Y. Bar ; N. Davids-Brumer ; A. Bernick ; D.R. Dawson ; (2024): Effectiveness of a Meta-Cognitive Group Intervention for Older Adults with Subjective Cognitive Decline or Mild Cognitive Impairment: The ASPIRE Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.166
EFFECTS OF VITAMIN D3 COMBINED WITH FOLIC ACID ON DOMAIN AND SPECIFIC COGNITIVE FUNCTION AMONG PATIENTS WITH MILD COGNITIVE IMPAIRMENT: A RANDOMIZED CLINICAL TRIAL
W. Liu, D. Zheng, X. Li, T. Wang, L. Wang, L. Hao, M. Ju, W. Feng, Z. Guo, X. Sun, H. Yu, Z. Qin, R. Xiao
Show summaryHide summary
INTRODUCTION: To investigate the effect of vitamin D3 (VD3) combined with folic acid (FA) intervention on the cognitive function among patients with mild cognitive impairment (MCI) and vitamin D deficiency.
METHODS: Our study is a single-center, randomized, controlled trial. A total of 402 patients were randomly assigned to the placebo group (n=135), FA group (n=134), and FA+1600IU VD3 group (n=133). The intervention period was 24 weeks. The primary endpoint was the mean change in Montreal Cognitive Assessment (MoCA) compared to baseline. Secondary endpoints included other cognitive functions, serum vitamin D, folic acid, and homocysteine levels.
RESULTS: The Intention-to-Treat analysis results of MoCA showed that the adjusted Least Squares Means (LSM) differences between the FA+1600IU VD3 group and the placebo or FA group were 0.456 (95% CI -0.198 to 1.11; p=0.171) and 0.038 (95% CI -0.600 to 0.676; p=0.907), respectively, and the Per-protocol set analysis results showed that the adjusted LSM differences between the FA+1600IU VD3 group and the placebo or FA group were 0.659 (95% CI 0.005 to 1.313; p=0.048) and 0.251 (95% CI -0.387 to 0.889; p=0.44), respectively.
CONCLUSION: The effect of FA+1600IU VD3 intervention for 6 months on overall cognitive function in MCI patients with vitamin D deficiency was not significant, but its role may be underestimated and requires further long-term studies to confirm.
CITATION:
W. Liu ; D. Zheng ; X. Li ; T. Wang ; L. Wang ; L. Hao ; M. Ju ; W. Feng ; Z. Guo ; X. Sun ; H. Yu ; Z. Qin ; R. Xiao (2024): Effects of Vitamin D3 Combined with Folic Acid on Domain and Specific Cognitive Function among Patients with Mild Cognitive Impairment: A Randomized Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.165
ASSOCIATION BETWEEN COGNITIVE RESERVE INDICATOR AND CHRONIC DISEASE-FREE SURVIVAL: A LARGE COMMUNITYBASED LONGITUDINAL STUDY
P. Li, W. Yang, J. Wang, H. Zhu, A. Dove, W. Xu
Show summaryHide summary
BACKGROUND: Cognitive reserve (CR) has been linked to dementia and might be a predictor of aged-related outcomes. However, the association between CR and risk of other chronic diseases and mortality remains unclear.
OBJECTIVES: We aimed to investigate the association of CR with survival free from major chronic diseases.
DESIGN, SETTING AND PARTICIPANTS: This community-based longitudinal study used data from the UK Biobank. A total of 412,509 participants (mean age 55.71+8.10) free of major chronic disease (including dementia, diabetes, cardiovascular diseases, chronic obstructive pulmonary disease, and cancer) completed the baseline examination between 2006 to 2010 and were followed for changes in health status.
MEASUREMENTS: Latent class analysis was used to generate an indicator of CR (categorized as low, moderate, or high) based on education, occupation, television viewing time, confiding, social connection, and leisure activities. Major chronic diseases and survival status were ascertained through self-reported history and/or linkages to medical and death records. Chronic disease-free survival was defined as survival without any of the aforementioned chronic diseases. Effect modifications and interactions between the CR indicator and sex, age, and lifestyle factors (including smoking status, alcohol consumption, physical activity, and body mass index) were explored.
RESULTS: Over a median follow-up of 12.49 (interquartile range 11.42-13.41, range 0.01-15.87) years, 112,190 (27.2%) participants died or developed at least one chronic disease. High CR indicator was associated with lower risk of chronic disease/death (hazard ratio 0.82, 95% confidence interval: 0.80-0.83) compared to low CR indicator. Chronic disease-free survival was prolonged by 1.33 (1.21-1.44) years among participants with high CR compared to low CR indicator. Furthermore, the association between the CR indicator and chronic disease-free survival was strengthened among individuals aged <60 years and current smokers.
CONCLUSION: High CR indicator is associated with a lower risk of chronic disease/death and may prolong chronic disease-free survival. Our findings underscore the importance of CR-enhancing lifestyle and experiences in health longevity, especially for younger individuals and current smokers.
CITATION:
P. Li ; W. Yang ; J. Wang ; H. Zhu ; A. Dove ; W. Xu ; (2024): Association between Cognitive Reserve Indicator and Chronic Disease-Free Survival: A Large Community-Based Longitudinal Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.160
PHASE 1 STUDIES OF THE ANTI-TAU MONOCLONAL ANTIBODY JNJ-63733657 IN HEALTHY PARTICIPANTS AND PARTICIPANTS WITH ALZHEIMER’S DISEASE
W.R. Galpern, G. Triana-Baltzer, L. Li, K. Van Kolen, M. Timmers, K. Haeverans, L. Janssens, H. Kolb, P. Nandy, K. Aida, H. Shimizu, M. Mercken, H. Sun
Show summaryHide summary
BACKGROUND: JNJ-63733657 (posdinemab) is a humanized IgG1/kappa monoclonal anti-phospho tau antibody that binds with high affinity to phosphorylated amino acid 217 (pT217) in the proline-rich domain. The parent molecule, PT3, was raised against Alzheimer’s disease brain purified paired helical filament, and preclinical studies with the humanized version, JNJ-63733657, have demonstrated reductions in tau seeding. The results of the first-in-human clinical trial of JNJ-63733657 and a separate single ascending dose study in Japanese participants are presented.
OBJECTIVES: To evaluate the safety and tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of JNJ-63733657 after single and multiple intravenous dose administrations in healthy participants and participants with prodromal or mild Alzheimer’s disease.
DESIGN: A two part first-in-human, phase 1, randomized, double-blind, placebo-controlled trial: Single ascending dose (Part 1) and multiple ascending dose (Part 2). And a phase 1, randomized, double-blind, placebo-controlled single ascending dose trial in healthy Japanese participants.
SETTING: 7 sites in Belgium, Netherlands, Spain, and Germany; 1 site in Japan.
PARTICIPANTS: A total of 40 healthy participants aged 55-75 were enrolled in Part 1 of the first-in-human study; a total of 16 healthy participants and 13 participants with prodromal or mild AD aged 55-80 years were enrolled in Part 2. In the Japanese trial, a total of 24 participants aged 55-75 were enrolled.
INTERVENTION: In Part 1, single doses of 1, 3, 10, 30, or 60 mg/kg of JNJ-63733657 or placebo were administered to healthy participants. In Part 2, two dose levels of JNJ-63733657 (5 mg/kg or 50 mg/kg) or placebo were evaluated in healthy participants, and 2 dose levels (15 mg/kg or 30 mg/kg) or placebo were evaluated in participants with Alzheimer’s disease; doses were administered on Days 1, 29, and 57. In the Japanese trial, single doses of 3, 15, or 60 mg/kg of JNJ-63733675 or placebo were administered. All doses were administered intravenously.
MEASUREMENTS: Safety assessments, serum and cerebrospinal fluid pharmacokinetic parameters, immunogenicity, and cerebrospinal fluid pharmacodynamic changes in free and total p217+tau, total tau, and p181tau were evaluated.
RESULTS: JNJ-63733657 was generally safe and well-tolerated in healthy participants and participants with Alzheimer’s disease. In healthy participants and participants with Alzheimer’s disease, JNJ-63733657 demonstrated linear PK, and serum Cmax and AUC were approximately dose proportional following single and multiple doses. Dose-dependent reductions in free and total p217+tau in cerebrospinal fluid were observed. No changes in total tau or p181tau were observed in healthy participants whereas Alzheimer’s disease participants showed decreases in these tau species following administration of JNJ-63733657.
CONCLUSION: In these Phase 1 trials, no safety or tolerability concerns were identified, and dose dependent reductions in p217+tau in the cerebrospinal fluid were demonstrated following administration of JNJ-63733657. The safety and biomarker profiles support the continued investigation of this compound for the slowing of disease progression in Alzheimer’s disease.
CITATION:
W.R. Galpern ; G. Triana-Baltzer ; L. Li ; K. Van Kolen ; M. Timmers ; K. Haeverans ; L. Janssens ; H. Kolb ; P. Nandy ; K. Aida ; H. Shimizu ; M. Mercken ; H. Sun (2024): Phase 1 Studies of the Anti-Tau Monoclonal Antibody JNJ-63733657 in Healthy Participants and Participants with Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.163
INITIAL EXPERIENCE WITH LECANEMAB AND LESSONS LEARNED IN 71 PATIENTS IN A REGIONAL MEDICAL CENTER
L.B.E. Shields, H. Hust, S.D. Cooley, G.E. Cooper, R.N. Hart, B.C. Dennis, S.W. Freeman, J.F. Cain, W.Y. Shang, K.M. Wasz, A.T. Orr, C.B. Shields, S.S. Barve, K.G. Pugh
Show summaryHide summary
BACKGROUND AND OBJECTIVES: On July 6, 2023 the U.S. Food and Drug Administration approved the anti-amyloid monoclonal antibody lecanemab (Leqembi®) for treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD). Our early experience and lessons learned with lecanemab in a regional community medical center are described.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational study highlights the first 71 patients treated with lecanemab at our multidisciplinary Norton Neuroscience Institute Memory Center. All patients had positive cerebrospinal fluid biomarkers for AD and underwent at least 1 lecanemab infusion. Two patients had additional amyloid PET scans which were positive.
RESULTS: The mean age was 72 years (49-90 years), and 44 (62%) patients were female. Most were Caucasian (68 [96%]), and 54 [76%] were referred to our Memory Center by their primary care provider. Comorbidities were common, including hypertension (34 [48%]), hypercholesterolemia (51 [72%]), diabetes mellitus (17 [24%]), and cardiovascular disease excluding hypertension (22 [31%]). The mean body mass index was 27.0 (range: 17.8-45.0). A total of 36 (51%) patients were heterozygous for the ApoE4 genotype, and 9 (13%) were homozygous. A total of 61 [86%] patients had been treated with donepezil; 40 (56%) patients had received memantine. Of the 50 patients who completed 1 or more safety monitoring brain MRIs following infusion, 12 (24%) had amyloid-related imaging abnormalities (ARIA) detected: solitary ARIA-H (hemorrhage) in 5, solitary ARIA-E (edema) in 3, and both ARIA-H and ARIA-E in 4. Of the 12 patients with ARIA, 9 were asymptomatic, 4 were homozygous for the ApoE4 genotype, and 6 were heterozygous for the ApoE4 genotype. Of the 9 who were homozygous for the ApoE4 genotype in this study, 4 (44%) had evidence of ARIA. Of the 36 who were heterozygous for the ApoE4 genotype, 6 (17%) were diagnosed with ARIA. Twenty-six (37%) patients experienced infusion reactions after their first lecanemab infusion: headaches (12 patients) and shaking/chills/rigors (11 patients) were most common. Twenty-three (88%) of these 26 patients reported the side effects either at the infusion center or within the first 24 hours post-infusion. One patient died shortly after the first lecanemab infusion of a myocardial infarction. It is uncertain whether or not this death was related to lecanemab treatment.
CONCLUSION: Through our early experience with lecanemab, we have recognized several areas of improvement which have clarified and enhanced the lecanemab infusion experience.
CITATION:
L.B.E. Shields ; H. Hust ; S.D. Cooley ; G.E. Cooper ; R.N. Hart ; B.C. Dennis ; S.W. Freeman ; J.F. Cain ; W.Y. Shang ; K.M. Wasz ; A.T. Orr ; C.B. Shields ; S.S. Barve ; K.G. Pugh (2024): Initial Experience with Lecanemab and Lessons Learned in 71 Patients in a Regional Medical Center. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.159
VIEWS AND PERCEPTIONS OF AMYLOID IMAGING IN A PRECLINICAL ALZHEIMER’S DISEASE TRIAL
M. Ritchie, R. Raman, K. Ernstrom, S. Wang, M.C. Donohue, P. Aisen, D. Henley, G. Romano, G.P. Novak, H.R. Brashear, R.A. Sperling, J.D. Grill
Show summaryHide summary
BACKGROUND: Many cognitively unimpaired older adults are interested in learning their Alzheimer’s disease (AD) biomarker status, but little is known about motivations to undergo biomarker testing and result disclosure in the setting of preclinical AD trials.
OBJECTIVES: Examine whether motivations to undergo AD biomarker testing and disclosure differ for individuals who have elevated amyloid compared to those with not elevated amyloid, and whether disclosure of amyloid results impacts participants’ motivations.
DESIGN, SETTING, PARTICIPANTS: We conducted post-hoc analyses using data from the EARLY study, a preclinical AD trial of the beta-secretase inhibitor atabecestat. As part of the screening process of the trial, participants underwent biomarker testing and disclosure. We analyzed data from n=2241 participants.
MEASUREMENTS: We analyzed data from the Views and Perceptions of Amyloid Imaging (VPAI), a 9-item questionnaire assessing how strongly participants agreed with motivating factors for undergoing amyloid testing. The VPAI was administered at the first screening visit and again after amyloid disclosure.
RESULTS: Prior to amyloid disclosure, a greater proportion of participants in the elevated amyloid group responded at the two highest levels of endorsement for the items, “to confirm the feeling that I might already be developing symptoms of AD dementia” (p<0.001) and “to prepare my family for my possible illness in the future” (p=0.008), compared to participants in the not elevated amyloid group. Following disclosure, the not elevated amyloid group had higher odds of positive change in categorical VPAI item level scores for the items “to put mind at ease” (OR: 0.54; p<0.001), “to confirm the feeling that I might already be developing symptoms of AD dementia” (OR: 0.79; p=0.049), and “to prepare my family for my possible illness in the future” (OR: 0.67; p=<0.001), while the elevated amyloid group had higher odds of positive change for the item “curiosity” (OR:1.32; p=0.014).
CONCLUSIONS: Investigators might consider adjusting recruitment strategies for future trials to align with the motivations to undergo biomarker testing and disclosure most strongly endorsed by participants with elevated amyloid.
CITATION:
M. Ritchie ; R. Raman ; K. Ernstrom ; S. Wang ; M.C. Donohue ; P. Aisen ; D. Henley ; G. Romano ; G.P. Novak ; H.R. Brashear ; R.A. Sperling ; J.D. Grill ; (2024): Views and Perceptions of Amyloid Imaging in a Preclinical Alzheimer’s Disease Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.157
ANTI-HYPERTENSIVES REDUCE THE RATE OF ALZHEIMER’S DISEASE PROGRESSION: A COHORT STUDY LINKED WITH GENETIC AND NEUROPATHOLOGICAL ANALYSES
Z. Sternberg, R. Podolsky, J. Yu, S. Hua, S. Halvorsen, D. Hojnacki, B.J. Schaller
Show summaryHide summary
BACKGROUND: Arterial hypertension contributes to both the development and progression of dementia due to both Alzheimer’s disease (A.D.) and vascular pathology. However, the effects of different classes of anti-hypertensives (A.H.T.s), on the rate of dementia progression and brain neuropathology are unknown.
OBJECTIVE: To investigate the effect of each class of A.H.T., both as single and combined, on the rate of dementia progression. In addition, we analyzed the effect of A.H.T.s on brain neuropathology in AD participants, indicated by Braak staging, hippocampal atrophy, and baseline CSF levels of A-β42, total (T) tau, and P-181 tau.
METHODS: We have used the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS).
RESULTS: A.H.T.s were associated with reduced yearly increase in the CDR-SOB scores of 1.025 during a 10-year follow-up (P<0.001). The overall survival rate was higher in A.H.T. users than non-users [HR: 0.912: 0.860, 0.967) P=0.002]. These trends continued when stratifying participants by age, gender, and APOE4 allele. Participants who did not use A.H.T.s had a mean yearly increase of 1.71±1.7 in the CDR-SOB scores. This value was reduced to 1.48±1.6, P=0.006 and 1.45±1.6, P=0.024 for participants with documented use of βB and A.R.B.s, respectively. Combining diuretics with α1-AB or ACEI led to synergistic effects in reducing the rise in CDR-SOB scores. The proportion of participants who were diagnosed having AD postmortem with severe Braak staging was significantly lower in A.H.T.-users than non-users. The severity of Braak staging, and hippocampal atrophy differed in participants> 70 vs. <70 years old, in both males and females. A significant relationship was observed between hippocampal atrophy and Braak staging; and between hippocampal atrophy and baseline CSF levels of P-181 tau.
CONCLUSION: Our results could have implications for halting the progression of dementia regardless of the etiology being related to AD or vascular pathology. The choice of combination of A.H.T. therapy should also consider the combination which would lead to an optimum benefit in slowing the progression of dementia. Additionally, our results underline a more complex A.D. disease model than previously thought, which opens new treatment options.
CITATION:
Z. Sternberg ; R. Podolsky ; J. Yu ; S. Hua ; S. Halvorsen ; D. Hojnacki ; B.J. Schaller ; (2024): Anti-Hypertensives Reduce the Rate of Alzheimer’s Disease Progression: A Cohort Study Linked with Genetic and Neuropathological Analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.156
ACOUSTIC SPEECH ANALYSIS IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
S. Saeedi, S. Hetjens, M.O.W. Grimm, B. Barsties v. Latoszek
Show summaryHide summary
BACKGROUND: The potential of biomarkers in the detection of Alzheimer’s disease (AD) is prominent. Acoustics may be useful in this context but the evaluation and weighting for specific acoustic parameters on continuous speech is missing. This meta-analysis aimed to explore the significance of acoustic parameters from acoustic speech analysis on continuous speech, as a diagnostic tool for clinical AD.
METHODS: Applying PRISMA protocol, a comprehensive search was done in MEDLINE, Scopus, Web of Science, and CENTRAL, from 1960 to January 2024. Cross-sectional studies comparing the acoustic speech analysis between AD patients and healthy controls (HC), were taken into account. The bias risk of the included studies were examined via JBI checklist. Using Review Manager v.5.4.1, the mean differences of acoustic speech parameters among AD and HC were weighted, and the pooled analysis and the heterogeneity statistics were conducted.
RESULTS: In total, 1112 records (without duplicates) were obtained, and 11 papers with 7 acoustic parameters were included for this study, and 8 from 11 studies were identified with a low level of bias. Five from 7 acoustic parameters revealed significant differences among the two groups (p-values ≤ 0.01), in which for all rate-related and interruption-related acoustic parameters were the most prominent and less in temporal-related acoustic parameters.
CONCLUSIONS: Although a small number of acoustic parameters on continuous speech could be evaluated in the detection of clinical AD, the greatest potential of acoustic biomarkers for AD appeared to exist in two of three categories. Further contributions of high-quality studies are needed to support evidence for acoustics as biomarkers for AD.
CITATION:
S. Saeedi ; S. Hetjens ; M.O.W. Grimm ; B. Barsties v. Latoszek (2024): Acoustic Speech Analysis in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.132
A PILOT ELECTROENCEPHALOGRAPHY STUDY OF THE EFFECT OF CT1812 TREATMENT ON SYNAPTIC ACTIVITY IN PATIENTS WITH MILD TO MODERATE ALZHEIMER’S DISEASE
E. Vijverberg, W. de Haan, E. Scheijbeler, M.E. Hamby, S. Catalano, P. Scheltens, M. Grundman, A.O. Caggiano
Show summaryHide summary
BACKGROUND: CT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity.
OBJECTIVES: Evaluate CT1812 impact on synaptic function using qEEG measurements.
DESIGN: Phase 2, randomized, double-blind, placebo-controlled, 4-week crossover study.
SETTING: VU University Medical Center and Brain Research Center Amsterdam, The Netherlands.
PARTICIPANTS: Adults with mild or moderate Alzheimer’s disease (AD).
INTERVENTION: A daily 300 mg dose of CT1812 or placebo for 4 weeks.
MEASUREMENTS: A resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4-8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed.
RESULTS: 16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo - most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported.
CONCLUSION: CT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.
CITATION:
E. Vijverberg ; W. de Haan ; E. Scheijbeler ; M.E. Hamby ; S. Catalano ; P. Scheltens ; M. Grundman ; A.O. Caggiano (2024): A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.154
HYPOTHETICAL INTERVENTIONS ON CARDIOVASCULAR HEALTH METRICS FOR ABNORMAL COGNITIVE AGING: AN APPLICATION OF THE PARAMETRIC G-FORMULA IN THE CLHLS COHORT STUDY WITH 12 YEARS FOLLOW-UP
S. Huang, Z. Zhao, S. Wang, Y. Xu, Z. Wang, J. Wang, H. Wang, X. Yu, X. Lv
Show summaryHide summary
BACKGROUND: Abnormal cognitive aging is closely related to dementia.
OBJECTIVES: This study aimed to estimate the effect of cardiovascular health (CVH) metrics on abnormal cognitive aging.
DESIGN: A longitudinal cohort study.
SETTING: Participants were recruited from the Chinese Longitudinal Health Longevity Survey.
PARTICIPANTS: A total of 3298 participants aged ≥65 years with normal cognitive performance at baseline were included.
MEASUREMENTS: Cognitive performance was measured by the Chinese version of the Mini-Mental State Examination (MMSE). CVH was assessed with six metrics, including hypertension, diabetes, exercise, body mass index (BMI), diet, and smoking. Group-based trajectory model was used to identify the trajectory groups of cognitive aging over 12 years (2002-2014 and 2005-2018). The parametric g-formula was applied to estimate the effect of each single six CVH metrics and their combinations on the 12-year cognitive aging trajectory.
RESULTS: Four trajectory groups of cognitive aging were identified: Stable-high (77.4%), Unstable (4.9%), Slow decline (11.1%), and Rapid decline (6.6%). Unstable, Slow decline, and Rapid decline trajectory groups were considered as abnormal cognitive aging (22.6%). Single interventions on hypertension, exercise, BMI, and diet could reduce the risk of abnormal cognitive aging. Moreover, the risk ratios of joint intervention on exercise, BMI, and diet for Unstable, Slow decline, and Rapid decline trajectory groups were 0.38 (95% CI: 0.30-0.48), 0.45 (95% CI: 0.37-0.54), and 0.3 (95% CI: 0.23-0.41), respectively.
CONCLUSION: A considerable proportion of the participants experienced abnormal cognitive aging during their aging process. Interventions on these CVH metrics (i.e., exercise, BMI, and diet), which are fairly practical and feasible for older adults, may be effective strategies for preventing abnormal cognitive aging.
CITATION:
S. Huang ; Z. Zhao ; S. Wang ; Y. Xu ; Z. Wang ; J. Wang ; H. Wang ; X. Yu ; X. Lv (2024): Hypothetical Interventions on Cardiovascular Health Metrics for Abnormal Cognitive Aging: An Application of the Parametric g-formula in the CLHLS Cohort Study with 12 Years Follow-Up. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.143
ROLES OF TREM2 IN THE PATHOLOGICAL MECHANISM AND THE THERAPEUTIC STRATEGIES OF ALZHEIMER’S DISEASE
M. Lin, J.-X. Yu, W.-X. Zhang, F.-X. Lao, H.-C. Huang
Show summaryHide summary
Alzheimer’s disease (AD) is an age-related degenerative disease, which is characteristic by the deposition of senile plaques (SP) outside the cells, the neurofibrillary tangles (NFTs) inside the neurons, and the loss of synapse and neurons. Neuroinflammation may play an important role in the pathogenesis of AD. Microglia are the immune cells in the central nervous system. However, microglia might become disease-related microglia (DAMs) when stimulated by the external environment. DAMs have been shown to be involved in a series of events of AD development including Aβ accumulation and tau phosphorylation. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor that is mainly expressed by microglia in the central nervous system (CNS). TREM2 plays an important role in the physiological function of microglia, and the dyshomeostasis of TREM2 is related to the development of late-onset AD. This article summarized the latest advances in TREM2 biology and its impact on the roles of microglia in AD development, with a particular emphasis on the structure, ligands, signal transduction, and the agonistic antibodies of TREM2 for AD treatment. We further discussed the survival, migration, phagocytosis, inflammation, and cellular metabolism of microglia, as well as the role of sTREM2 in neuroprotection and as a biomarker for AD. It provides a reference for further research on the molecular mechanism of microglial TREM2 in the occurrence and development of AD and on the therapeutic strategies targeted on the microglial TREM2.
CITATION:
M. Lin ; J.-X. Yu ; W.-X. Zhang ; F.-X. Lao ; H.-C. Huang (2024): Roles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.164
INFORMING ALZHEIMER’S BIOMARKER COMMUNICATION: CONCERNS AND UNDERSTANDING OF COGNITIVELY UNIMPAIRED ADULTS DURING AMYLOID RESULTS DISCLOSURE
F.B. Ketchum, C.M. Erickson, K.E. Basche, N.A. Chin, M.L. Eveler, C.E. Conway, D.M. Coughlin, L.R. Clark
Show summaryHide summary
in research and clinical settings, but less is known about how individuals interpret their results or concerns raised during the disclosure visit that may need to be addressed by clinicians to ensure appropriate disclosure.
METHODS: Fifty-two cognitively unimpaired older adults aged 65 to 89 years old from the Wisconsin Registry for Alzheimer’s Prevention, who had undergone an amyloid PET scan in the previous 18 months, were enrolled in the disclosure substudy. After ensuring psychological readiness, trained study clinicians disclosed amyloid PET results using a structured protocol. We assessed participants’ level of understanding, concerns, and the perceived personal significance of their biomarker results during the disclosure visit through a series of question prompts in real-time.
RESULTS: Thirty-four received a non-elevated amyloid result and 18 received an elevated result. The average age was 72.2 years (range 65-81); most were women (64%) and non-Hispanic White (92%). Participants understood their results (98%), and both non-elevated and elevated groups provided similar responses around topics of sharing with others, privacy, accuracy of testing, and risk. Participants with elevated results were significantly more likely than those with non-elevated results to want to change their lifestyle (78% vs 12%, p=<0.01) and have questions about their results (61% vs 30%, p=0.05). Participants interpreted the personal significance of results in terms of several themes relating to individual risk status, emotional impact, whether the result was expected, and prevention/planning.
CONCLUSION: Results show that participants understand their biomarker results, and have a number of concerns during the disclosure process that clinical and research protocols could address. en These findings could be important considerations as effective processes are developed for widespread biomarker disclosure in clinical and research settings.
CITATION:
F.B. Ketchum ; C.M. Erickson ; K.E. Basche ; N.A. Chin ; M.L. Eveler ; C.E. Conway ; D.M. Coughlin ; L.R. Clark ; (2024): Informing Alzheimer’s Biomarker Communication: Concerns and Understanding of Cognitively Unimpaired Adults During Amyloid Results Disclosure . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.151
MODULATORY EFFECT OF BLOOD LDL CHOLESTEROL ON THE ASSOCIATION BETWEEN CEREBRAL AΒ AND TAU DEPOSITION IN OLDER ADULTS
S.M. Han, M.S. Byun, D. Yi, J.H. Jung, N. Kong, Y.Y. Chang, M. Keum, G.J. Jung, J.-Y. Lee, Y.-S. Lee, Y.K. Kim, K.M. Kang, C.-H. Sohn, D.Y. Lee, and for the KBASE Research Group
Show summaryHide summary
BACKGROUND: This study investigates the synergistic relationship between blood low-density lipoprotein cholesterol (LDL-C) and cerebral beta-amyloid (Aβ) in relation to tau deposition, a key factor in the pathology of Alzheimer’s disease (AD), in older adults across a diverse cognitive spectrum.
OBJECTIVES: To examine whether higher levels of LDL-C in the blood moderate the association of cerebral Aβ with tau deposition in older adults, including those with normal cognition, mild cognitive impairment, and Alzheimer’s disease dementia.
DESIGN: Cross-sectional design. Setting: The study was conducted as a part of a prospective cohort study. All assessments were done at the Seoul National University Hospital, Seoul, South Korea. Participants: A total of 136 older adults (aged 60-85 years) with normal cognition, mild cognitive impairment or Alzheimer’s disease (AD) dementia were included.
MEASUREMENTS: Serum lipid measurements, [11C] Pittsburgh Compound B-positron emission tomography (PET), [18F] AV-1451 PET, and magnetic resonance imaging were performed on all participants.
RESULTS: There was a significant Aβ x LDL-C interaction effect on tau deposition indicating a synergistic moderation effect of LDL-C on the relationship between Aβ and tau deposition. Subsequent subgroup analysis showed that the positive association between Aβ and tau deposition was stronger in higher LDL-C group than in lower LDL-C group. In contrast, other lipids, such as total cholesterol, high-density lipoprotein cholesterol, and triglycerides, did not show a similar moderation effect on the relationship between Aβ deposition and tau deposition.
CONCLUSION: Our findings suggest that blood LDL-C synergistically enhances the influence of Aβ deposition on tau pathology, emphasizing the need for greater attention to the role of LDL-C in AD progression.
CITATION:
S.M. Han ; M.S. Byun ; D. Yi ; J.H. Jung ; N. Kong ; Y.Y. Chang ; M. Keum ; G.J. Jung ; J.-Y. Lee ; Y.-S. Lee ; Y.K. Kim ; K.M. Kang ; C.-H. Sohn ; D.Y. Lee ; and for the KBASE Research Group ; (2024): Modulatory Effect of Blood LDL Cholesterol on the Association between Cerebral Aβ and Tau Deposition in Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.131
FREE RECALL OUTPERFORMS STORY RECALL IN ASSOCIATIONS WITH PLASMA BIOMARKERS IN PRECLINICAL ALZHEIMER DISEASE
A.J. Aschenbrenner, J.J. Hassenstab, S.E. Schindler, S. Janelidze, O. Hansson, J.C. Morris, E. Grober
Show summaryHide summary
BACKGROUND: A decline in episodic memory is one of the earliest cognitive characteristics of Alzheimer disease and memory tests are heavily featured in cognitive composite endpoints that are used to demonstrate treatment efficacy. Assessments of episodic memory can take many forms including free recall, associate learning, and paragraph or story recall. Plasma biomarkers of Alzheimer disease are now widely available and will likely form the backbone of cohort enrichment strategies for future clinical trials. Thus, it is critical to evaluate which episodic memory measures are most sensitive to plasma markers of Alzheimer disease pathology.
OBJECTIVES: To compare the associations of common episodic memory tests with plasma biomarkers of Alzheimer disease.
DESIGN: Longitudinal cohort study.
SETTING: Academic medical center in the midwestern United States.
PARTICIPANTS: A total of 161 cognitively normal older adults with at least one plasma biomarker assessment and two or more annual clinical and cognitive assessments which included up to three different tests of episodic memory.
MEASUREMENTS: Episodic memory performance using free recall, paired associates recall or paragraph recall. Plasma Aβ42, Aβ40, ptau217, and neurofilament light chain were measured.
RESULTS: Free recall on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) was substantially more sensitive to longitudinal cognitive change associated with abnormal baseline plasma Aβ42/Aβ40 and ptau217 compared to other measures of episodic memory. A cognitive composite that included only free recall showed larger decline associated with baseline Aβ42/Aβ40 when compared to those that included paragraph recall. Differences in decline across composites were minimal when considering baseline ptau217 or NfL.
CONCLUSION: Episodic memory is a critical domain to assess in preclinical Alzheimer disease. Methods of assessing memory are not equal and longitudinal change in free recall substantially outperformed both paired associates and paragraph recall. Clinical trial results will depend critically on the episodic memory test(s) that are chosen for a composite endpoint and free recall from the FCSRT + IR is an optimal memory measure to include rather than paired associates or paragraph recall.
CITATION:
A.J. Aschenbrenner ; J.J. Hassenstab ; S.E. Schindler ; S. Janelidze ; O. Hansson ; J.C. Morris ; E. Grober (2024): Free Recall Outperforms Story Recall in Associations with Plasma Biomarkers in Preclinical Alzheimer Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.130
DAYTIME SLEEPINESS, APNEA, NEUROIMAGING CORRELATES AND CORTISOL DYSREGULATION IN A MEMORY CLINIC COHORT
C. Sørensen, I. Kåreholt, G. Kalpouzos, C.T. Udeh-Momoh, J. Holleman, M. Aspö, G. Hagman, G. Spulber, M. Kivipelto, A. Solomon, S. Sindi
Show summaryHide summary
BACKGROUND: Sleep disturbances as well as cortisol hypersecretion are increasingly acknowledged as risk factors for Alzheimer’s disease (AD). However, the mechanisms underlying the association, and the interplay with cortisol abnormalities, remain unclear.
OBJECTIVES: This study aims to identify how self-reported sleep disturbances are associated with structural brain measures and diurnal cortisol dysregulation among memory clinic patients.
DESIGN: A cross-sectional study performed at Karolinska University Hospital Memory Clinic, Sweden.
PARTICIPANTS: The study was based on 146 memory clinic patients diagnosed with either subjective cognitive impairment or mild cognitive impairment.
MEASUREMENTS: Self-reported sleep was measured using the Karolinska Sleep Questionnaire. MRI or CT was used to quantify structural brain measures using four visual rating scales (Scheltens, Pasquier, Koedam, and Fazekas scales), and salivary cortisol was sampled to measure diurnal cortisol patterns through measures of cortisol immediately after awakening, cortisol awakening response, bedtime cortisol, total cortisol from awakening to bedtime, and the AM/PM cortisol ratio.
RESULTS: Increased sleep apnea index (OR=1.20, 95% CI=1.04:1.39, p=0.015) was associated with greater odds of posterior brain atrophy, measured by the Koedam visual rating scale, and reduced awakening cortisol (β=-0.03, 95% CI=-0.07:0.00, p=0.045). Increased daytime sleepiness was associated with both reduced awakening cortisol (β=-0.03, 95% CI=-0.06:0.00, p=0.025) and a reduced AM/PM cortisol ratio (β=-0.04, CI=-0.08:-0.01, p= 0.021).
CONCLUSION: In a memory clinic cohort self-reported sleep disturbances are associated with both worse structural brain tissue integrity and altered diurnal cortisol profiles. These findings may add insights into possible mechanisms behind sleep disturbances in aging with subjective and cognitive impairment.
CITATION:
C. Sørensen ; I. Kåreholt ; G. Kalpouzos ; C.T. Udeh-Momoh ; J. Holleman ; M. Aspö ; G. Hagman ; G. Spulber ; M. Kivipelto ; A. Solomon ; S. Sindi ; (2024): Daytime Sleepiness, Apnea, Neuroimaging Correlates and Cortisol Dysregulation in a Memory Clinic Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.145
UNVEILING POTENTIAL BIOMARKERS IN CEREBROSPINAL FLUID FOR AMYLOID PATHOLOGICAL POSITIVITY IN NON-DEMENTED INDIVIDUALS
F. Meng, X. Zhang, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Show summaryHide summary
BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque accumulation and neurofibrillary tangles. The recent approval of anti-amyloid therapeutic medications highlights the crucial need for early detection of Aβ pathological abnormalities in individuals without dementia to facilitate timely intervention and treatment.
OBJECTIVE: The primary aim of this study was to identify cerebrospinal fluid (CSF) biomarkers strongly associated with Aβ pathological positivity in a non-demented cohort and evaluate their clinical values.
METHODS: A comprehensive analysis was conducted on 51 CSF proteins (excluding Aβ42, pTau, and Tau) obtained from 474 non-demented participants sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. By utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) regression, we identified potential proteins indicative of Aβ pathological positivity and evaluated their performance in tracking longitudinal pathological progression.
RESULTS: Our LASSO analysis unveiled three candidates: apolipoprotein E (APOE), chitinase-3-like protein 1 (CHI3L1), and SPARC-related modular calcium-binding protein 1 (SMOC1). While SMOC1 did not correlate with Aβ42-related cognitive alterations, it displayed better abilities in discriminating both CSF-Aβ positivity and Aβ-positron emission tomography (PET) positivity than the other two candidates. It could precisely predict longitudinal Aβ-PET status conversion. Notably, SMOC1 was the only protein showing associations with longitudinal Aβ-PET trajectory and enhancing the diagnostic accuracy of Aβ42. The assessment of combined Aβ42 and SMOC1 yielded valuable clinical insights.
CONCLUSION: Our findings elucidated SMOC1 as a potential biomarker for detecting Aβ abnormalities. Aβ42 combining SMOC1 offered critical implications in AD pathological diagnosis and management.
CITATION:
F. Meng ; X. Zhang ; for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) ; (2024): Unveiling Potential Biomarkers in Cerebrospinal Fluid for Amyloid Pathological Positivity in Non-Demented Individuals. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.129
QUANTIFYING PERSONALIZED SHIFT-WORK MOLECULAR PORTRAITS UNDERLYING ALZHEIMER’S DISEASE THROUGH COMPUTATIONAL BIOLOGY
Y. Xu, G. Zhang, L. Yang, H. Qin, Z. Zhou, Q. Li, H. Liu, R. Wang, Z. Cai, L. Jing, Y. Li, Y. Yao, Z. Gong, P. Yuan, T. Fu, X. Zhao, T. Peng, Y. Jia
Show summaryHide summary
BACKGROUND: Shift work, the proven circadian rhythm-disrupting behavior, has been linked to the increased risk of Alzheimer’s disease (AD). However, the putative causal effect and potential mechanisms of shift work for AD were still unclear.
METHODS: Mendelian randomization (MR) analysis was performed to discover the putative causal effect of shift work for AD. Expression quantitative trait loci (eQTLs) and transcriptome data were integrated to identify genes causally associated with AD from circadian-related genes. An in vitro experiment was also conducted to validate the expression of target genes. Based on the identified genes, a novel integrative program and 4,077 samples from 16 microarray datasets were leveraged to assess the extent of circadian rhythm disruption (CRD), defined as the clock deviation level (CDL).
FINDINGS/RESULTS: Shift work causally increased the risk of AD [odds ratio (OR) = 2.49, 95% CI = 1.79 - 3.19, p = 0.01]. Seven circadian-related genes were causally associated with AD, including CCS, CDS2, MYRIP, NRP1, PLEKHA5, POLR1D, and PPP4C. These genes were significantly correlated with the circadian rhythm pathway. CDL was higher in CRD mice group, shift work group, sleep restriction group, and AD patients compared to control mice group (p = 0.043), non-shift group (p = 0.004), sleep extension group (p = 0.025), and health controls (multiple cohorts, p < 0.05). Additionally, CDL was also significantly correlated with AD’s clinical biomarkers.
INTERPRETATIONS/CONCLUSION: By combining GWAS and transcriptome data, this study demonstrated the causal role of CRD behavior in AD, identified the potential target genes in shift work-induced AD, and generated CDL to characterize CRD status, which provided evidence and prospects for disease prevention and future therapeutic interventions.
CITATION:
Y. Xu ; G. Zhang ; L. Yang ; H. Qin ; Z. Zhou ; Q. Li ; H. Liu ; R. Wang ; Z. Cai ; L. Jing ; Y. Li ; Y. Yao ; Z. Gong ; P. Yuan ; T. Fu ; X. Zhao ; T. Peng ; Y. Jia (2024): Quantifying Personalized Shift-Work Molecular Portraits Underlying Alzheimer’s Disease through Computational Biology. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.161
THE CAUSAL RELATIONSHIP BETWEEN GENETICALLY PREDICTED BIOLOGICAL AGING, ALZHEIMER’S DISEASE AND COGNITIVE FUNCTION: A MENDELIAN RANDOMISATION STUDY
Y. Hao, W. Tian, B. Xie, X. Fu, S. Wang, Y. Yang
Show summaryHide summary
Aging is one of the most important risk factors for Alzheimer’s disease (AD). Biological aging is a better indicator of the body’s functional state than age (chronological aging). Leukocyte telomere length (LTL) and epigenetic clocks constructed from DNA methylation patterns have emerged as reliable markers of biological aging. Recent studies have shown that it may be possible to slow down or even reverse biological aging, offering promising prospects for treating AD. Several observational studies have reported an association between biological aging, AD, and cognitive function, but the causality behind this association and the effects of different biological aging markers on AD risk and cognitive function remain unclear. Therefore, we explored the causal relationship between them by Mendelian randomization (MR) study. Inverse-variance weighted (IVW) method is the most dominant analytical method in MR studies, which is a weighted average of estimates from different genotype combinations, and this weighted average provides an overall estimate of the causal effect. The results of the IVW analyses showed that HannumAge acceleration and LTL shortening were able to increase the risk of late-onset AD (LOAD), but not early-onset AD (EOAD). Excellent prospective memory and fluid intelligence are potentially protective against GrimAge acceleration. GrimAge acceleration and HorvathAge acceleration increase the risk of LOAD through effects on LTL. Our findings provide important insights into the role of biological aging in the pathogenesis of AD, while also highlighting the interplay of different biological aging markers and their complexity in different AD subtypes.
CITATION:
Y. Hao ; W. Tian ; B. Xie ; X. Fu ; S. Wang ; Y. Yang (2024): The Causal Relationship between Genetically Predicted Biological Aging, Alzheimer’s Disease and Cognitive Function: A Mendelian Randomisation Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.128
EFFECTS OF THE COVID-19 PANDEMIC ON THE NUMBER OF NEW DEMENTIA DIAGNOSES AND THE QUALITY OF DEMENTIA DIAGNOSTICS AND TREATMENT
M.T. Hoang, P.G. Jurado, T. Abzhandadze, S. Mostafaei, M. Mo, M. Åkerman, K. Vestling, C. Chen, H. Xu, M. Eriksdotter, S. Garcia-Ptacek
Show summaryHide summary
BACKGROUND: Care trajectories were disrupted during the COVID-19 pandemic. However, how COVID-19 influenced the number of new dementia diagnoses, and the quality of dementia work-ups, and treatment is understudied.
OBJECTIVE: To investigate the change in new dementia registrations, diagnostics, and treatment in the pre-, COVID-19 and post-COVID-19 pandemic periods.
DESIGN: A nationwide cohort study.
SETTING: This population-based study used data from the Swedish Registry for Cognitive/Dementia disorders – SveDem, and other nationwide registries in Sweden.
PARTICIPANTS: Persons with dementia diagnosed between 2019 and 2021 were divided into three groups based on the date of diagnosis: the pre-COVID-19 period (01 January 2019 - 29 February 2020), the COVID-19 period (01 March 2020 – 31 December 2020), and the post-COVID-19 period (01 January 2021 – 31 August 2021).
MEASUREMENTS: Outcomes included dementia diagnostics and treatments.
RESULTS: The monthly average number of new dementia cases registered in SveDem was 595, 415 and 470, respectively in the pre-COVID-19, COVID-19 and post-COVID-19 period. Compared to the pre-COVID-19 period, the monthly number of registrations decreased, but provision of the basic diagnostic work-up, its individual tests, and the use of cholinesterase inhibitors, memantine and antipsychotics were not significantly different in the COVID-19 period. Compared to the pre-COVID-19 period, new dementia diagnoses continued to be low in the post-COVID-19 period, but diagnosed individuals were more likely to receive the complete basic diagnostic work-up (OR 1.14, 95% CI 1.00 – 1.29), blood analysis (OR 1.88, 95% CI 1.44 – 2.49), computed tomography and magnetic resonance imaging (OR 1.22, 95% CI 1.01 – 1.48), occupational therapy assessment (OR 1.13, 95% CI 1.04 – 1.22), and memantine (OR 1.19, 95% CI 1.07 – 1.31).
CONCLUSION: The quantity of new dementia registrations in SveDem decreased in the COVID-19 period and has not returned to pre-COVID-19 levels, but the quality of the work-ups which were conducted and registered in SveDem was similar or higher than in the pre-COVID-19 period. It is imperative to implement policies to increase SveDem registration with the aim of matching or exceeding pre-COVID-19 levels.
CITATION:
M.T. Hoang ; P.G. Jurado ; T. Abzhandadze ; S. Mostafaei ; M. Mo ; M. Åkerman ; K. Vestling ; C. Chen ; H. Xu ; M. Eriksdotter ; S. Garcia-Ptacek ; (2024): Effects of the COVID-19 Pandemic on the Number of New Dementia Diagnoses and the Quality of Dementia Diagnostics and Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.150
DIAGNOSTIC ACCURACY OF PLASMA P-TAU217 FOR DETECTING PATHOLOGICAL CEREBROSPINAL FLUID CHANGES IN COGNITIVELY UNIMPAIRED SUBJECTS USING THE LUMIPULSE PLATFORM
F. Martínez-Dubarbie, A. Guerra-Ruiz, S. López-García, C. Lage, M. Fernández-Matarrubia, J. Infante, A. Pozueta-Cantudo, M. García-Martínez, A. Corrales-Pardo, M. Bravo, M. López-Hoyos, J. Irure-Ventura, E. Valeriano-Lorenzo, M.T. García-Unzueta, P. Sánchez-Juan, E. Rodríguez-Rodríguez
Show summaryHide summary
BACKGROUND: Plasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice.
OBJECTIVES: To evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD.
DESIGN: Cross-sectional analyses from a prospective cohort.
SETTING: A population-based study.
PARTICIPANTS: Volunteers over 55 years without cognitive impairment or contraindications for complementary tests.
MEASUREMENTS: Plasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Aβ40, Aβ42, p-tau181, and t-tau levels. We correlated plasma p-tau217 with CSF Aβ40, Aβ42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A-/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor.
RESULTS: We screened 209 cognitively unimpaired volunteers with a mean age 64 years (60-69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho=-0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85.
CONCLUSIONS: Plasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology.
CITATION:
F. Martínez-Dubarbie ; A. Guerra-Ruiz ; S. López-García ; C. Lage ; M. Fernández-Matarrubia ; J. Infante ; A. Pozueta-Cantudo ; M. García-Martínez ; A. Corrales-Pardo ; M. Bravo ; M. López-Hoyos ; J. Irure-Ventura ; E. Valeriano-Lorenzo ; M.T. García-Unzueta ; P. Sánchez-Juan ; E. Rodríguez-Rodríguez ; (2024): Diagnostic Accuracy of Plasma p-tau217 for Detecting Pathological Cerebrospinal Fluid Changes in Cognitively Unimpaired Subjects Using the Lumipulse Platform. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.152
UNIVERSAL PREVENTION OF DEMENTIA IN ITALY: A DOCUMENT ANALYSIS OF THE 21 ITALIAN REGIONAL PREVENTION PLANS
S. Salemme, D. Marconi, S.M. Pani, G. Zamboni, C. Sardu, G. Lazzeri, M. Corbo, E. Lacorte, N. Locuratolo, A. Ancidoni, N. Vanacore, G. Bellomo
Show summaryHide summary
BACKGROUND: Up to 40% of dementia cases are theoretically avoidable and population-level interventions (i.e., universal prevention) are a key component in facing the global public health challenge of dementia. However, information on the agenda for the universal prevention of dementia at the national and sub-national levels is still lacking.
OBJECTIVES: We aim to provide a comprehensive description of the universal prevention strategies specific to dementia in Italian regions and autonomous provinces (APs).
DESIGN: We conducted a document analysis of the 21 Italian Regional Prevention Plans (RPPs), with a focus on interventions that target potentially modifiable risk factors for dementia. We analysed the final version of the documents, which were previously downloaded from the dedicated section of the Italian Ministry of Health website in January 2023. We classified the interventions as direct, indirect, or absent. Additionally, we created a quality checklist to outline the essential programmatic elements and applied it to summarise the key findings of the RPPs.
MEASUREMENTS: We reported the number of population-level interventions specific for dementia with sub-national detail. We reported information on the risk factor targeted by the interventions, the age groups and populations they were designed for. We summarized the presence or absence of 63 programmatic items using a four-domain checklist.
RESULTS: We identified 248 interventions for dementia prevention among the assessed RPPs: 100% of the plans addressed physical inactivity; 30-35% addressed smoking, alcohol, obesity, and social isolation; 25% addressed hypertension, diabetes, and air pollution; only 5-10% addressed education, depression, and hearing loss. Most interventions targeted the general population. Quality checklist scores significantly varied among regions, with demographics and prevention strategies domains scoring higher than disease burden and intervention feasibility ones.
CONCLUSIONS: The population-level interventions in the Italian Regional Prevention Programs dedicated to dementia prevention primarily focus on vascular risk factors, with limited coverage of dementia-specific factors such as traumatic brain injury and hearing loss. This data should be considered when planning future interventions for dementia prevention.
CITATION:
S. Salemme ; D. Marconi ; S.M. Pani ; G. Zamboni ; C. Sardu ; G. Lazzeri ; M. Corbo ; E. Lacorte ; N. Locuratolo ; A. Ancidoni ; N. Vanacore ; G. Bellomo (2024): Universal Prevention of Dementia in Italy: A Document Analysis of the 21 Italian Regional Prevention Plans. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.144
LEVERAGING DIVERSE REGULATED CELL DEATH PATTERNS TO IDENTIFY DIAGNOSIS BIOMARKERS FOR ALZHEIMER’S DISEASE
L. Ren, Q. Zhang, J. Zhou, X. Wang, D. Zhu, X. Chen
Show summaryHide summary
BACKGROUND: The functions of regulated cell death (RCD) are closely related to Alzheimer’s disease (AD). However, very few studies have systematically investigated the diagnosis and immunologic role of RCD-related genes in AD patients.
METHODS: 8 multicenter AD cohorts were included in this study, and then were merged into a meta cohort. Then, an unsupervised clustering analysis was carried out to detect unique subtypes of AD based on RCD-related genes. Subsequently, differently expressed genes (DEGs) and weighted correlation network analysis (WGCNA) between subtypes were identified. Finally, to establish an optimal risk model, an RCD.score was constructed by using computational algorithm (10 machine-learning algorithms, 113 combinations).
RESULTS: We identified two distinct subtypes based on RCD-related genes, each exhibiting distinct hallmark pathway activity and immunologic landscape. Specifically, cluster.A patients had a higher immune infiltration, a higher immune modulators and poor AD progression. Utilizing the shared DEGs and WGCNA of these subtypes, we constructed an RCD.score that demonstrated excellent predictive ability in AD across multiple datasets. Furthermore, RCD.score was identified to exhibit the strongest association with poor AD progression. Mechanistically, we observed activation of signaling pathways and effective immune infiltration and immune modulators in the high RCD.score group, thus leading to a poor AD progression. Additionally, Mendelian randomization screening revealed four genes (CXCL1, ENTPD2, METTL7A, and SERPINB6) as feature genes for AD.
CONCLUSION: The RCD model is a valuable tool in categorizing AD patients. This model can be of great assistance to clinicians in determining the most suitable personalized treatment plan for each individual AD patient.
CITATION:
L. Ren ; Q. Zhang ; J. Zhou ; X. Wang ; D. Zhu ; X. Chen (2024): Leveraging Diverse Regulated Cell Death Patterns to Identify Diagnosis Biomarkers for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.119
DEVELOPMENT AND VALIDATION THE MOBILE TOOLBOX (MTB) SPELLING TEST
E. LaForte, S.R. Young, E.M. Dworak, M.A. Novack, A.J. Kaat, H. Adam, C.J. Nowinski, Z. Hosseinian, J. Slotkin, S. Amagai, M.V. Diaz, A.A. Correa, K. Alperin, M. Camacho, B. Landavazo, R. Nosheny, M.W. Weiner, R.M. Gershon
Show summaryHide summary
BACKGROUND: Spelling assessments can provide a valuable marker of cognitive change in Alzheimer’s disease and related dementias (ADRD) and play an important role in ADRD research. However, most commercial assessments are not well-suited to the needs of researchers or participants; they are expensive and often require face-to-face administration by a trained examiner. To help overcome these barriers and foster progress in ADRD research, the National Institute on Aging (NIA)-funded Mobile Toolbox (MTB) offers a library of cognitive measures that can be self-administered remotely on a participant’s own smartphone, including a brand-new Spelling test.
OBJECTIVE: The goal of this paper is to describe the design, piloting, calibration, and validation of the MTB Spelling test.
DESIGN: We describe a pilot study, calibration study, and three validation studies, all of which use a cross-sectional design.
SETTING: The pilot study, calibration study, and validation studies 2 and 3 were conducted remotely, while validation study 1 was conducted in the lab.
PARTICIPANTS: Participants for all of the studies were recruited from the general population by a thirdparty market research firm and the samples were stratified by age, gender, race, ethnicity, and education to represent the U.S. population. The pilot sample included 1,950 participants and the calibration study included 1335 participants over the age of 8. Validation study 1 included 92 participants ages 20 to 84, validation study 2 included 1021 participants ages 18 to 90, and validation study 3 included 168 participants ages 28 to 87.
MEASUREMENTS: Participants in each of the studies completed the MTB Spelling test. Participants in validation studies 1 and 2 completed measures from the NIH Toolbox including Oral Reading Recognition as a measure of convergent validity, and Visual Reasoning and the Rey Auditory Verbal Learning as measures of divergent validity. As an additional measure of convergent validity, participants in study 1 also completed the Spelling subtest from the Wechsler Individual Achievement Test, 4th Edition.
RESULTS: The MTB Spelling test demonstrated evidence of internal consistency (r=.79 to .83) convergent validity (r=.56 to .81, p<.01), discriminant validity (r = .23 to .36, p <.01), test-retest reliability ( ICC=.63 ), and correlations with normal cognitive aging (r = -.06 to -.04, p >.01).
CONCLUSION: Findings suggest the MTB Spelling test is a reliable and valid measure of English spelling abilities in general population samples, and has potential in ADRD research.
CITATION:
E. LaForte ; S.R. Young ; E.M. Dworak ; M.A. Novack ; A.J. Kaat ; H. Adam ; C.J. Nowinski ; Z. Hosseinian ; J. Slotkin ; S. Amagai ; M.V. Diaz ; A.A. Correa ; K. Alperin ; M. Camacho ; B. Landavazo ; R. Nosheny ; M.W. Weiner ; R.M. Gershon (2024): Development and Validation the Mobile Toolbox (MTB) Spelling Test. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.158
EXAMINING THE ROLE OF COMMUNITY ENGAGEMENT IN ENHANCING THE PARTICIPATION OF RACIAL AND ETHNIC MINORITIZED COMMUNITIES IN ALZHEIMER’S DISEASE CLINICAL TRIALS; A RAPID REVIEW
S. Dabiri, R. Raman, J. Grooms, D. Molina-Henry
Show summaryHide summary
BACKGROUND: Despite higher dementia prevalence in racial and ethnic minoritized communities, they are underrepresented in Alzheimer’s disease clinical trials. Community-based recruitment strategies are believed to yield positive outcomes in various fields, such as cancer and cardiovascular clinical trials, but their outcomes in Alzheimer’s disease and Related Dementias (AD/ADRD) require further study. In this systematic rapid review, we synthesized the available evidence on community-engaged recruitment strategies in enhancing participation in AD/ADRD clinical trials and observational study participation.
METHODS: We searched and identified studies describing a community-based recruitment approach for racial and ethnic minoritized communities across seven databases (Pubmed, OVID MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, PsychINFO, Web of Science, and EMBASE).
RESULTS: Out of 1915 screened studies, 49 met the inclusion criteria. Most studies employed multiple community-based recruitment approaches, including educational presentations, collaborations with community-based faith organizations, community advisory boards, and engagement with local clinics or health professionals. 52% of studies targeted more than one racial and ethnic minoritized population, primarily African Americans and then Hispanic/Latino. Gaps in knowledge about AD/ADRD, its increased risk among minoritized populations, distrust, and stigma were noted as barriers to research participation. Approximately 50% of the studies specified whether they evaluated their recruitment approaches, and in studies where approaches were evaluated, there was substantial heterogeneity in methods utilized.
CONCLUSION: The quality of available evidence on the use of community-based recruitment approaches to include racial and ethnic minoritized populations in AD/ADRD research, particularly in clinical trials, is limited. Systematic assessment of recruitment strategies is urgently needed to increase the evidence base around community-engaged recruitment approaches.
CITATION:
S. Dabiri ; R. Raman ; J. Grooms ; D. Molina-Henry ; (2024): Examining the Role of Community Engagement in Enhancing the Participation of Racial and Ethnic Minoritized Communities in Alzheimer’s Disease Clinical Trials; A Rapid Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.149
MULTIDOMAIN INTERVENTION TRIAL FOR PREVENTING COGNITIVE DECLINE AMONG OLDER ADULTS WITH TYPE 2 DIABETES: J-MIND-DIABETES
T. Sugimoto, A. Araki, H. Fujita, K. Fujita, K. Honda, N. Inagaki, T. Ishida, J. Kato, M. Kishi, Y. Kishino, K. Kobayashi, K. Kouyama, Y. Kuroda, S. Kuwahata, N. Matsumoto, T. Murakami, H. Noma, J. Ogino, M. Ogura, M. Ohishi, H. Shimada, K. Sugimoto, T. Takenaka, Y. Tamura, H. Tokuda, K. Uchida, H. Umegaki, T. Sakurai, J-MIND-Diabetes study group
Show summaryHide summary
BACKGROUND: No multidomain intervention trials have been designed for the prevention of cognitive decline in older adults with type 2 diabetes.
OBJECTIVES: To investigate the efficacy of a multidomain intervention in preventing cognitive decline in older adults with type 2 diabetes and cognitive impairment.
DESIGN: Eighteen-month, multi-centered, randomized controlled trial.
SETTING: Twelve hospitals in Japan.
PARTICIPANTS: Outpatients with type 2 diabetes aged 70–85 years with cognitive impairment.
INTERVENTION: The multidomain intervention program includes management of metabolic and vascular risk factors, exercise, nutritional counseling, and promotion of social participation. Participants in the control group received usual care and treatment for type 2 diabetes.
MEASUREMENTS: The primary outcome was the change in a composite score combining several neuropsychological tests from baseline to the 18-month follow-up. To assess the differences in cognitive changes between the intervention and control groups, a mixed-effects model for repeated measures was used.
RESULTS: Between March 13, 2019, and May 8, 2020, 361 participants were screened, and 154 were randomly assigned to either the intervention group (n = 81) or the control group (n = 73). Finally, 110 participants completed the trial. The between-group difference in the composite score changes was 0.068 (95% confidence interval, −0.091 to 0.226). Analyses for secondary outcomes indicated a positive impact of the intervention on memory and indicated that the intervention led to changes in dietary habits with increased intakes of niacin and meat, along with weight reduction compared to the control group.
CONCLUSION: The multidomain intervention did not demonstrate efficacy in preventing cognitive decline. However, this trial provided proof-of-concept evidence that multidomain interventions may offer cognitive benefits and contribute to changes in dietary behavior and weight reduction in older adults with type 2 diabetes and cognitive impairment. These findings should be confirmed in future studies.
CITATION:
T. Sugimoto ; A. Araki ; H. Fujita ; K. Fujita ; K. Honda ; N. Inagaki ; T. Ishida ; J. Kato ; M. Kishi ; Y. Kishino ; K. Kobayashi ; K. Kouyama ; Y. Kuroda ; S. Kuwahata ; N. Matsumoto ; T. Murakami ; H. Noma ; J. Ogino ; M. Ogura ; M. Ohishi ; H. Shimada ; K. Sugimoto ; T. Takenaka ; Y. Tamura ; H. Tokuda ; K. Uchida ; H. Umegaki ; T. Sakurai ; J-MIND-Diabetes study group ; (2024): Multidomain Intervention Trial for Preventing Cognitive Decline among Older Adults with Type 2 Diabetes: J-MIND-Diabetes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.117
CORRELATES OF SUBJECTIVE COGNITIVE DECLINE IN BLACK AMERICAN MEN
D.K. Esiaka, C. Nwakasi, A.Q. Briggs, D.F. Conserve, R.J. Thorpe Jr
Show summaryHide summary
BACKGROUND: Past research suggests that subjective cognitive decline serves as an early and potentially important indicator that individuals may be at risk for future cognitive decline or neurodegenerative conditions. However, there is a dearth of studies on factors influencing the experience of subjective cognitive decline in Black Americans, especially in Black American men.
OBJECTIVE: The current study explored correlates of subjective cognitive decline in Black American men.
PARTICIPANTS: A total of 117 Black American men, with a mean age of 38.5 (SD = 7.14) years, participated in the study.
MEASUREMENT: Participants completed a survey that assessed their demographic characteristics, self-rated health, neighborhood problems, length of residency in neighborhood, bodily symptoms, sleep comorbidities, sleep difficulties, and subjective cognitive decline. Linear regression analyses was performed and standardized beta coefficients were reported to describe the estimated independent effect of the predictor variables.
RESULTS: We found that socioecomic status (β = -.222, p=.003), bodily symptoms (β = .246, p=.005), length of residency in neighborhood (β = .157, p=.029), and sleep difficulties (β = .305, p<.001) were significant correlates of subjective cognitive decline among Black American men.
CONCLUSION: These findings underscore the intricate roles of socioeconomic status, bodily symptoms, neighborhood factors, and sleep health in shaping subjective cognitive experiences in this population. Research on subjective cognitive decline can contribute to the early identification of individuals at risk for cognitive decline, allowing for timely interventions, lifestyle modifications, and potential preventive measures.
CITATION:
D.K. Esiaka ; C. Nwakas ; A.Q. Briggs ; D.F. Conserve ; R.J. Thorpe Jr (2024): Correlates of Subjective Cognitive Decline in Black American Men. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.162
NO ASSOCIATION FOUND: ADVERSE CHILDHOOD EXPERIENCES AND COGNITIVE IMPAIRMENT IN OLDER AUSTRALIAN ADULTS
J. Lian, K.M. Kiely, B.L. Callaghan, R. Eramudugolla, M. Mortby, K.J. Anstey
Show summaryHide summary
OBJECTIVE: This study aimed to investigate the relationship between childhood adversity and cognitive impairment in older adults.
METHODS: We analysed data from 1568 participants aged 72-79 (M = 75.1, SD = 1.5, % male = 52.6%) from Wave 4 of the Personality and Total Health (PATH) Through Life Project. The outcome variable was the presence of mild cognitive impairment (MCI) or dementia, determined through a clinically validated algorithmic diagnostic criteria. Childhood adversity was assessed using a 17-item scale covering various domestic adversities such as poverty, neglect, physical abuse, and verbal abuse. Adversity was operationalised using cumulative analysis, dichotomisation (<3 adversities; 3+ adversities), and latent class analysis. Multiple logistic regressions were employed to estimate the association between childhood adversity and cognitive impairment, while controlling for covariates including education, gender, ethnicity, and APOE ε4 status.
RESULTS: Our analyses revealed no significant association between childhood adversity and the presence of MCI or dementia across all tested models. Sensitivity analyses, exploring alternative scenarios, consistently failed to yield statistically significant findings.
CONCLUSION: In contrast to prevailing research findings, this study does not support a link between childhood domestic adversity and late-life cognitive outcomes. These results underscore the mixed results on adversity and cognition, highlighting the need for further research. Future investigations should consider the roles of potential mediating and protective factors within this complex relationship.
CITATION:
J. Lian ; K.M. Kiely ; B.L. Callaghan ; R. Eramudugolla ; M. Mortby ; K.J. Anstey (2024): No Association Found: Adverse Childhood Experiences and Cognitive Impairment in Older Australian Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.133
DEVELOPMENT AND CONCURRENT VALIDITY OF THE SHORTFORM COGDRISK DEMENTIA RISK ASSESSMENT TOOL
K.J. Anstey, M.H. Huque, S. Kootar, R. Eramudugolla, M. Li
Show summaryHide summary
Evidence-based dementia risk assessment is required to inform individual and policy-level dementia risk reduction interventions. We developed the CogDrisk Short Form (CogDrisk-SF) to assess dementia risk factors, for situations where time and resources are limited. To evaluate concurrent validity with the original CogDrisk, we conducted an online survey using a repeated-measures, counterbalanced design. Community dwelling participants (n = 647, 50.1% were female, mean age 62.2 years, age range 40-89) completed the survey. The mean(sd) score for CogDrisk-SF and the CogDrisk was 9.7 (5.3) and 9.9 (5.5), respectively. The intraclass correlation between the risk score obtained from CogDrisk and CogDrisk-SF was 0.92. Fish intake, insomnia and depression had percentage agreements of 79%, 87% and 89% respectively. Other items had >95% agreement except for loneliness (94%), hypertension (94%), cholesterol (93%), atrial fibrillation (91%) and cognitive activity (90%). Very high agreement between the CogDrisk-SF and original CogDrisk shows that CogDrisk-SF is valid for use in research and clinical practice.
CITATION:
K.J. Anstey ; M.H. Huque ; S. Kootar ; R. Eramudugolla ; M. Li (2024): Development and Concurrent Validity of the Short-Form CogDrisk Dementia Risk Assessment Tool. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.108
PERFORMANCE OF A SHORT VERSION OF THE EVERYDAY COGNITION SCALE (ECOG-12) TO DETECT COGNITIVE IMPAIRMENT
M. Manjavong, A. Diaz, M.T. Ashford, A. Aaronson, M.J. Miller, J.M. Kang, S. Mackin, R. Tank, B. Landavazo, D. Truran, S.T. Farias, M. Weiner, R. Nosheny, for the Alzheimer’s Disease Neuroimaging Initiative
Show summaryHide summary
BACKGROUND: The Everyday Cognition (ECog) 12-item scale, a functional decline measurement, can distinguish dementia from cognitively unimpaired (CU). Limited data compare ECog-12 performance by raters (self vs. informant) and scoring systems (average numeric vs. categorical grouping) to differentiate cognitive statuses.
OBJECTIVES: To evaluate the performance of ECog-12 in differentiation cognitive statuses.
DESIGN: A cross-sectional diagnostic test study.
SETTING AND PARTICIPANTS: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study are analyzed. Participants were aged 55-90 years old divided into subgroups based on diagnostic criteria.
MEASUREMENTS: We evaluated ECog-12 performance across different diagnostic groups, such as CU vs cognitive impairment (CI; mild cognitive impairment (MCI), and dementia), and the association between ECog-12 and CI. This procedure was repeated for self- and partner (informant)-reports. Additionally, types of ECog scores were also assessed, where an average ECog score was calculated (continuous numeric) as well as a categorical grouping (“any occasional declined” or “any consistently declined”) based on item-level responses to ECog questions.
RESULTS: ECog-12 cut-off scores of 1.36 (self-reported) and 1.45 (partner-reported) distinguish CU from CI with AUC 0.7 and 0.78, respectively. Adding a memory-concern question improved self-reported-ECog AUC to 0.79. Self- and partner-reported “consistently-declined” ECog-12 categorical grouping provided AUC 0.69 and 0.78. The study partner reported ECog-12 showed a greater association with CI than self-reported, with odds ratios of 35.45 and 8.79, respectively.
CONCLUSION: Study partner-reported ECog scores performed better than self-reported ECog-12 in differentiating cognitive statuses, and a higher study partner reported ECog score was a higher prognostic risk for CI. A memory concern question could enhance self-reported ECog-12 performance. This further emphasizes the need to obtain data from study partners for research and clinical practice.
CITATION:
M. Manjavong ; A. Diaz ; M.T. Ashford ; A. Aaronson ; M.J. Miller ; J.M. Kang ; S. Mackin ; R. Tank ; B. Landavazo ; D. Truran ; S.T. Farias ; M. Weiner ; R. Nosheny ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Performance of a Short Version of the Everyday Cognition Scale (ECog-12) to Detect Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.109
EVALUATING CAUSAL EFFECTS OF GUT MICROBIOME ON ALZHEIMER’S DISEASE
Q. Zhao, A. Baranova, H. Cao, F. Zhang
Show summaryHide summary
BACKGROUND: The preceding evidence indicates a close correlation between imbalances in the gut microbiome and Alzheimer’s disease (AD), yet the direct causal relationship remains unclear. Our objective is to investigate this potential causal connection.
METHODS: We obtained summary results from two significant genome-wide association studies (GWAS) on gut microbiota (the MibioGen consortium and the Dutch Microbiome Project), along with one GWAS summary result for AD. Using a two-sample Mendelian randomization (TSMR) analysis, we examined the potential causal effects of gut microbiota on AD.
RESULTS: Our TSMR analysis revealed that 16 gut bacterial taxa were linked to a reduced risk of AD. These included phylum Tenericutes, classes Bacilli and Clostridia along with its order Clostridiales, family Bacteroidaceae, genus Bacteroides, and species Bifidobacterium bifidum (OR: 0.867~0.971, P ≤ 0.045). Conversely, the presence of 12 taxa correlated with an increased risk of AD. These comprised class Actinobacteria and its family Coriobacteriaceae, as well as class Betaproteobacteria, its order Burkholderiales, and its family Sutterellaceae (OR: 1.042~1.140, P ≤ 0.035).
CONCLUSION: Our research uncovered evidence suggesting certain gut bacterial species might play a causal role in AD risk, providing a fresh angle for AD treatment strategies.
CITATION:
Q. Zhao ; A. Baranova ; H. Cao ; F. Zhang ; (2024): Evaluating Causal Effects of Gut Microbiome on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.113
BLOOD CATHEPSINS ON THE RISK OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGICAL BIOMARKERS: RESULTS FROM OBSERVATIONAL COHORT AND MENDELIAN RANDOMIZATION STUDY
X.-H. Qian, G.-Y. Ding, S.-Y. Chen, X.-L. Liu, M. Zhang, H.-D. Tang
Show summaryHide summary
BACKGROUND: Alzheimer’s disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD.
METHODS: This study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer’s disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers.
RESULTS: Using MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ- cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants.
CONCLUSION: This study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.
CITATION:
X.-H. Qian ; G.-Y. Ding ; S.-Y. Chen ; X.-L. Liu ; M. Zhang ; H.-D. Tang (2024): Blood Cathepsins on the Risk of Alzheimer’s Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.107
JPAD Volume 11, N°05 - 2024
EDITORIAL: AMPLIFYING EFFICIENCY AND ACCURACY IN DEMENTIA DRUG DEVELOPMENT
O. Lerch, S.Z. Levine, S. Sivakumaran, M.W. Lutz, O. Chiba-Falek, N. Mazer, M. Bairu, I.R.J. Hebold Haraldsen, P.M. Rossini, P.J. Snyder, J. Bouteiller, Z.S. Khachaturian, A.S. Khachaturian
J Prev Alz Dis 2024;5(11):1180-1182
Show summaryHide summary
CITATION:
O. Lerch ; S.Z. Levine ; S. Sivakumaran ; M.W. Lutz ; O. Chiba-Falek ; N. Mazer ; M. Bairu ; I.R.J. Hebold Haraldsen ; P.M. Rossini ; P.J. Snyder ; J. Bouteiller ; Z.S. Khachaturian ; A.S. Khachaturian (2024): Amplifying Efficiency and Accuracy in Dementia Drug Development. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.167
PREVALENCE ESTIMATION OF DEMENTIA/ALZHEIMER’S DISEASE USING HEALTH AND RETIREMENT STUDY DATABASE IN THE UNITED STATES
A.A. Tahami Monfared, N. Hummel, A. Chandak, A. Khachatryan, R. Zhang, Q. Zhang
J Prev Alz Dis 2024;5(11):1183-1188
Show summaryHide summaryBACKGROUND: Updated prevalence estimates along the continuum of Alzheimer’s disease (AD) can foster a more nuanced and effective approach to managing AD within the current healthcare landscape.
OBJECTIVES: This study aims to estimate the prevalence and severity distribution of dementia/AD (including mild, moderate, and severe stages) and all-cause mild cognitive impairment (MCI) in the United States using data from the Health and Retirement Study (HRS).
DESIGN: Retrospective study.
SETTING: Data from the bi-annual HRS surveys involving in-depth interviews of a representative sample of Americans aged >50 years.
PARTICIPANTS: Dementia/AD and all-cause MCI patients from the 4 most recent HRS surveys (2014, 2016, 2018 and 2020).
MEASUREMENTS: AD was identified based on diagnosis (self-report). Cognitive performance (modified Telephone Interview of Cognitive Status [TICS-m]) scores in the dementia/AD range were also captured; all-cause MCI was similarly identified using the TICS-m. Dementia/AD and MCI prevalence, as well as the distribution by dementia/AD stage (mild, moderate, or severe), were estimated. Sampling weights developed by HRS were applied to ensure the sample’s representativeness of the target population and unbiased estimates for population parameters.
RESULTS: Across the four HRS surveys, the total number of HRS respondents ranged from 15,000 to 21,000 (unweighted); 7,000 to 14,000 had TICS-m scores. The estimated prevalence of AD (all severity categories combined) in the 2014, 2016, 2018, and 2020 HRS surveys was 1.2%, 1.2%, 1.3% and 1.0%, respectively using the diagnosis-based approach; using the cognitive performance-based approach, 23-27% patients had scores in the dementia/AD ranges across the 4 surveys. The estimated prevalence of all-cause MCI was consistently 23% in each survey. In the 2020 survey, the distribution of mild, moderate, and severe disease stages was 34%, 45%, and 21%, respectively, in patients self-reporting an AD diagnosis, and 55%, 40%, and 5%, respectively in all patients meeting TICS-m threshold for dementia/AD.
CONCLUSION: The prevalence of AD diagnosis based on self-report was approximately 1% across the 4 most recent HRS surveys and may reflect the proportion of patients who have actively sought healthcare for AD. Among HRS survey respondents with cognitive scores available, over 20% were in the dementia/AD range. The distribution of disease by stage differed for self-reported AD diagnosis vs dementia/AD based on cognitive scores. Discordance in estimates of dementia/AD and stage distributions underscores a need for better understanding of clinical practice patterns in AD diagnosis, use of clinical assessment tools, and severity classification in the United States. Accurate patient identification is needed, especially early in the AD disease continuum, to allow for timely and appropriate initiation of new anti-amyloid treatments.
CITATION:
A.A. Tahami Monfared ; N. Hummel ; A. Chandak ; A. Khachatryan ; R. Zhang ; Q. Zhang (2024): Prevalence Estimation of Dementia/Alzheimer’s Disease Using Health and Retirement Study Database in the United States. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.114
PLASMA BIOMARKERS OF ALZHEIMER’S DISEASE AND NEURODEGENERATION ACCORDING TO SOCIODEMOGRAPHIC CHARACTERISTICS AND CHRONIC HEALTH CONDITIONS
H.T. Zheng, Z. Wu, M.M. Mielke, A.M. Murray, J. Ryan
J Prev Alz Dis 2024;5(11):1189-1197
Show summaryHide summaryUltrasensitive assays have been developed which enable biomarkers of Alzheimer’s disease pathology and neurodegeneration to be measured in blood. These biomarkers can aid in diagnosis, and have been used to predict risk of cognitive decline and Alzheimer’s disease. The ease and cost-effectiveness of blood collections means that these biomarkers could be applied more broadly in population-based screening, however it is critical to first understand what other factors could affect blood biomarker levels. The aim of this review was to determine the extent that sociodemographic, lifestyle and health factors have been associated with blood biomarkers of Alzheimer’s disease and neuropathology. Of the 32 studies included in this review, all but one measured biomarker levels in plasma, and age and sex were the most commonly investigated factors. The most consistent significant findings were a positive association between age and neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), and females had higher GFAP than men. Apolipoprotein ε4 allele carriers had lower Aβ42 and Aβ42/40 ratio. Body mass index was negatively associated with GFAP and NfL, and chronic kidney disease with higher levels of all biomarkers. Too few studies have investigated other chronic health conditions and this requires further investigation. Given the potential for plasma biomarkers to enhance Alzheimer’s disease diagnosis in primary care, it is important to understand how to interpret the biomarkers in light of factors that physiologically impact blood biomarker levels. This information will be critical for the establishment of reference ranges and thus the correct interpretation of these biomarkers in clinical screening.
CITATION:
H.T. Zheng ; Z. Wu ; M.M. Mielke ; A.M. Murray ; J. Ryan ; (2024): Plasma Biomarkers of Alzheimer’s Disease and Neurodegeneration According to Sociodemographic Characteristics and Chronic Health Conditions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.142
PERFORMANCE OF PLASMA BIOMARKERS COMBINED WITH STRUCTURAL MRI TO IDENTIFY CANDIDATE PARTICIPANTS FOR ALZHEIMER’S DISEASE-MODIFYING THERAPY
M. Manjavong, J.M. Kang, A. Diaz, M.T. Ashford, J. Eichenbaum, A. Aaronson, M.J. Miller, S. Mackin, R. Tank, M. Weiner, R. Nosheny, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;5(11):1198-1205
Show summaryHide summaryBACKGROUND: Recently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer’s disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aβ42/Aβ40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy.
OBJECTIVES: To evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI.
DESIGN: A cross-sectional and longitudinal study.
SETTING AND PARTICIPANTS: Data were from the Alzheimer’s Disease Neuroimaging Initiative. Participants were aged 55-90 years old with plasma biomarker and structural MRI brain data.
MEASUREMENTS: The optimum cut-off point for plasma Aβ42/Aβ40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis.
RESULTS: A total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aβ42/Aβ40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68-0.77) to detect drug candidate participants at baseline. Combined plasma Aβ42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively).
CONCLUSION: Plasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.
CITATION:
M. Manjavong ; J.M. Kang ; A. Diaz ; M.T. Ashford ; J. Eichenbaum ; A. Aaronson ; M.J. Miller ; S. Mackin ; R. Tank ; M. Weiner ; R. Nosheny ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Performance of Plasma Biomarkers Combined with Structural MRI to Identify Candidate Participants for Alzheimer’s Disease-Modifying Therapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.110
VALIDATION OF AN ULTRA-SENSITIVE METHOD FOR QUANTITATION OF PHOSPHO-TAU 217 (PTAU217) IN HUMAN PLASMA, SERUM, AND CSF USING THE ALZPATH PTAU217 ASSAY ON THE QUANTERIX HD-X PLATFORM
H. Zhang, J. Liu, N. Zhang, A. Jeromin, Z.J. Lin
J Prev Alz Dis 2024;5(11):1206-1211
Show summaryHide summaryBACKGROUND: Both blood (plasma and serum) and CSF tau phosphorylated at Threonine 217 (pTau217) have been shown to be able to discriminate early to mild Alzheimer’s disease (AD) from non-AD neurodegenerative disorders and healthy controls with high sensitivity and specificity.
OBJECTIVES: We report the full validation of the ALZpath ultra-sensitive pTau217 research-use only (RUO) assays for human EDTA plasma, serum, and CSF using the Quanterix Simoa HD-X platform, in support of clinical trials and early diagnosis of Alzheimer’s disease.
METHODS: The ALZpath pTau217 Simoa Advantage v2 kit from ALZpath/Quanterix was used for method development and validation of pTau217 in human plasma, serum, and CSF. All three method validations have followed the 2018 FDA BMV and 2022 ICH M10 guidelines.
RESULTS: Validation of pTau217 quantitation in human plasma, serum, and CSF demonstrated that the validated pTau217 assay has an analytical LLOQ of 0.00977 pg/mL. It is one of the most sensitive assays with a minimal required sample volume of 33.3 µl for plasma and serum, and 5 µl for CSF, and is relatively cost-effective, compared to the currently published data. The minimum required dilution (MRD) for plasma, serum, and CSF were determined. The analyte passed short-term stability tests. It was also tolerant of moderate hemolytic, and lipemic interferences in plasma and serum. pTau217 was detected in 100% of tested healthy control plasma, 90.0% of healthy control serum, 92.3% of healthy control CSF samples, and 100% of AD plasma and CSF samples. The validated assay was successfully applied in the analysis of AD samples, with data showing dramatic differences in the pTau217 levels between healthy control subjects and AD patients in both plasma and CSF.
CONCLUSION: Validation of the ALZpath pTau217 Simoa assay in human plasma, serum, and CSF demonstrates ultra sensitivity, high accuracy, and assay robustness. Together with other established and sensitive assays for pTau181, GFAP, and NfL, these assays have immediate utility for application in clinical trials and can play a role in the early diagnosis of neurodegenerative diseases.
CITATION:
H. Zhang ; J. Liu ; N. Zhang ; A. Jeromin ; Z.J. Lin ; (2024): Validation of an Ultra-Sensitive Method for Quantitation of Phospho-Tau 217 (pTau217) in Human Plasma, Serum, and CSF using the ALZpath pTau217 Assay on the Quanterix HD-X Platform. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.155
PROGRESS IN THE TREATMENT OF ALZHEIMER’S DISEASE IS NEEDED – POSITION STATEMENT OF EUROPEAN ALZHEIMER’S DISEASE CONSORTIUM (EADC) INVESTIGATORS
F. Jessen, M.G. Kramberger, D. Angioni, D. Aarsland, M. Balasa, K. Bennys, M. Boada, M. Boban, A. Chincarini, L. Exalto, A. Felbecker, K. Fliessbach, G.B. Frisoni, A.J. Garza-Martínez, T. Grimmer, B. Hanseeuw, J. Hort, A. Ivanoiu, S. Klöppel, L. Krajcovicova, B. McGuinness, P. Mecocci, A. de Mendonca, A. Nous, P.-J. Ousset, C. Paquet, R. Perneczky, O. Peters, M. Tabuas-Pereira, F. Piazza, D. Plantone, M. Riverol, A. Ruiz, G. Sacco, I. Santana, N. Scarmeas, E. Solje, E. Stefanova, S. Sutovsky, W. van der Flier, T. Welsh, A. Wimo, B. Winblad, L. Frölich, S. Engelborghs
J Prev Alz Dis 2024;5(11):1212-1218
Show summaryHide summaryβ-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.
CITATION:
F. Jessen ; M.G. Kramberger ; D. Angioni ; D. Aarsland ; M. Balasa ; K. Bennys ; M. Boada ; M. Boban ; A. Chincarini ; L. Exalto ; A. Felbecker ; K. Fliessbach ; G.B. Frisoni ; A.J. Garza-Martínez ; T. Grimmer ; B. Hanseeuw ; J. Hort ; A. Ivanoiu ; S. Klöppel ; L. Krajcovicova ; B. McGuinness ; P. Mecocci ; A. de Mendonca ; A. Nous ; P.-J. Ousset ; C. Paquet ; R. Perneczky ; O. Peters ; M. Tabuas-Pereira ; F. Piazza ; D. Plantone ; M. Riverol ; A. Ruiz ; G. Sacco ; I. Santana ; N. Scarmeas ; E. Solje ; E. Stefanova ; S. Sutovsky ; W. van der Flier ; T. Welsh ; A. Wimo ; B. Winblad ; L. Frölich ; S. Engelborghs ; ; (2024): Progress in the Treatment of Alzheimer’s Disease Is Needed – Position Statement of European Alzheimer’s Disease Consortium (EADC) Investigators. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.153
CLINICAL MEANINGFULNESS IN ALZHEIMER’S DISEASE CLINICAL TRIALS. A REPORT FROM THE EU-US CTAD TASK FORCE
D. Angioni, J. Cummings, C.J. Lansdall, L. Middleton, C. Sampaio, S. Gauthier, S. Cohen, R.C. Petersen, D.M. Rentz, A.M. Wessels, S.B. Hendrix, F. Jessen, M.C. Carrillo, R.S. Doody, M. Irizarry, J.S. Andrews, B. Vellas, P. Aisen
J Prev Alz Dis 2024;5(11):1219-1227
Show summaryHide summaryRecent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer’s disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address.
CITATION:
D. Angioni ; J. Cummings ; C.J. Lansdall ; L. Middleton ; C. Sampaio ; S. Gauthier ; S. Cohen ; R.C. Petersen ; D.M. Rentz ; A.M. Wessels ; S.B. Hendrix ; F. Jessen ; M.C. Carrillo ; R.S. Doody ; M. Irizarry ; J.S. Andrews ; B. Vellas ; P. Aisen (2024): Clinical Meaningfulness in Alzheimer’s Disease Clinical Trials. A Report from the EU-US CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.112
A STATISTICAL FRAMEWORK FOR ASSESSING THE RELATIONSHIP BETWEEN BIOMARKERS AND CLINICAL ENDPOINTS IN ALZHEIMER’S DISEASE
T. Chen, R.M. Hutchison, C. Rubel, J. Murphy, J. Xie, P. Montenigro, W. Cheng, K. Fraser, G. Dent, S. Hendrix, O. Hansson, P. Aisen, Y. Tian, J. O’Gorman
J Prev Alz Dis 2024;5(11):1228-1240
Show summaryHide summaryChanges in biomarker levels of Alzheimer’s disease (AD) reflect underlying pathophysiological changes in the brain and can provide evidence of direct and downstream treatment effects linked to disease modification. Recent results from clinical trials of anti–amyloid β (Aβ) treatments have raised the question of how to best characterize the relationship between AD biomarkers and clinical endpoints. Consensus methodology for assessing such relationships is lacking, leading to inconsistent evaluation and reporting. In this review, we provide a statistical framework for reporting treatment effects on early and late accelerating AD biomarkers and assessing their relationship with clinical endpoints at the subject and group levels. Amyloid positron emission tomography (PET), plasma p-tau, and tau PET follow specific trajectories during AD and are used as exemplar cases to contrast biomarkers with early and late progression. Subject-level correlation was assessed using change from baseline in biomarkers versus change from baseline in clinical endpoints, and interpretation of the correlation is dependent on the biomarker and disease stage. Group-level correlation was assessed using the placebo-adjusted treatment effects on biomarkers versus those on clinical endpoints in each trial. This correlation leverages the fundamental advantages of randomized placebo-controlled trials and assesses the predictivity of a treatment effect on a biomarker or clinical benefit. Harmonization in the assessment of treatment effects on biomarkers and their relationship to clinical endpoints will provide a wealth of comparable data across clinical trials and may yield new insights for the treatment of AD.
CITATION:
T. Chen ; R.M. Hutchison ; C. Rubel ; J. Murphy ; J. Xie ; P. Montenigro ; W. Cheng ; K. Fraser ; G. Dent ; S. Hendrix ; O. Hansson ; P. Aisen ; Y. Tian ; J. O’Gorman (2024): A Statistical Framework for Assessing the Relationship between Biomarkers and Clinical Endpoints in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.126
SEMORINEMAB PHARMACOKINETICS AND THE EFFECT ON PLASMA TOTAL TAU PHARMACODYNAMICS IN CLINICAL STUDIES
V. Ramakrishnan, B. Bender, J. Langenhorst, M.O. Magnusson, M. Dolton, J. Shim, R.N. Fuji, C. Monteiro, E. Teng, N. Kassir, J. Jin
J Prev Alz Dis 2024;5(11):1241-1250
Show summaryHide summaryBACKGROUND: Semorinemab is a monoclonal antibody that targets the N-terminal domain of the tau protein that is in clinical development for the treatment of Alzheimer’s disease.
OBJECTIVES: To perform model-based evaluations of the observed pharmacokinetics in serum and the total plasma tau target-engagement dynamics from clinical studies evaluating semorinemab.
DESIGN: The observed semorinemab pharmacokinetics and plasma tau target engagement from phase 1 and 2 clinical studies were modeled using a non-linear mixed effect target-mediated drug disposition model. The model was simulated to understand target engagement at clinical dose levels.
SETTINGS AND PARTICIPANTS: The clinical studies testing semorinemab were evaluated in healthy volunteers, subjects with prodromal-to-mild Alzheimer’s disease, and subjects with mild-to-moderate Alzheimer’s disease. The data included a total of 8430 semorinemab serum concentrations and 4772 total tau protein plasma concentrations from 463 subjects treated with a range of single and multiple doses of semorinemab.
MEASUREMENTS: Serum concentrations of semorinemab and the total plasma tau concentrations were measured after administration of a range of doses of semorinemab to subjects with Alzheimer’s disease. A sensitivity analysis was performed wherein key target-mediated drug disposition model parameters were estimated separately between healthy volunteers, subjects with prodromal-to-mild Alzheimer’s disease, and subjects with mild-to-moderate Alzheimer’s disease.
RESULTS: Serum concentrations of semorinemab were consistent across studies and showed a dose-proportional increase across the evaluated dose range. The pharmacokinetic profile was comparable between healthy volunteers and subjects with Alzheimer’s disease. Total plasma tau concentrations increased in a dose-dependent non-linear manner upon semorinemab administration. The target-mediated drug disposition model adequately described the serum pharmacokinetics and protein dynamics with an estimated antibody-ligand binding strength, Kss, of 42.7 nM. The estimated values of clearance and central volume of distribution were 0.109 L/day/70 kg and 2.95 L/70 kg, respectively, and were consistent with typical values for IgG mAbs. In the sensitivity analysis, Kss (32 nM) and baseline tau protein (0.30 µM) were estimated to be lower for healthy volunteers compared to subjects with Alzheimer’s disease but were comparable between subjects with Alzheimer’s disease of different severities (Kss: 52-57 nM, baseline tau: 0.44-0.47 µM). The models suggested that peripheral target engagement was over 90% at the clinical doses in each of the diagnostic subgroups.
CONCLUSION: Our target-mediated drug disposition model adequately described the serum pharmacokinetics and the peripheral non-linear increase with dose of the total tau. The model confirmed that these dose-response relationships were consistent across populations of healthy volunteers and subjects with different severities of Alzheimer’s disease.
CITATION:
V. Ramakrishnan ; B. Bender ; J. Langenhorst ; M.O. Magnusson ; M. Dolton ; J. Shim ; R.N. Fuji ; C. Monteiro ; E. Teng ; N. Kassir ; J. Jin (2024): Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.146
ALZHEIMER’S DISEASE LINKAGE TO REAL-WORLD EVIDENCE (AD-LINE) STUDY: LINKING CLAIMS DATA TO PHASE 3 GRADUATE STUDY OF GANTENERUMAB
H. Fillit, S. Seleri Assunção, T. Majda, C.D. Ng, T.M. To, I.M. Abbass, K. Raimundo, C. Wallick, O.V. Tcheremissine
J Prev Alz Dis 2024;5(11):1251-1259
Show summaryHide summaryBACKGROUND: Linking data from clinical trials and real-world claims may improve the robustness of trial data and provide information on the health, economic, and societal impacts of a disease.
OBJECTIVE: To report on the feasibility of linking trial data to Medicare claims data in early symptomatic Alzheimer’s disease (AD) in the US.
DESIGN AND SETTING: Alzheimer’s Disease Linkage to Real-World Evidence (AD-LINE) was a noninterventional cohort study that included participants recruited from the GRADUATE program whose trial data were linked to their Medicare claims.
PARTICIPANTS: AD-LINE participants were 66 years and older with early symptomatic AD (ie, mild cognitive impairment [MCI] due to AD or mild AD dementia) and were enrolled in the GRADUATE program and a Medicare fee-for-service or Medicare Advantage plan.
MEASUREMENTS: The Centers for Medicare & Medicaid Services linked participants’ clinical trial identifiers to their Medicare beneficiary identifiers using a deterministic, exact matching process. Demographics and clinical characteristics of the AD-LINE cohort at baseline were collected. Outcomes measured in this study included healthcare resource utilization derived from Medicare claims data.
RESULTS: In total, 147 participants across 21 US sites were invited to participate and 111 provided informed consent. Of those, 61 patients had linkable data (ie, Medicare beneficiary identifier), Medicare Parts A/B enrollment, and no health maintenance organization (HMO) enrollment in the year before trial entry. Of the 61 participants whose data were analyzed in this study, 30 had MCI due to AD and 31 had mild AD dementia. Participants in the MCI due to AD group had more healthcare resource utilization on average in the baseline period than those in the mild AD dementia group (29.9 [SD, 20.9] vs 24.5 claims [SD, 12.3]). In an ad hoc analysis, a relatively high concordance (85.3%) was seen between the rates of clinically confirmed AD diagnosis and evidence of AD diagnosis in claims data.
CONCLUSION: This linkage process may serve as a proof of concept for researchers interested in linking clinical trial and real-world claims data. The lessons learned from AD-LINE and innovation of data linkage approaches may encourage key stakeholders to link data in the future.
CITATION:
H. Fillit ; S. Seleri Assunção ; T. Majda ; C.D. Ng ; T.M. To ; I.M. Abbass ; K. Raimundo ; C. Wallick ; O.V. Tcheremissine (2024): Alzheimer’s Disease Linkage to Real-World Evidence (AD-LINE) Study: Linking Claims Data to Phase 3 GRADUATE Study of Gantenerumab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.115
JAPANESE SUBGROUP ANALYSES FROM EMERGE AND ENGAGE, PHASE 3 CLINICAL TRIALS OF ADUCANUMAB IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE
Y. Toda, T. Iwatsubo, Y. Nakamura, N. Matsuda, M. Miyata, M. Jin, T. Chen, K. Kuribayashi, Y. Tian, R. Hughes, J. Yamamoto, K.K. Muralidharan, C. Rubel, R.M. Hutchison, S. Budd Haeberlein
J Prev Alz Dis 2024;5(11):1260-1269
Show summaryHide summaryBACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer’s disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway.
OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies.
DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia).
SETTING: These studies involved 348 sites in 20 countries.
PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50–85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia.
INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks.
MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity.
RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population.
CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.
CITATION:
Y. Toda ; T. Iwatsubo ; Y. Nakamura ; N. Matsuda ; M. Miyata ; M. Jin ; T. Chen ; K. Kuribayashi ; Y. Tian ; R. Hughes ; J. Yamamoto ; K.K. Muralidharan ; C. Rubel ; R.M. Hutchison ; S. Budd Haeberlein (2024): Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.106
FLAVONOID-RICH FRUIT INTAKE IN MIDLIFE AND LATE-LIFE AND ASSOCIATIONS WITH RISK OF DEMENTIA: THE FRAMINGHAM HEART STUDY
C. Lyu, P.F. Jacques, P.M. Doraiswamy, B. Young, A.S. Gurnani, R. Au, P.H. Hwang
J Prev Alz Dis 2024;5(11):1270-1279
Show summaryHide summaryBACKGROUND: Fruits are an important source of flavonoids, and greater intake of dietary flavonoids in older adults has been shown to be associated with decreased risk of dementia. It is unclear whether this relationship is similar or different between younger adults and older adults.
OBJECTIVES: We examined for associations between midlife and late-life intake of flavonoid-rich fruits and incident dementia. We hypothesized that greater total cumulative intake of flavonoid-rich fruits in midlife and late-life adults would be associated with reduced risk of all-cause dementia.
DESIGN: Longitudinal, cohort study design.
SETTING: Framingham Heart Study, which is a longitudinal, multi-generational community-based cohort based in Framingham, Massachusetts, USA.
PARTICIPANTS: Participants from the Framingham Heart Study Offspring cohort were included (n = 2,790) who attended the fifth core exam between 1991 to 1995, and were dementia-free and at least 45 years of age at that time, as well as had valid food frequency questionnaires from the fifth to ninth core exams.
MEASUREMENTS: Consumption of fruits with high flavonoid content or are important contributors to overall flavonoid intake was collected via food frequency questionnaire. Flavonoid-rich fruits from the food frequency questionnaire included raisins or grapes, prunes, bananas, fresh apples or pears, apple juice or cider, oranges, orange juice, grapefruit, grapefruit juice, strawberries, blueberries, and peaches, apricots, or plums. Dementia ascertainment was based on a multidisciplinary consensus committee, and included all-cause dementia and Alzheimer’s disease dementia diagnoses based on research criteria. Cox models were used to examine associations between cumulative fruit intake and incident dementia, stratified by midlife (45-59 years; n = 1,642) and late-life (60-82 years; n = 1,148).
RESULTS: Greater cumulative total fruit intake in midlife, but not late-life, was significantly associated with a 44% decreased risk of all-cause dementia (HR = 0.56; 95% CI = 0.32 – 0.98; p = 0.044). Decreased risk of all-cause dementia was also associated with higher intake of apples or pears in midlife and late-life, as well as higher intake of raisins or grapes in midlife only, and higher intake of oranges, grapefruit, blueberries, and peaches, apricots, or plums in late-life only.
CONCLUSIONS: Among participants from the Framingham Heart Study, greater overall consumption of flavonoid-rich fruits in midlife was associated with reduced risk of dementia, though intake of specific fruits in midlife and late-life may have a protective role against developing dementia. These findings may help to inform future recommendations on when dietary interventions may be most beneficial to healthy brain aging across the life course.
CITATION:
C. Lyu ; P.F. Jacques ; P.M. Doraiswamy ; B. Young ; A.S. Gurnani ; R. Au ; P.H. Hwang (2024): Flavonoid-Rich Fruit Intake in Midlife and Late-Life and Associations with Risk of Dementia: The Framingham Heart Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.116
EVALUATING THE CAUSAL EFFECT OF TYPE 2 DIABETES ON ALZHEIMER’S DISEASE USING LARGE-SCALE GENETIC DATA
D. Liu, A. Baranova, F. Zhang
J Prev Alz Dis 2024;5(11):1280-1282
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present.
OBJECTIVES: We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data.
METHODS: Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques.
RESULTS: In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95-1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64-1.47, P=0.884).
CONCLUSION: Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.
CITATION:
D. Liu ; A. Baranova ; F. Zhang (2024): Evaluating the Causal Effect of Type 2 Diabetes on Alzheimer’s Disease Using Large-Scale Genetic Data. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.148
METABOLIC SYNDROME STATUS CHANGES AND COGNITIVE FUNCTIONING: INSIGHTS FROM THE LIFELINES COHORT STUDY
I. Frentz, S. Marcolini, C.C.I. Schneider, M.A. Ikram, J. Mondragon, P.P. De Deyn
J Prev Alz Dis 2024;5(11):1283-1290
Show summaryHide summaryBACKGROUND: Metabolic syndrome is associated with increased risk of dementia. Yet, findings on how longitudinal development of metabolic syndrome status affects cognition remain controversial.
OBJECTIVES: This study examines whether individuals with different changes in metabolic syndrome status differ in cognitive functioning. Additionally, the prevalence of metabolic syndrome within the Lifelines population-based study is investigated.
DESIGN: 14609 Lifelines participants (mean age 60.8, 56.4% women) were divided into four groups based on their metabolic syndrome status changes between 2007-2013 (1) and between 2014-2017 (2): without metabolic syndrome (N=10863; absent at 1 and 2), de novo metabolic syndrome (N=1340; absent at 1 and present at 2), remitting metabolic syndrome (N=825; present at 1 and absent at 2), and persistent metabolic syndrome (N=1581; present at 1 and 2). ANCOVA models were employed to assess group differences in psychomotor function, visual attention, visual learning, and working memory assessed using the Cogstate Brief Battery.
RESULTS: Accounting for education, age, sex, and time between examinations, groups did not statistically differ in any of the four cognitive outcomes. The prevalence of metabolic syndrome within the Lifelines population increased with age and differed among men and women.
CONCLUSION: Performance in psychomotor function, visual attention, visual learning, and working memory measured by the Cogstate Brief Battery did not differ between individuals with different changes in metabolic syndrome. The length of metabolic syndrome exposure was unknown, making our results exploratory and calling for future studies addressing this gap.
CITATION:
I. Frentz ; S. Marcolin ; C.C.I. Schneider ; M.A. Ikram ; J. Mondragon ; P.P. De Deyn (2024): Metabolic Syndrome Status Changes and Cognitive Functioning: Insights from the Lifelines Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.90
MULTIDOMAIN INTERVENTION FOR THE REVERSAL OF COGNITIVE FRAILTY USING A PERSONALIZED APPROACH (AGELESS TRIAL): RECRUITMENT AND BASELINE CHARACTERISTICS OF PARTICIPANTS
A.M. Ibrahim, D.K.A. Singh, A.F.M. Ludin, P. Subramaniam, C. Ai -Vyrn, N. Ibrahim, H. Haron, A.M. Safien, N.M. Khalid, P. Ponvel, N.H.M. Fadzil, J.M. Hanipah, F. Mangialasche, M. Kivipelto, S. Shahar
J Prev Alz Dis 2024;5(11):1291-1306
Show summaryHide summaryBACKGROUND: Reversal of cognitive frailty through a multidomain intervention is desirable to prevent dementia. AGELESS Trial was conducted to determine the effectiveness of a comprehensive, multidomain intervention on older adults with cognitive frailty in Malaysia. However, conducting a clinical trial, particularly during and after Covid-19, posed unique challenges.
OBJECTIVE: We aimed to investigate the recruitment process and baseline characteristics of the AGELESS Trial participants to better understand an at-risk population and those who agree to participate in an intervention.
DESIGN/SETTING: 24-month, randomized controlled trial.
PARTICIPANTS: Community-dwelling older adults with independent mobility, aged ≥ 60 years, with a mini mental state examination score of 19-25, a clinical dementia rating of 0.5 ≥ 1 Fried’s physical frailty criteria, and < 22 Beck depression inventory.
INTERVENTION: Participants were randomized 1:1 to a structured multidomain intervention consisting of vascular management, diet, exercise, cognitive and psychosocial stimulation, or to the arm, including routine care and general health consultation.
MEASUREMENT: We analyzed the group differences between (1) cognitive frailty and non- cognitive frailty screened subjects, (2) recruited and non-recruited participants, (3) baseline characteristics of participants by arm, (4) adherence to AGELESS intervention at 12 months, and (5) preliminary findings on the effectiveness of the intervention at 12 months.
RESULTS: A total of 957 older adults from two locations, i.e., urban (n = 764) and rural (n = 193) areas, were screened, of whom 38.9% had cognitive frailty and were eligible to participate. Those with cognitive frailty had fewer years of education (B = -0.08; 95%CI = 0.88-0.97; p = 0.002), and lower functioning cognition (B = -0.24; 95%CI = 0.74-0.84; p < 0.001). Among those from urban areas, only 33.1% (n = 106) agreed to participate, particularly those with multimorbidity (B = 0.86; 95%CI = 1.31-4.30; p = 0.01), higher physical activity (B = -1.02; 95%CI = 0.19-0.69; p = 0.002), slower walking speed (B = 1.26; 95%CI = 1.62-7.61; p = 0.001), and higher systolic blood pressure (B = 0.02; 95%CI = 1.00-1.03; p = 0.03). At baseline, participants’ mean age was 68.1±5.6, years of education was 8.3±3.9, body mass index was 27.5±5.3 kg/m2, and mini mental state examination score was 22.7±4.0. Generally, there were no significant differences between the intervention and control groups for the main outcomes, except those in the intervention group had higher body mass index, mid-upper-arm circumference, and waist circumference (p < 0.05 for all parameters). Overall intervention adherence at 12 months was 52.8%, ranging from 52.8%-90.6% for each of the modules. Preliminary analysis of the effectiveness of the intervention at 12 months was positive on most of the cognitive domains, some of the nutrient intake and food groups, physical function, and vascular outcomes (p < 0.05 for all parameters).
CONCLUSION: Despite the challenges posed by the pandemic, screening, recruitment, and 12-month intervention delivery were achieved in a Malaysian multidomain preventive randomized controlled trial in older adults at risk of dementia, with a satisfactory adherence rate and cognitive benefits at 12 months.
CITATION:
A.M. Ibrahim ; D.K.A. Singh ; A.F.M. Ludin ; P. Subramaniam ; C. Ai -Vyrn ; N. Ibrahim ; H. Haron ; A.M. Safien ; N.M. Khalid ; P. Ponvel ; N.H.M. Fadzil ; J.M. Hanipah ; F. Mangialasche ; M. Kivipelto ; S. Shahar (2024): Multidomain Intervention for the Reversal of Cognitive Frailty Using a Personalized Approach (AGELESS Trial): Recruitment and Baseline Characteristics of Participants. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.111
META ANALYSIS OF THE CORRELATION BETWEEN PERIODONTAL HEALTH AND COGNITIVE IMPAIRMENT IN THE OLDER POPULATION
Y.-D. Fu, C.-L. Li, C.-L. Hu, M.-D. Pei, W.-Y. Cai, Y.-Q. Li, L. Xu, Y. Zeng
J Prev Alz Dis 2024;5(11):1307-1315
Show summaryHide summaryOBJECTIVE: To explore the correlation between periodontal health and cognitive impairment in the older population to provide the evidence for preventing cognitive impairment from the perspective of oral health care in older adults.
METHODS: A comprehensive search was conducted in PubMed, Embase, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure, Wanfang Data, the China Science and Technology Journal Database, and the China Biomedical Literature Database, to include both cross-sectional and longitudinal cohort studies on the association between periodontal health and cognitive impairment in older adults. The search was completed in April 2023. Following quality assessment and data organization of the included studies, meta-analysis was performed using Review Manager 5.4.
RESULTS: Twenty-two studies involving a total of 4,246,608 patients were included to comprehensively assess periodontal health from four dimensions (periodontitis, tooth loss, occlusal support, and masticatory ability), with the outcome variable of cognitive impairment (including mild cognitive impairment, Alzheimer’s disease and all-cause dementia). Meta-analysis showed that, compared to those of periodontally healthy older adults, the risk of cognitive impairment in older adults with poor periodontal health, after adjusting for confounders, was significantly greater for those with periodontitis (OR=1.45, 95% CI: 1.20-1.76, P<0.001), tooth loss (OR=1.80, 95% CI: 1.50-2.15, P<0.001), compromised occlusal support (OR=1.87, 95% CI: 1.29-2.70, P=0.001), and reduced masticatory ability (OR=1.39, 95% CI: 1.11-1.75, P=0.005). The risk of cognitive impairment was higher in older adults with low-dentition than in those with high-dentition. Subgroup analysis revealed older individuals with fewer remaining teeth were at a higher risk of developing cognitive impairment compared to those with more remaining teeth, as shown by the comparison of number of teeth lost (7-17 teeth compared to 0-6 teeth) (OR=1.64, 95% CI: 1.13-2.39, P=0.01), (9-28 teeth compared to 0-8 teeth) (OR=1.13, 95% CI: 1.06-1.20, P<0.001), (19-28 teeth compared to 0-18 teeth) (OR=2.52, 95% CI: 1.32-4.80, P=0.005), and (28 teeth compared to 0-27 teeth) (OR=2.07, 95% CI: 1.54-2.77, P<0.001). In addition, tooth loss in older adults led to a significantly increased risk of mild cognitive impairment (OR=1.66, 95% CI: 1.43-1.91, P<0.001) and all-cause dementia (OR=1.35, 95% CI: 1.11-1.65, P=0.003), although the correlation between tooth loss and the risk of Alzheimer’s disease was not significant (OR=3.89, 95% CI: 0.68-22.31, P=0.13).
CONCLUSION: Poor periodontal health, assessed across four dimensions (periodontitis, tooth loss, occlusal support, and masticatory ability), represents a significant risk factor for cognitive impairment in older adults. The more missing teeth in older adults, the higher risk of developing cognitive impairment, with edentulous individuals particularly susceptible to cognitive impairment. While a certain degree of increased risk of Alzheimer’s disease was observed, no significant association was found between tooth loss and the risk of developing Alzheimer’s disease. Enhancing periodontal health management and delivering high-quality oral health care services to older adults can help prevent cognitive impairment.
CITATION:
Y.-D. Fu ; C.-L. Li ; C.-L. Hu ; M.-D. Pei ; W.-Y. Cai ; Y.-Q. Li ; L. Xu ; Y. Zeng (2024): Meta Analysis of the Correlation between Periodontal Health and Cognitive Impairment in the Older Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.87
EVALUATING THE PERFORMANCE OF DIFFERENT CRITERIA IN DIAGNOSING AD AND PRECLINICAL AD WITH THE BAYESIAN LATENT CLASS MODEL
X. Wang, G. Niu, J. Zhao, H. Zhu, F. Li, J. Tian, Z. Zhang, G. Chen, Y. He, Q. Gao
J Prev Alz Dis 2024;5(11):1316-1324
Show summaryHide summaryBACKGROUND: The diagnostic criteria for Alzheimer’s disease (AD) should be highly sensitive and specific. Clinicians have varying opinions on the different criteria, including the International Working Group-1 (IWG-1), International Working Group-2 (IWG-2), and AT(N) criteria. Few studies had evaluated the performance of these criteria in diagnosing AD and preclinical AD when the gold standard was absent.
METHODS: We estimated and compared the performance of these criteria in diagnosing AD using data from 908 subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Additionally, 622 subjects were selected to evaluate and compare the performance of IWG-2 and AT(N) criteria in diagnosing preclinical AD. A novel approach, Bayesian latent class models with fixed effect dependent, was utilized to estimate the diagnostic accuracy of these criteria in detecting different AD statuses simultaneously.
RESULTS: The sensitivity of the IWG-1, IWG-2, and AT(N) criteria in diagnosing AD was 0.850, 0.836, and 0.665. The specificity of these criteria was 0.788, 0.746, and 0.747. The IWG-1 criteria had the highest Youden Index in detecting AD. When diagnosing preclinical AD, the sensitivity of the IWG-2 and AT(N) criteria was 0.797 and 0.955. The specificity of these criteria was 0.922 and 0.720. The IWG-2 criteria had the highest Youden Index.
CONCLUSION: IWG-1 was more suitable than the IWG-2 and AT(N) criteria in detecting AD. IWG-2 criteria was more suitable than AT(N) criteria in detecting preclinical AD.
CITATION:
X. Wang ; G. Niu ; J. Zhao ; H. Zhu ; F. Li ; J. Tian ; Z. Zhang ; G. Chen ; Y. He ; Q. Gao (2024): Evaluating the Performance of Different Criteria in Diagnosing AD and Preclinical AD with the Bayesian Latent Class Model. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.71
VISUAL EVENT-RELATED POTENTIALS UNDER EXTERNAL EMOTIONAL STIMULI AS EARLY SIGNS FOR MILD COGNITIVE IMPAIRMENT
C. Wang, W. Yu, T. Xu, H. Zeng, A. González-Cuello, E. Fernández-Villalba, F. Xu, F. Chu, M.T. Herrero, M. Tao
J Prev Alz Dis 2024;5(11):1325-1338
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disorder featured by progressive cognitive decline, which manifests in severe impairment of memory, attention, emotional processing and daily activities, leading to significant disability and social burden. Investigation on Mild Cognitive Impairment (MCI), the prodromal and transitional stage between normal aging and AD, serves as a key in diagnosing and slowing down the progression of AD. Numerous effects have been made up to date, however, the attentional mechanisms under different external emotion stimuli in MCI and AD are still unexplored in deep.
OBJECTIVE: To further explore the attentional mechanisms under different external emotion stimuli in both MCI and AD patients.
DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: In 51 healthy volunteers (Controls, 24 males and 27 females), 52 MCI (19 males and 33 females), and 47 AD (15 males and 32 females) patients, we administered the visual oddball event-related potentials (ERPs) under three types of external emotional stimuli: Neutral, Happiness and Sadness, in which the components N1, P2, N2 and P3 as well as the abnormal cortical activations corresponding to the significant ERP differences in the three groups were observed.
RESULTS: Under all three external emotions, in AD patients, N2 and P3 latencies were significantly prolonged compared to both Controls and MCI. In addition, under Happiness, in MCI, P3 latencies were significantly delayed compared to Controls. Meanwhile, under both Happiness and Sadness, in AD patients, P3 amplitudes were significantly decreased compared to Controls and MCI, respectively. During N2 time window, under Neutral emotion, significant hypoactivation in the right superior temporal gyrus was found in AD patients compared to Controls, and under Happiness, the activation of the right inferior frontal gyrus was significantly attenuated in MCI compared to Controls. Under Sadness, in AD patients, the activation of the right superior frontal gyrus was significantly decreased compared to MCI. During P3 time window, under both Happiness and Sadness, when AD patients compared to MCI, the significantly attenuated activations were located in the right fusiform gyrus and the right middle occipital gyrus, respectively.
CONCLUSION: Our results demonstrated visual attentional deficits under external emotional stimuli in both MCI and AD patients, highlighting the function of Happiness for early detecting MCI, in which the P3 latency and the hypoactivation of right inferior frontal gyrus during N2 time window can be early signs. The current study sheds further light of attentional mechanisms in MCI and AD patients, and indicates the value of emotional processing in the early detection of cognitive dysfunction.
CITATION:
C. Wang ; W. Yu ; T. Xu ; H. Zeng ; A. González-Cuello ; E. Fernández-Villalba ; F. Xu ; F. Chu ; M.T. Herrero ; M. Tao ; (2024): Visual Event-Related Potentials under External Emotional Stimuli as Early Signs for Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.72
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS AND DEMENTIA PREVENTION: A SYSTEMATIC REVIEW OF OBSERVATIONAL EVIDENCE IN RHEUMATOID ARTHRITIS
C.-Y. Wu, L.Y. Xiong, Y.Y. Wong, S. Noor, G. Bradley-Ridout, W. Swardfager
J Prev Alz Dis 2024;5(11):1339-1347
Show summaryHide summaryBACKGROUND: Many observational studies have examined the association of disease-modifying antirheumatic drugs (DMARDs) with dementia risk, but the evidence has been mixed, possibly due to methodological reasons. This systematic review (PROSPERO: CRD42023432122) aims to assess existing observational evidence and to suggest if repurposing DMARDs for dementia prevention merits further investigation.
METHODS: Four electronic databases up to October 26, 2023, were searched. Cohort or case-control studies that examined dementia risk associated with DMARDs in people with rheumatoid arthritis were included. Risk of bias was evaluated using the Cochrane Collaboration’s Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) criteria. Findings were summarized by individual drug classes and by risk of bias.
RESULTS: Of 12,180 unique records, 14 studies (4 case-control studies, 10 cohort studies) were included. According to the ROBINS-I criteria, there were 2 studies with low risk of bias, 1 study with moderate risk, and 11 studies with serious or critical risk. Among studies with low risk of bias, one study suggested that hydroxychloroquine versus methotrexate was associated with lower incident dementia, and the other study showed no associations of tumor necrosis factor (TNF) inhibitors, tocilizumab, and tofacitinib, compared to abatacept, with incident dementia.
CONCLUSION: Studies that adequately addressed important biases were limited. Studies with low risk of bias did not support repurposing TNF inhibitors, tocilizumab, abatacept or tofacitinib for dementia prevention, but hydroxychloroquine may be a potential candidate. Further studies that carefully mitigate important sources of biases are warranted, and long-term evidence will be preferred.
CITATION:
C.-Y. Wu ; L.Y. Xiong ; Y.Y. Wong ; S. Noor ; G. Bradley-Ridout ; W. Swardfager ; (2024): Disease-Modifying Antirheumatic Drugs and Dementia Prevention: A Systematic Review of Observational Evidence in Rheumatoid Arthritis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.78
THE RELATIONSHIP BETWEEN HISTORY OF TRAUMATIC BRAIN INJURY AND LONGITUDINAL CHANGES IN CORTICAL THICKNESS AMONG PATIENTS WITH ALZHEIMER’S DISEASE
G.M. D’Souza, N.W. Churchill, D.X. Guan, M.A. Khoury, S.J. Graham, S. Kumar, C.E. Fischer, T.A. Schweizer
J Prev Alz Dis 2024;5(11):1348-1354
Show summaryHide summaryBACKGROUND: There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer’s disease (AD).
METHODS: The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness.
RESULTS: Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI.
CONCLUSION: These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions.
CITATION:
G.M. D’Souza ; N.W. Churchill ; D.X. Guan ; M.A. Khoury ; S.J. Graham ; S. Kumar ; C.E. Fischer ; T.A. Schweizer (2024): The Relationship between History of Traumatic Brain Injury and Longitudinal Changes in Cortical Thickness among Patients with Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.86
BACILLUS CALMETTE-GUERIN (BCG) VACCINE IMPACT ON DEMENTIA RISK IN BLADDER CANCER PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
M. Ibrahim, P. Kim, R. Marawar, K.I. Avgerinos
J Prev Alz Dis 2024;5(11):1355-1362
Show summaryHide summaryBACKGROUND: The BCG vaccine has been traditionally administered to prevent TB. It has been additionally used in bladder cancer patients as a therapy with success. Some observational studies found that bladder cancer patients receiving BCG may have reduced dementia risk, however, the evidence is not conclusive.
OBJECTIVE: To investigate the impact of BCG vaccine on dementia risk in bladder cancer patients.
METHODS: Six databases were searched from inception to January 13, 2024, for published and unpublished studies that examine the association between BCG and dementia risk in bladder cancer patients. We conducted meta-analyses using a random-effects model.
RESULTS: Eight retrospective cohort studies were included in the systematic review and seven in the meta-analyses. Because there were studies with overlapping populations, two separate main analyses were performed reassuring the avoidance of overlap. The first analysis showed that compared to controls, BCG did not reduce dementia risk [5 studies pooled, n=88,852, HR = 0.65, 95% CI (0.40, 1.06), I2 = 85%] whereas there was a marginally significant risk reduction in the second analysis [6 studies pooled, n=70,025, HR = 0.63, 95% CI (0.40, 0.97), I2 = 83%]. Sensitivity analysis excluding the unpublished studies did not affect the outcome importantly. Additional meta-analysis showed that BCG did not reduce the risk of Alzheimer’s disease.
CONCLUSION: This meta-analysis of observational studies found that BCG administration in bladder cancer patients has likely a minimally positive impact on dementia risk if any. To better understand the effect of BCG on dementia, randomized controlled trials are needed.
CITATION:
M. Ibrahim ; P. Kim ; R. Marawar ; K.I. Avgerinos ; (2024): Bacillus Calmette-Guerin (BCG) Vaccine Impact on Dementia Risk in Bladder Cancer Patients: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.94
DOES PLAYING MAHJONG BENEFIT OLDER INDIVIDUALS? A SCOPING REVIEW
Z.C.K. Tse, Y. Cao, B.K.H. Chau, M.K. Yeung, C. Leung, D.H.K. Shum
J Prev Alz Dis 2024;5(11):1363-1377
Show summaryHide summaryPlaying mahjong is a popular intellectual and social leisure activity in Asian countries. It is culturally believed that this activity is beneficial to cognitive and psychological functioning in older adults. However, empirical evidence of the benefits of playing mahjong is scant and scattered across the Western and Asian literature. This scoping review comprehensively examined previous studies of the relationships between playing mahjong and cognitive, psychological, and functional abilities in older adults, highlighted gaps in the literature, and identified directions for future research. A systematic search of the literature was conducted across thirteen Western and Asian databases. Fifty-three studies, including forty-seven observational and six intervention studies, were identified. Overall, the results of the observational studies suggested that more mahjong-playing experience was associated with better cognitive, psychological, and functional abilities. As an intervention, playing mahjong was found to enhance general cognitive abilities and short-term memory and relieve depressive symptoms. However, because most of the reviewed studies adopted a correlational methodology, the neural mechanism underlying the benefits of playing mahjong awaits further elucidation. The findings of this review suggest that more randomized controlled trials should be conducted to explore the effects of playing mahjong on higher-level cognitive functioning in older populations.
CITATION:
Z.C.K. Tse ; Y. Cao ; B.K.H. Chau ; M.K. Yeung ; C. Leung ; D.H.K. Shum ; (2024): Does Playing Mahjong Benefit Older Individuals? A Scoping Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.102
RISK OF DEMENTIA IN KOREAN VIETNAM WAR VETERANS
W. Lee, S. Lee, S.-K. Kang, W.-J. Choi
J Prev Alz Dis 2024;5(11):1378-1383
Show summaryHide summaryBACKGROUND: The number of cases of all types of dementia is increasing, and a significant increase in prevalence has been noted among veterans. Evidence of an association between dementia and exposure to chemicals such as Agent Orange from the Vietnam War is still limited, and there is a reported lack of awareness.
OBJECTIVE: This study aimed to investigate the risk of dementia among Vietnam War veterans in Korea.
DESIGN: This retrospective longitudinal study compared the incidence of dementia between Vietnam War veterans and the general population.
SETTING: This study used data from the nationally representative Korean Vietnam War Veterans’ Health Study Cohort, a combined dataset sourced from the Ministry of Patriots and Veterans Affairs in Korea and the National Health Insurance Sharing Service database.
PARTICIPANTS: There were 191,272 Vietnam War veterans and 1,000,320 people of different ages, sexes, and residences. matched control in 2002. The total number of person-years were 18,543,181.
MEASUREMENTS: The dementia group included participants who had visited a medical facility with any of the following ICD-10 codes in the follow-up periods: “F00 Dementia in Alzheimer’s disease,” “F01 Vascular dementia,” “F02 Dementia in other diseases classified elsewhere,” or “F03 Unspecified dementia.”
RESULTS: The incidence rate ratio for all types of dementia was 1.16, with higher ratios observed for vascular and unspecified dementia, particularly in the younger age groups. There was a significant increase in the risk of dementia, Alzheimer’s disease, vascular dementia, and unspecified dementia.
CONCLUSION: Vietnam War veterans showed an increased risk for all types of dementia. These findings are hypothesized to be due to the effects of the chemicals used during the Vietnam War, which can cause a variety of neurodegenerative diseases. Further studies are warranted to investigate the potential health determinants related to the Vietnam War, focusing on the neurodegenerative effects.
CITATION:
W. Lee ; S. Lee ; S.-K. Kang ; W.-J. Choi ; (2024): Risk of Dementia in Korean Vietnam War Veterans. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.84
MEDICAL COSTS AND CAREGIVER BURDEN OF DELIVERING DISEASE-MODIFYING ALZHEIMER’S TREATMENTS WITH DIFFERENT DURATION AND ROUTE OF ADMINISTRATION
T. Ozawa, G. Franguridi, S. Mattke
J Prev Alz Dis 2024;5(11):1384-1389
Show summaryHide summaryBACKGROUND: Multiple disease modifying treatment for Alzheimer’s disease are currently in clinical development or have been recently approved for use. They have vastly different treatment properties but so far, little work has been done to quantify the impact of treatment properties on the treatment’s value in terms of medical and social care costs and caregiver burden.
OBJECTIVES: This study aims to analyze how the mode of treatment administration, treatment frequency and duration, and monitoring requirements affect the value of disease modifying treatments. In order to isolate these effects, we compare five hypothetical disease modifying treatments with equal efficacy and safety: (1) chronic bi-weekly intravenous infusion, (2) chronic four-weekly intravenous infusion, (3) 52 weeks fixed duration four-weekly intravenous infusion, (4) chronic subcutaneous injections, and (5) chronic oral prescription on their direct medical costs, caregiver burden, and preservation of treatment value.
DESIGN: Survey of Alzheimer’s disease treatment clinics and retrospective data analysis.
SETTING: United States.
MEASUREMENTS: Direct medical cost and caregiver burden of treatment administration and monitoring compared to gross treatment benefit.
RESULTS: Chronic bi-weekly infusion treatment had the highest direct medical cost ($45,208) and caregiver burden ($6,095), reducing the treatment value by 44%, while oral treatment with the lowest direct medical cost ($1,983) and caregiver burden ($457) reduced the treatment value by only 2%. Substantial caregiver burden was reported from the survey, with a reported average of 2.3 hours for an office visit and infusion, 44 minutes of round-trip travel time, and 78% of patients being accompanied by a caregiver for treatment.
CONCLUSION: Burden of chronic intravenous treatments exceed the gross medical and social care cost savings and value of caregiver benefit. The results suggest the need for less complex treatments that require fewer clinic visits to preserve the economic value of disease modifying treatments.
CITATION:
T. Ozawa ; G. Franguridi ; S. Mattke (2024): Medical Costs and Caregiver Burden of Delivering Disease-Modifying Alzheimer’s Treatments with Different Duration and Route of Administration. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.81
MENDELIAN RANDOMIZATION ANALYSIS TO ASSESS WHETHER MAGNETIC RESONANCE IMAGING SIGNS OF CEREBRAL SMALL VESSEL DISEASE CAN CAUSE COGNITIVE DECLINE AND DEMENTIA
L. Liu, Q. Shen, D. Zhang, Y. Bao, F. Xu, H. Huang, Y. Xu
J Prev Alz Dis 2024;5(11):1390-1396
Show summaryHide summaryOBJECTIVE: Cognitive decline and dementia have been linked to cerebral small vessel disease, so we explored using Mendelian randomization whether cerebral small vessel disease visible as 10 neuroimaging signs may cause cognitive decline and dementia.
METHODS: We analyzed publicly available data from genome-wide association studies using two-sample Mendelian randomization involving inverse variance weighting, weighted median, MR-Egger, and MR-PRESSO approaches.
RESULTS: Mendelian randomization suggested that cognitive decline can be caused by lacunar stroke (inverse variance weighting, β = -0.012, 95% CI -0.024 to -0.001, P = 0.033). Furthermore, an elevated burden of white matter hyperintensities was associated with an increased risk of Dementia due to Parkinson’s disease (inverse variance weighting, OR 2.035, 95% CI 1.105 to 3.745, P = 0.023). Notably, no significant associations were observed between neuroimaging markers of Cerebral Small Vessel Disease and other types of dementia.
CONCLUSION: This Mendelian randomization study provides evidence that lacunar stroke and white matter lesions can cause cognitive decline, and that white matter hyperintensity may increase risk of dementia due to Parkinson’s disease. These results underscore the need for further investigations into the neurocognitive effects of cerebral small vessel disease.
CITATION:
L. Liu ; Q. Shen ; D. Zhang ; Y. Bao ; F. Xu ; H. Huang ; Y. Xu (2024): Mendelian Randomization Analysis to Assess Whether Magnetic Resonance Imaging Signs of Cerebral Small Vessel Disease Can Cause Cognitive Decline and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.95
LOWER INCIDENCE OF DEMENTIA FOLLOWING CANCER DIAGNOSES: EVIDENCE FROM A LARGE COHORT AND MENDELIAN RANDOMIZATION STUDY
D.T. Bassil, B. Zheng, B. Su, D. Kafetsouli, C. Udeh-Momoh, I. Tzoulaki, S. Ahmadi-Abhari, D.C. Muller, E. Riboli, L.T. Middleton
J Prev Alz Dis 2024;5(11):1397-1405
Show summaryHide summaryBACKGROUND: The reported inverse association between cancer and subsequent Alzheimer’s disease and related dementias (ADRD) remains uncertain.
OBJECTIVES: To investigate the association between these common conditions of old age and explore possible causal factors.
DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We conducted a large population-based cohort analysis using data from 3,021,508 individuals aged 60 and over in the UK Clinical Practice Research Datalink (CPRD), over a period up to 30 years (1988-2018). Cox proportional hazards models were fitted to estimate hazard ratios (HR) for risk of dementia associated with previous cancer diagnosis. Competing risk models were employed to account for competing risk of death. Two-sample Mendelian Randomization analysis based on meta-analysis data from large-scale GWAS studies was also conducted.
RESULTS: In the CPRD cohort, 412,903 participants had cancer diagnosis and 230,558 were subsequently diagnosed with dementia over a median follow-up period of 7.9 years. Cancer survivors had a 25% lower risk of developing dementia (HR=0.75, 95% CI:0.74-0.76) after adjustment for potential confounders. Accounting for competing risk of death provided a sub-distribution HR of 0.56 (95% CI:0.55-0.56). Results were consistent for prevalent and incident cancer and different common cancer types. Two-sample Mendelian Randomization analysis, using 357 cancer-related instrumental single-nucleotide polymorphisms (SNPs) revealed evidence of vertical pleiotropy between genetically predicted cancer and reduced risk of Alzheimer’s disease (OR=0.97,95% CI:0.95-0.99).
CONCLUSION: Our results provide strong epidemiological evidence of the inverse association between cancer and risk of ADRD and support the potential causal nature of this association via genetic instruments. Further investigations into the precise underlying biological mechanisms may reveal valuable information for new therapeutic approaches.
CITATION:
D.T. Bassil ; B. Zheng ; B. Su ; D. Kafetsouli ; C. Udeh-Momoh ; I. Tzoulaki ; S. Ahmadi-Abhari ; D.C. Muller ; E. Riboli ; L.T. Middleton (2024): Lower Incidence of Dementia Following Cancer Diagnoses: Evidence from a Large Cohort and Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.135
ASSOCIATION BETWEEN FAMILY HOUSEHOLD INCOME AND COGNITIVE RESILIENCE AMONG OLDER US ADULTS: A CROSSSECTIONAL STUDY
M. Iskandar, J. Martindale, J.P.W. Bynum, M.A. Davis
J Prev Alz Dis 2024;5(11):1406-1409
Show summaryHide summaryCognitive resilience has emerged as a mechanism that may help explain individual differences in cognitive function associated with aging and/or pathology. It is unknown whether an association exists between family income level and cognitive resilience. We performed a cross-sectional study to estimate the relationship between family income level and high cognitive resilience using the National Health and Nutrition Examination Survey (NHANES) among older adults (age≥60). Logistic regression was used to estimate the association between income level and high cognitive resilience adjusted for other factors. Accounting for differences in education, occupation, and health status, older adults in the highest income category were twice as likely compared to those with very low income to have high cognitive resilience (OR: 1.90, 95% CI: 1.05,3.43). A doseresponse was apparent between income category and high cognitive resilience. The finding that income, above and beyond that of known factors, affects cognitive function is important for future public health strategies that aim to prevent or delay cognitive impairment.
CITATION:
M. Iskandar ; J. Martindale ; J.P.W. Bynum ; M.A. Davis (2024): Association between Family Household Income and Cognitive Resilience among Older US Adults: A Cross-Sectional Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.97
LATER-LIFE COGNITIVE TRAJECTORIES AND RISK OF DEATH: RESULTS FROM A 6-YEAR LONGITUDINAL STUDY OF 7082 CHINESE
Y. Zhao, W. Zhou, M. Xing, L. Zhang, Y. Tong, X. Lv, Y. Ma, W. Li
J Prev Alz Dis 2024;5(11):1410-1417
Show summaryHide summaryBACKGROUND AND OBJECTIVES: To identify cognitive decline trajectories in a Chinese elderly population, explore the associations between these trajectories and mortality, and further identify risk factors related to certain trajectories of cognitive decline.
DESIGN: Prospective cohort study.
SETTING: The group-based trajectory modeling and Cox proportional hazards models were conducted to explore the association between cognitive trajectory groups and mortality, while multinomial logistic regression models were constructed to estimate potential risk factors.
PARTICIPANTS: We included 7082 participants aged 65 years or above in three consecutive but non-overlapping cohorts of the Chinese Longitudinal Healthy Longevity Survey with the Chinese version of the Mini-Mental State Examination up to 6 years. Participants were subsequently followed for a median (IQR) of 2.89 (1.38-3.12) years to obtain their survival status and date of death.
MEASUREMENTS: Chinese version of the Mini-Mental State Examination was used to measure participants’ cognitive function.
RESULTS: Through use of group-based trajectory modeling, we determined three cognitive trajectory groups. Then, after adjusting for confounding factors, we found a monotonic and positive association between cognitive decline and mortality risk. Meanwhile, the association varied among elderly populations in different age groups and BMI categories, but did not differ by sex, smoking, drinking and exercising. Older seniors, females and those with poorer baseline cognitive function and less social participation tended to be more likely to be in the unfavorable trajectory groups.
CONCLUSION: We found that the faster the cognitive decline, the higher the mortality, especially among those aged 65-79 years and those overweight. Our findings suggested the importance of implement better monitoring of the cognitive function of the elderly population.
CITATION:
Y. Zhao ; W. Zhou ; M. Xing ; L. Zhang ; Y. Tong ; X. Lv ; Y. Ma ; W. Li ; (2024): Later-Life Cognitive Trajectories and Risk of Death: Results from a 6-Year Longitudinal Study of 7082 Chinese. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.96
ESTIMATING SOCIO-ECONOMIC STATUS FOR ALZHEIMER’S DISEASE TRIALS
D.M. Rentz, J.D. Grill, D.P. Molina-Henry, G.A. Jicha, M.S. Rafii, A. Liu, R.A. Sperling, P.S. Aisen, R. Raman
J Prev Alz Dis 2024;5(11):1418-1425
Show summaryHide summaryINTRODUCTION: Metrics of a participant’s socioeconomic status (SES) are not routinely collected or standardized in clinical trials. This omission limits the ability to evaluate the generalizability of trial results and restricts clinicians from confidently interpreting the efficacy of new treatments across important sub-populations.
METHODS: We adapted an SES measure of social disparity; the Hollingshead Two Factor Index of Social Position, which combines education and occupation into a single metric. We modernized the 1965 occupations to reflect the 2017 careers tabulated by the US Bureau of Labor Statistics. We currently use this adapted measure in Alzheimer’s Clinical Trials Consortium studies.
RESULTS: We present the revised table of occupations. We found that the collection of SES data using the modified Hollingshead was feasible in a multi-site clinical trial and scores were distributed across all SES strata.
DISCUSSION: The modified Hollingshead provides a standardized method for collecting SES information, enabling data aggregation, monitoring, and reporting.
CITATION:
D.M. Rentz ; J.D. Grill ; D.P. Molina-Henry ; G.A. Jicha ; M.S. Rafii ; A. Liu ; R.A. Sperling ; P.S. Aisen ; R. Raman (2024): Estimating Socio-Economic Status for Alzheimer’s Disease Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.88
ASSOCIATIONS OF BLOOD PRESSURE TRAJECTORIES WITH SUBSEQUENT COGNITIVE DECLINE, DEMENTIA AND MORTALITY
Y. Zhu, C. Li, D. Gao, X. Huang, Y. Zhang, M. Ji, F. Zheng, W. Xie
J Prev Alz Dis 2024;5(11):1426-1434
Show summaryHide summaryBACKGROUND: Hypertension may harm cognitive performance, but the potential correlates of longitudinal patterns of blood pressure (BP), especially diastolic BP (DBP), to cognition have been unclear.
OBJECTIVES: To examine long-term BP trajectories in relation to subsequent cognitive decline, incident dementia and all-cause mortality in the general population.
DESIGN: Population-based cohort study.
SETTING: Communities in England.
PARTICIPANTS: The study included 7566 participants from the English Longitudinal Study of Ageing (ELSA).
MEASUREMENTS: BP were measured in 1998, 2004, 2008. Group-based trajectory modeling was used to identify long-term patterns of systolic BP (SBP) and DBP. Outcomes including cognitive function, incident dementia, and all-cause mortality were followed up to 10 years.
RESULTS: Five distinct trajectories were identified for SBP and DBP, respectively. The normal-stable trajectory was used as the reference. For cognitive decline, both SBP and DBP trajectories were independently associated with subsequent cognitive decline, with the fastest decline appeared in the high-stable SBP group of 180 mmHg and the low-stable DBP group of 60 mmHg (both P<0.005). For incident dementia, the multivariable adjusted hazard ratio (HR) was also greatest in high-stable group (4.79, 95% confidence interval: 2.84 to 8.07) across all SBP trajectories. Conversely, low (HR: 1.58) and moderate-low stable (HR: 1.56) DBP trajectories increased dementia risk (both P<0.005). Similar patterns were found in BP trajectories in relation to all-cause mortality.
CONCLUSION: Our study evaluates the potential health impact from different BP trajectories and suggests that controlling long-term SBP and maintaining adequate DBP may be relevant for the current practice to promote cognitive health and extend lifespan.
CITATION:
Y. Zhu ; C. Li ; D. Gao ; X. Huang ; Y. Zhang ; M. Ji ; F. Zheng ; W. Xie ; (2024): Associations of Blood Pressure Trajectories with Subsequent Cognitive Decline, Dementia and Mortality. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.91
THE ALZMATCH PILOT STUDY - FEASIBILITY OF REMOTE BLOOD COLLECTION OF PLASMA BIOMARKERS FOR PRECLINICAL ALZHEIMER’S DISEASE TRIALS
S. Walter, O. Langford, G.A. Jimenez-Maggiora, S. Abdel-Latif, R.A. Rissman, J.D. Grill, J. Karlawish, A. Atri, S. Bruschi, K. Hussen, M.C. Donohue, G.A. Marshall, G. Jicha, M. Racke, R.S. Turner, C.H. van Dyck, V. Venkatesh, K.E. Yarasheski, R. Sperling, J. Cummings, P.S. Aisen, R. Raman
J Prev Alz Dis 2024;5(11):1435-1444
Show summaryHide summaryBACKGROUND: Advances in plasma biomarkers to detect Alzheimer’s disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimer’s Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD.
OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based phlebotomy centers and plasma biomarker quantification to assess an individual’s eligibility for AD preclinical trials.
DESIGN: Pilot feasibility study with co-primary outcomes.
SETTING: This pilot feasibility study included participants from the APT Webstudy, the remote assessment arm of the Trial-ready cohort for Preclinical and Prodromal AD (TRC-PAD) Platform. Novel design included collection of electronic consent, use of community laboratories for plasma collection, mass spectrometry-based biomarker assay, and telephone communication of plasma biomarker screening eligibility.
PARTICIPANTS: Participants invited to the AlzMatch pilot feasibility study were active in the APT Webstudy, 50 years of age or older, resided within 50 miles of both a Quest Diagnostics Patient Services Center (a national diagnostic laboratory with convenient locations for sample collection and processing) and one of six TRC-PAD vanguard clinical trial sites, had no self-reported dementia diagnosis, were able to communicate in English and engaged with the APT Webstudy within the prior 6 months.
MEASUREMENTS: Primary feasibility outcomes were completion of electronic consent (e-consent) for invited participants and collection of usable blood samples. Additional feasibility outcomes included invitation response rate, plasma biomarker eligibility status (based on amyloid beta-42/40 [Aβ42/40] concentration ratio), ApoE proteotype, and trial inclusion criterion), and completion of telephone contact to learn eligibility to screen for a study.
RESULTS: 300 APT Webstudy participants were invited to consent to the AlzMatch study. The AlzMatch e-consent rate was 39% (n=117) (95% CI of 33.5%-44.5%) overall, which was higher than the expected rate of 25%. Similar consent rates were observed across participants based on self-defined sex (41% Female (n=75), 37% Male (n=42)) and race and ethnicity (37% from underrepresented groups (URG) (n=36), 40% not from URG (n=79)). Among those that consented (n=117), plasma was successfully collected from 74% (n=87) (95% CI of 66%-82%), with similar rates across sex (76% Female (n=57), 71% Male (n=30)) and race and ethnicity (75% URG (n=27) and 75% not from URG (n=59)). 60% (n=51) of participants with plasma biomarker results were eligible to screen for future preclinical AD trials.
CONCLUSION: Electronic consent of participants through an online registry, blood sample collection at community-based centers, plasma biomarker quantification and reporting, and biomarker assessments for study eligibility were all feasible with similar engagement rates across demographic groups. Although this pilot was a small and selective sample, participants engaged and consented at higher than expected rates. We conclude that collecting blood at community laboratories for biomarker analyses may improve accessibility beyond research, and may facilitate broader access for clinical use of AD plasma biomarkers. Based on our results, an expanded version of the AlzMatch study is underway, which involves expanding invitations to additional APT Webstudy participants and clinical trial sites.
CITATION:
S. Walter ; O. Langford ; G.A. Jimenez-Maggiora ; S. Abdel-Latif ; R.A. Rissman ; J.D. Grill ; J. Karlawish ; A. Atri ; S. Bruschi ; K. Hussen ; M.C. Donohue ; G.A. Marshall ; G. Jicha ; M. Racke ; R.S. Turner ; C.H. van Dyck ; V. Venkatesh ; K.E. Yarasheski ; R. Sperling ; J. Cummings ; P.S. Aisen ; R. Raman (2024): The AlzMatch Pilot Study - Feasibility of Remote Blood Collection of Plasma Biomarkers for Preclinical Alzheimer’s Disease Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.101
HEIGHTENED PREVALENCE OF COMMON HOSPITAL-TREATED INFECTIONS PRECEDING DEMENTIA DIAGNOSIS WITH ACCELERATED DEMENTIA ONSET AFTER INFLUENZA
H. Untersteiner, R. Wurm, B. Reichardt, S. Goeschl, E. Berger-Sieczkowski, T. König, T. Parvizi, S. Silvaieh, E. Stögmann
J Prev Alz Dis 2024;5(11):1445-1454
Show summaryHide summaryBACKGROUND: Since the beginning of Alzheimer’s disease research, the hypothesis that infections are to some extent associated with neurodegenerative processes has been tested repeatedly. Epidemiological studies on the associations between infections and dementia have reported conflicting results.
OBJECTIVES: This study analyses common hospital-treated infections (herpes, influenza, intestinal infections, pneumonia, sepsis, urinary tract infections) and their association with subsequent dementia and time until dementia onset.
DESIGN, SETTING, AND PARTICIPANTS: For this nationwide population-based case-control study, the dataset of the Austrian National Health Insurance Association was used, including dementia patients (dementia cohort) and age- and gender-matched non-demented individuals (control cohort). Only subjects with data availability of at least 10 years prior to the index date (date of dementia diagnosis or date of censoring) were included.
MEASUREMENTS: The incidence of six common infections in older adults (herpes, influenza, intestinal infections, pneumonia, sepsis, and urinary tract infections) was analyzed over a period of 10 years before the censoring date.
RESULTS: The study population consists of 58208 subjects (29104 per study cohort), mean age: 81 years, 54% females. Patients of the dementia cohort had suffered from infections significantly more often than patients of the control cohort (6002, 20.6% vs. 4826, 16.6%; p < 0.001). Influenza, urinary tract infections, intestinal infections, and sepsis showed independent positive associations with subsequent dementia diagnosis, irrespective of other comorbidities (odds ratios: 1.26 (95% CI: 1.06-1.49), 1.23 (95% CI: 1.16-1.30), 1.16 (95% CI: 1.07-1.27), 1.17 (95% CI: 1.01-1.37), respectively). Time from infection to dementia diagnosis was shorter after influenza compared to all other infections (median: 3.4 years (95% CI: 3.1-3.7) vs. 6.6 years (95% CI: 6.4-6.8); p < 0.001).
CONCLUSION: This is the first study to assess the association between infections and dementia over such a long minimum reporting period. These results, supported by consistent data from other epidemiological studies, emphasize the critical importance of infection prevention measures, especially for older adults. Further research is crucial to better understand the nature of the relationship between infections and dementia.
CITATION:
H. Untersteiner ; R. Wurm ; B. Reichardt ; S. Goeschl ; E. Berger-Sieczkowski ; T. König ; T. Parvizi ; S. Silvaieh ; E. Stögmann (2024): Heightened Prevalence of Common Hospital-Treated Infections Preceding Dementia Diagnosis with Accelerated Dementia Onset after Influenza. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.92
VALIDATION OF A COMMUNITY-BASED APPROACH TOWARD PERSONALIZED DEMENTIA RISK REDUCTION: THE KIMEL FAMILY CENTRE FOR BRAIN HEALTH AND WELLNESS
N.D. Anderson, D. D’Amico, S. Rotenberg, D.R. Addis, J. Gillen, D. Moore, J.A. Furlano, B. Tan, M. Binns, M. Santarossa, H. Chertkow, for the Canadian Consortium on Neurodegeneration in Aging (CCNA) CAN-THUMBS UP Study Group
J Prev Alz Dis 2024;5(11):1455-1466
Show summaryHide summaryBACKGROUND/OBJECTIVES: The Kimel Family Centre for Brain Health and Wellness is a research-driven community centre testing the efficacy of personalized dementia risk reduction programming on dementia risk and cognition. The objective of this protocol is to validate this approach by following people for two years.
DESIGN/SETTING: Participants will receive a comprehensive dementia risk assessment, including nonmodifiable and modifiable risk factors, from which they will receive a Personalized Dementia Risk Report and Program Strategy, indicating their health conditions increasing and their risk level in five modifiable risk domains: physical activity, brain-healthy eating, cognitive engagement, social connections, and mental wellbeing. Equipped with this information, participants will enroll in programs within the Centre to address their risk factors. Changes to their dementia risk, cognition, and Personalized Program Strategy will be communicated through re-assessments of risk factors every six months (risk and cognition) and every year (comprehensive assessment).
PARTICIPANTS: Participants (n = 450) will be 50 years of age or older, without a diagnosis of dementia, and sufficiently fluent in English to complete the assessments and understand program instructors. One goal is that our participant sample will include people of low income (with fundraising providing free community centre membership), and from various ethno-racial backgrounds.
INTERVENTION: Participants will select programs to meet their Personalized Program Strategy. For physical activity, they will gradually work toward the Canadian Society for Exercise Physiology guidelines. For brain-healthy eating, they will learn about the Brain Health Food Guide and food label reading, and then take additional programs. For cognitive engagement and mental wellbeing, they will take at least one hour of relevant programming per week. Social connections will be reinforced throughout all programs. All participants will also have access to the Canadian Consortium on Neurodegeneration’s CAN-THUMBS Up online, educational program on modifiable dementia risk factors, called Brain Health PRO.
MEASUREMENTS: The comprehensive assessment includes numerous dementia risk factors, but the primary measures are risk in the five domains, health conditions proximal to those five risk domains, and cognition, and how these are affected by adherence and quality of goal-directed future simulation. We hypothesize a reduced risk in the five domains within six months, improvements in health biomarkers within a year, and maintenance of cognition within two years, with these benefits accruing with greater adherence, but only up to a point, at which benefits will plateau, and greater benefits among participants whose goal-directed simulations are more vivid, personally-relevant, achievable, and positive.
CONCLUSIONS: This innovative approach overcomes a number of limitations present in prior multidomain dementia prevention trials. Adapting a preference clinical trial that is embedded in a community centre, where participants have autonomy to choose programs to address their modifiable dementia risk factors, has real-world applicability in the global effort to reduce dementia risk.
CITATION:
N.D. Anderson ; D. D’Amico ; S. Rotenberg ; D.R. Addis ; J. Gillen ; D. Moore ; J.A. Furlano ; B. Tan ; M. Binns ; M. Santarossa ; H. Chertkow ; for the Canadian Consortium on Neurodegeneration in Aging (CCNA) CAN-THUMBS UP Study Group (2024): Validation of a Community-Based Approach Toward Personalized Dementia Risk Reduction: The Kimel Family Centre for Brain Health and Wellness. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.98
CONTINUOUS ASSOCIATIONS BETWEEN REMOTE SELFADMINISTERED COGNITIVE MEASURES AND IMAGING BIOMARKERS OF ALZHEIMER’S DISEASE
E.A. Boots, R.D. Frank, W.Z. Fan, T.J. Christianson, W.K. Kremers, J.L. Stricker, M.M. Machulda, J.A. Fields, J. Hassenstab, J. Graff-Radford, P. Vemuri, C.R. Jack, D.S. Knopman, R.C. Petersen, N.H. Stricker
J Prev Alz Dis 2024;5(11):1467-1479
Show summaryHide summaryBACKGROUND: Easily accessible and self-administered cognitive assessments that can aid early detection for Alzheimer’s disease (AD) dementia risk are critical for timely intervention.
OBJECTIVES/DESIGN: This cross-sectional study investigated continuous associations between Mayo Test Drive (MTD) – a remote, self-administered, multi-device compatible, web-based cognitive assessment – and AD-related imaging biomarkers.
PARTICIPANTS/SETTING: 684 adults from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center participated (age=70.4±11.2, 49.7% female). Participants were predominantly cognitively unimpaired (CU; 94.0%).
MEASUREMENTS: Participants completed (1) brain amyloid and tau PET scans and MRI scans for hippocampal volume (HV) and white matter hyperintensities (WMH); (2) MTD remotely, consisting of the Stricker Learning Span and Symbols Test which combine into an MTD composite; and (3) in-person neuropsychological assessment including measures to obtain Mayo Preclinical Alzheimer’s disease Cognitive Composite (Mayo-PACC) and Global-z. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers and scores from remote and in-person cognitive measures.
RESULTS: Lower performances on MTD were associated with greater amyloid, entorhinal tau, and global tau PET burden, lower HV, and higher WMH. Mayo-PACC and Global-z were associated with all imaging biomarkers except global tau PET burden. MCI/Dementia participants showed lower performance on all MTD measures compared to CU with large effect sizes (Hedge’s g’s=1.65-2.02), with similar findings for CU versus MCI only (Hedge’s g’s=1.46-1.83).
CONCLUSION: MTD is associated with continuous measures of AD-related imaging biomarkers, demonstrating ability to detect subtle cognitive change using a brief, remote assessment in predominantly CU individuals and criterion validity for MTD.
CITATION:
E.A. Boots ; R.D. Frank ; W.Z. Fan ; T.J. Christianson ; W.K. Kremers ; J.L. Stricker ; M.M. Machulda ; J.A. Fields ; J. Hassenstab ; J. Graff-Radford ; P. Vemuri ; C.R. Jack ; D.S. Knopman ; R.C. Petersen ; N.H. Stricker (2024): Continuous Associations between Remote Self-Administered Cognitive Measures and Imaging Biomarkers of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.99
DIGITAL HEALTH TECHNOLOGIES FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS: INITIAL RESULTS FROM A LANDSCAPE ANALYSIS AND COMMUNITY COLLABORATIVE EFFORT
S.A. Lott, E. Streel, S.L. Bachman, K. Bode, J. Dyer, C. Fitzer-Attas, J.C. Goldsack, A. Hake, A. Jannati, R.S. Fuertes, P. Fromy
J Prev Alz Dis 2024;5(11):1480-1489
Show summaryHide summaryDigital health technologies offer valuable advantages to dementia researchers and clinicians as screening tools, diagnostic aids, and monitoring instruments. To support the use and advancement of these resources, a comprehensive overview of the current technological landscape is essential. A multi-stakeholder working group, convened by the Digital Medicine Society (DiMe), conducted a landscape review to identify digital health technologies for Alzheimer’s disease and related dementia populations. We searched studies indexed in PubMed, Embase, and APA PsycInfo to identify manuscripts published between May 2003 to May 2023 reporting analytical validation, clinical validation, or usability/feasibility results for relevant digital health technologies. Additional technologies were identified through community outreach. We collated peer-reviewed manuscripts, poster presentations, or regulatory documents for 106 different technologies for Alzheimer’s disease and related dementia assessment covering diverse populations such as Lewy Body, vascular dementias, frontotemporal dementias, and all severities of Alzheimer’s disease. Wearable sensors represent 32% of included technologies, non-wearables 61%, and technologies with components of both account for the remaining 7%. Neurocognition is the most prevalent concept of interest, followed by physical activity and sleep. Clinical validation is reported in 69% of evidence, analytical validation in 34%, and usability/feasibility in 20% (not mutually exclusive). These findings provide clinicians and researchers a landscape overview describing the range of technologies for assessing Alzheimer’s disease and related dementias. A living library of technologies is presented for the clinical and research communities which will keep findings up-to-date as the field develops.
CITATION:
S.A. Lott ; E. Streel ; S.L. Bachman ; K. Bode ; J. Dyer ; C. Fitzer-Attas ; J.C. Goldsack ; A. Hake ; A. Jannati ; R.S. Fuertes ; P. Fromy (2024): Digital Health Technologies for Alzheimer’s Disease and Related Dementias: Initial Results from a Landscape Analysis and Community Collaborative Effort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.103
POTENTIALLY MODIFIABLE DEMENTIA RISK FACTORS IN CANADA: AN ANALYSIS OF CANADIAN LONGITUDINAL STUDY ON AGING WITH A MULTI-COUNTRY COMPARISON
S. Son, M. Speechley, G.Y. Zou, M. Kivipelto, F. Mangialasche, H.H. Feldman, H. Chertkow, S. Belleville, H. Nygaard, V. Hachinski, F. Pieruccini-Faria, M. Montero-Odasso
J Prev Alz Dis 2024;5(11):1490-1499
Show summaryHide summaryBACKGROUND: It has been suggested that up to 40% of dementia cases worldwide are associated with modifiable risk factors; however, these estimates are not known in Canada. Furthermore, sleep disturbances, an emerging factor, has not been incorporated into the life-course model of dementia prevention.
OBJECTIVE: To estimate the population impact of 12 modifiable risk factors in Canadian adults including sleep disturbances, by sex and age groups, and to compare with other countries.
DESIGN: Cross-sectional analysis of Canadian Longitudinal Study on Aging baseline data.
SETTING: Community.
PARTICIPANTS: 30,097 adults aged 45 years and older.
MEASUREMMENTS: Prevalence and Population Attributable Fractions (PAFs) associated with less education, hearing loss, traumatic brain injury, hypertension, excessive alcohol, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and sleep disturbances.
RESULTS: The risk factors with the largest PAF were later life physical inactivity (10.2%; 95% CI, 6.8% to 13%), midlife hearing loss (6.5%; 3.7% to 9.3%), midlife obesity (6.4%; 4.1% to 7.7%), and midlife hypertension (6.2%; 2.7% to 9.3%). The PAF of later life sleep disturbances was 3.0% (95% CI, 1.8% to 3.8%). The 12 risk factors accounted for 51.9% (32.2% to 68.0%) of dementia among men and 52.4% (32.5% to 68.7%) among women. Overall, the combined PAF of all risk factors was 49.2% (31.1% to 64.9%), and it increased with age.
CONCLUSION: Nearly up to 50% of dementia cases in Canada are attributable to 12 modifiable risk factors across the lifespan. Canadian risk reduction strategies should prioritize targeting physical inactivity, hearing loss, obesity, and hypertension.
CITATION:
S. Son ; M. Speechley ; G.Y. Zou ; M. Kivipelto ; F. Mangialasche ; H.H. Feldman ; H. Chertkow ; S. Belleville ; H. Nygaard ; V. Hachinski ; F. Pieruccini-Faria ; M. Montero-Odasso (2024): Potentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.105
A PILOT STUDY OF BRAIN BOOTCAMP, A LOW-INTENSITY INTERVENTION ON DIET, EXERCISE, COGNITIVE ACTIVITY, AND SOCIAL INTERACTION TO IMPROVE OLDER ADULTS’ DEMENTIA RISK SCORES
J. Siette, L. Dodds, K. Deckers, S. Köhler, I. Heger, P. Strutt, C. Johnco, V. Wuthrich, C.J. Armitage
J Prev Alz Dis 2024;5(11):1500-1512
Show summaryHide summaryBACKGROUND: Little is known about the impact of short, low-intensity multidomain dementia risk reduction interventions in older adults.
OBJECTIVES: To examine the effectiveness and feasibility of a low-intensity multidomain lifestyle intervention on dementia risk and dementia literacy in Australian older adults.
DESIGN: Single-group pre-post design.
SETTING: Community-dwelling.
PARTICIPANTS: A total of 853 older Australians (Mean age=73.3 years, SD=6.1) recruited from the community.
INTERVENTION: A 3-month dementia risk reduction program, BRAIN BOOTCAMP, including education, personalised risk information, physical cues for healthier choices and goal setting and planning to target four modifiable risk factors of diet, exercise, cognitive activity and social interaction in older adults.
MEASUREMENTS: The ‘LIfestyle for BRAin health’ (LIBRA) index was used to assess participants’ modifiable dementia risk based on 12 factors, with higher scores indicating greater risk. Dementia literacy was measured using a modified questionnaire derived from Dutch and British surveys, encompassing knowledge, risk reduction, and awareness aspects. Paired t-tests were used to compare dementia risk scores and dementia literacy before and after the program. Multivariate regressions were performed to identify sociodemographic and psychological factors associated with change in the LIBRA index.
RESULTS: Program attrition was high (58.3%). Participants who completed the program had decreased dementia risk scores (Cohen’s d=0.59, p<0.001), increased dementia literacy and awareness (Cohen’s d=0.64, p<0.001) and increased motivation to change lifestyle behaviors (Cohen’s d=0.25-0.52, p<0.016). Participants with higher motivational beliefs had greater dementia risk reduction.
CONCLUSIONS: Improving older adults’ motivation and knowledge may help modify lifestyle behaviors to reduce dementia risk. However, program attrition remains a challenge, suggesting the need for strategies to enhance participant engagement and retention in such interventions.
CITATION:
J. Siette ; L. Dodds ; K. Deckers ; S. Köhler ; I. Heger ; P. Strutt ; C. Johnco ; V. Wuthrich ; C.J. Armitage (2024): A Pilot Study of BRAIN BOOTCAMP, a Low-Intensity Intervention on Diet, Exercise, Cognitive Activity, and Social Interaction to Improve Older Adults’ Dementia Risk Scores. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.104
INDEPENDENT AND JOINT ASSOCIATIONS OF SOCIOECONOMIC STATUS AND LIFESTYLE BEHAVIORS WITH COGNITIVE IMPAIRMENT AMONG ELDERLY CHINESE POPULATION
Y. Feng, S. Jia, W. Zhao, X. Wu, Y. Zuo, S. Wang, L. Zhao, M. Ma, X. Guo, C.S. Tarimo, Y. Miao, J. Wu
J Prev Alz Dis 2024;5(11):1513-1522
Show summaryHide summaryBACKGROUND: Numerous studies have shown that there are socioeconomic disparities in people’s health. Health behavior is considered to be an effective strategy to alleviate socio-economic differences. However, the independent or joint relationship between socioeconomic status (SES) and lifestyle behaviors (LBs) on the cognition of Chinese elderly are not clear. Therefore, this study aimed to reveal the impact of SES and LBs on cognitive impairment in elder Chinese.
METHODS: The data from the 2017-2018 wave of Chinese Longitudinal Healthy Longevity Survey was used. SES was created using latent class analysis based on annual per-capita household income, education level, and occupation. Six LBs were considered in calculating LB scores. Restricted cubic splines were used to model the association of LB scores and cognitive impairment to investigate the dose-response relationship. LB scores were divided into three groups: unhealthy, intermediate, and healthy lifestyle. Multivariate Logistic regression models were applied to explore both the independent and joint effects of SES and LB scores on cognitive impairment.
RESULTS: Among 10,116 participants, 1,872 (18.51%) were recorded as having cognitive impariment. After adjusting for multivariable confounding factors, compared with participants of high SES, those of low SES had higher risks of cognitive impairment [Odds ratio (OR): 1.385; 95% confidence interval (CI): 1.137-1.689]. In contrast to those with unhealthy lifestyle, participants adhering to a healthy lifestyle were found to be associated with a reduced risk of cognitive impairment (OR: 0.198; 95%CI: 0.150-0.263). A non-linear relationship was observed between LB scores and cognitive impairment (Pnonlinearity =0.001), indicating a protective effect on cognitive impairment when having more than two LBs. Participants with high SES and engaged in healthy lifestyle had the lowest risk of cognitive impairment compared to those with low SES and unhealthy lifestyle (OR: 0.123; 95% CI 0.073-0.207).
CONCLUSION: Cognitive impairment has socioeconomic disparities among the elderly Chinese population. A healthy lifestyle may attenuate the impact of socioeconomic inequality on cognitive impairment, emphasizing the important role of LBs modification in reducing the disease burden of cognitive impairment, especially in the elderly population with low SES.
CITATION:
Y. Feng ; S. Jia ; W. Zhao ; X. Wu ; Y. Zuo ; S. Wang ; L. Zhao ; M. Ma ; X. Guo ; C.S. Tarimo ; Y. Miao ; J. Wu ; (2024): Independent and Joint Associations of Socioeconomic Status and Lifestyle behaviors with Cognitive Impairment among Elderly Chinese Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.127