Ahead of print articles
JPAD Volume 11, N°04 - 2024
EDITORIAL: INTRODUCTION TO THE SPECIAL ISSUE ON THE A4 STUDY
P. Aisen, R. Sperling
J Prev Alz Dis 2024;4(11):801
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CITATION:
P. Aisen ; R. Sperling ; (2024): Editorial: Introduction to the Special Issue on the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.118
AMYLOID AND TAU PREDICTION OF COGNITIVE AND FUNCTIONAL DECLINE IN UNIMPAIRED OLDER INDIVIDUALS: LONGITUDINAL DATA FROM THE A4 AND LEARN STUDIES
R.A. Sperling, M.C. Donohue, R.A. Rissman, K.A. Johnson, D.M. Rentz, J.D. Grill, J.L. Heidebrink, C. Jenkins, G. Jimenez-Maggiora, O. Langford, A. Liu, R. Raman, R. Yaari, K.C. Holdridge, J.R. Sims, P.S. Aisen, for the A4 and LEARN Study Teams
J Prev Alz Dis 2024;4(11):802-813
Show summaryHide summaryBACKGROUND: Converging evidence suggests that markers of Alzheimer’s disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes.
OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay.
DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks.
SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia.
PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553).
MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo).
RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models.
CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.
CITATION:
R.A. Sperling ; M.C. Donohue ; R.A. Rissman ; K.A. Johnson ; D.M. Rentz ; J.D. Grill ; J.L. Heidebrink ; C. Jenkins ; G. Jimenez-Maggiora ; O. Langford ; A. Liu ; R. Raman ; R. Yaari ; K.C. Holdridge ; J.R. Sims ; P.S. Aisen ; for the A4 and LEARN Study Teams ; (2024): Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.122
CHARACTERIZING CLINICAL PROGRESSION IN COGNITIVELY UNIMPAIRED OLDER INDIVIDUALS WITH BRAIN AMYLOID: RESULTS FROM THE A4 STUDY
D.M. Rentz, P.B. Rosenberg, R.A. Sperling, M.C. Donohue, R. Raman, A. Liu, P.S. Aisen, and on behalf of the A4 study team
J Prev Alz Dis 2024;4(11):814-822
Show summaryHide summaryBACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.
OBJECTIVES: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) secondary prevention study.
DESIGN: All participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.
SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.
PARTICIPANTS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.
MEASUREMENTS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.
RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.
CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.
CITATION:
D.M. Rentz ; P.B. Rosenberg ; R.A. Sperling ; M.C. Donohue ; R. Raman ; A. Liu ; P.S. Aisen ; and on behalf of the A4 study team ; (2024): Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.123
LONGITUDINAL PHOSPHO-TAU217 PREDICTS AMYLOID POSITRON EMISSION TOMOGRAPHY IN ASYMPTOMATIC ALZHEIMER’S DISEASE
R.A. Rissman, M.C. Donohue, O. Langford, R. Raman, S. Abdel-Latif, R. Yaari, K.C. Holdridge, J.R. Sims, D. Molina-Henry, G. Jimenez-Maggiora, K.A. Johnson, P.S. Aisen, R.A. Sperling, for the A4 and LEARN Study teams
J Prev Alz Dis 2024;4(11):823-830
Show summaryHide summaryBACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool.
OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals.
SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.
PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study.
INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention.
MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL.
RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)).
CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.
CITATION:
R.A. Rissman ; M.C. Donohue ; O. Langford ; R. Raman ; S. Abdel-Latif ; R. Yaari ; K.C. Holdridge ; J.R. Sims ; D. Molina-Henry ; G. Jimenez-Maggiora ; K.A. Johnson ; P.S. Aisen ; R.A. Sperling ; for the A4 and LEARN Study teams ; (2024): Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.134
RELATIONSHIP BETWEEN PLASMA P-TAU217 AND AMYLOID PET IN RACIAL AND ETHNIC UNDERREPRESENTED GROUPS (REURG) COMPARED WITH NON RE-URG IN LEARN AND A4
D. Molina-Henry, O. Langford, M.C. Donohue, R. Raman, P. Aisen, K.A. Johnson, R.A. Rissman, R. Sperling, and the A4 & LEARN Study Teams
J Prev Alz Dis 2024;4(11):831-837
Show summaryHide summarygroups are severely underrepresented in Alzheimer’s disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aβ pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults.
OBJECTIVES: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer’s disease (A4) preclinical AD studies.
DESIGN: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity.
SETTING: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada.
PARTICIPANTS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification.
MEASUREMENTS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status.
RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR.
CONCLUSION: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.
CITATION:
D. Molina-Henry ; O. Langford ; M.C. Donohue ; R. Raman ; P. Aisen ; K.A. Johnson ; R.A. Rissman ; R. Sperling ; and the A4 & LEARN Study Teams ; (2024): Relationship between Plasma P-Tau217 and Amyloid PET in Racial and Ethnic Underrepresented Groups (RE-URG) Compared with Non RE-URG in LEARN and A4. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.124
LONGITUDINAL TRAJECTORIES OF THE COGNITIVE FUNCTION INDEX IN THE A4 STUDY
R.E. Amariglio, J.D. Grill, D.M. Rentz, G.A. Marshall, M.C. Donohue, A. Liu, P.S. Aisen, R.A. Sperling, and the A4 Study team
J Prev Alz Dis 2024;4(11):838-845
Show summaryHide summaryBACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period.
OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study.
DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally.
SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States.
PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab.
MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined.
RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile.
CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.
CITATION:
R.E. Amariglio ; J.D. Grill ; D.M. Rentz ; G.A. Marshall ; M.C. Donohue ; A. Liu ; P.S. Aisen ; R.A. Sperling ; and the A4 Study team4 ; (2024): Longitudinal Trajectories of the Cognitive Function Index in the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.125
CHANGE IN DIGITAL COGNITIVE TEST PERFORMANCE BETWEEN SOLANEZUMAB AND PLACEBO GROUPS IN PRECLINICAL ALZHEIMER’S DISEASE: SECONDARY ANALYSES FROM THE A4 STUDY
K.V. Papp, P. Maruff, D.M. Rentz, M.C. Donohue, A. Liu, P.S. Aisen, R.A. Sperling, on behalf of the A4 Study Team
J Prev Alz Dis 2024;4(11):846-856
Show summaryHide summaryBACKGROUND: Primary results from the Anti-Amyloid in Asymptomatic Alzheimer’s disease Study (A4) suggested no benefit of solanezumab on its primary cognitive outcome, a composite of paper and pencil tests (the Preclinical Alzheimer’s Cognitive Composite; PACC).
OBJECTIVE: To determine whether change in cognitive performance, assessed using the Computerized Cognitive Composite (C3) summary score and C3 individual tests, differed between treatment groups over 240 weeks, differed based on baseline Aβ burden, and tracked with PACC decline.
DESIGN: Longitudinal analysis of cognitive change over 240 weeks on the C3 Summary Score and C3 individual tests between participants randomly assigned to solanezumab at a dose of up to 1600 mg intravenously every 4 weeks versus placebo.
SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.
PARTICIPANTS: Cognitively unimpaired older adults (n=1117, Mean Age=71.9, 60.7% female) with elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) at baseline (n=549 in the solanezumab group; n=568 in the placebo group).
MEASUREMENTS: Participants completed the C3 battery and PACC every 6 months. The C3 Summary Score combines the Cogstate Brief Battery (CBB)-One Card Learning, the Behavioral Pattern Separation (BPS) Test- Object- Lure Discrimination Index, and the Face Name Associative Memory Exam (FNAME)- Face-Name Matching.
RESULTS: Change on the C3 Summary Score was moderately correlated with change on the PACC (Spearman’s corr=0.53, 95% CI: 0.49 to 0.57; p<0.001). At 240 weeks, mean change in the C3 Summary Score did not differ between groups; +0.24 in the solanezumab group and +0.27 in the placebo group (mean difference= −0.02; 95% CI: −0.13 to 0.08; p = 0.650). Lack of a treatment effect was similarly observed across most individual C3 tests. Performance on the C3 tests were influenced by level of amyloid burden, where higher levels were associated with worse performance.
CONCLUSION: This study provides corroborating evidence that solanezumab does not slow cognitive decline in preclinical AD as exhibited with a computerized cognitive assessment with some evidence that solanezumab may exacerbate cognition on select digital outcomes. This study also provides important information that amyloid related cognitive change manifests differently on individual C3 tests.
CITATION:
K.V. Papp ; P. Maruff ; D.M. Rentz ; M.C. Donohue ; A. Liu ; P.S. Aisen ; R.A. Sperling ; on behalf of the A4 Study Team ; (2024): Change in Digital Cognitive Test Performance between Solanezumab and Placebo Groups in Preclinical Alzheimer’s Disease: Secondary Analyses from the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.137
SAFETY PROFILE OF A COGNITIVELY UNIMPAIRED OLDER POPULATION WITH ELEVATED CEREBRAL AMYLOID IN A 4.5- YEAR CLINICAL TRIAL
R. Yaari, K.C. Holdridge, M. Mancini, M.S. Rafii, M. Case, C. Battioui, J.R. Sims, P.S. Aisen, R.A. Sperling, A4 Study Team
J Prev Alz Dis 2024;4(11):857-868
Show summaryHide summaryBACKGROUND: Preclinical Alzheimer’s disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer’s disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.
OBJECTIVES: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.
DESIGN: Phase 3, 4.5-year, multicenter, placebo-controlled trial.
SETTING: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.
PARTICIPANTS: Enrolled participants were aged 65–85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25–30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6–18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.
MEASUREMENTS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).
RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2–0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2–0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4–12.5), fall (incidence rate=7.7; 95% confidence interval=6.6–9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8–6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0–2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3–1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6–494.4; adjusted p<0.001).
CONCLUSION: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer’s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer’s disease.
CITATION:
R. Yaari ; K.C. Holdridge ; M. Mancini ; M.S. Rafii ; M. Case ; C. Battioui ; J.R. Sims ; P.S. Aisen ; R.A. Sperling ; A4 Study Team ; (2024): Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.138
GREATER WHITE MATTER HYPERINTENSITY VOLUME IS ASSOCIATED WITH THE NUMBER OF MICROHEMORRHAGES IN PRECLINICAL ALZHEIMER’S DISEASE
Z. Shirzadi, A.P. Schultz, M. Properzi, R. Yaari, W.-Y.W. Yau, A.M. Brickman, M.S. Rafii, M.C. Donohue, K. Ernstrom, S. Wang, C.R. Jack Jr, S.M. Greenberg, R. Raman, P. Aisen, R.A. Sperling, J.P. Chhatwal, and the A4 Study teams
J Prev Alz Dis 2024;4(11):869-873
Show summaryHide summaryBACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer’s disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH).
OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial.
DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period.
SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.
PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers).
MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group.
RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH.
CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.
CITATION:
Z. Shirzadi ; A.P. Schultz ; M. Properzi ; R. Yaari ; W.-Y.W. Yau ; A.M. Brickman ; M.S. Rafii ; M.C. Donohue ; K. Ernstrom ; S. Wang ; C.R. Jack Jr ; S.M. Greenberg ; R. Raman ; P. Aisen ; R.A. Sperling ; J.P. Chhatwal ; and the A4 Study teams ; (2024): Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.139
PRE-RANDOMIZATION PREDICTORS OF STUDY DISCONTINUATION IN A PRECLINICAL ALZHEIMER’S DISEASE RANDOMIZED CONTROLLED TRIAL
R. Raman, K. Hussen, M.C. Donohue, K. Ernstrom, K.C. Holdridge, O. Langford, D.P. Molina-Henry, A.L. Pierce, J.R. Sims, A. Smith, R. Yaari, P.S. Aisen, R. Sperling, J.D. Grill, and the A4 Study Team
J Prev Alz Dis 2024;4(11):874-880
Show summaryHide summaryBACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment.
OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.
DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers).
SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic.
PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants.
MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.
RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout.
CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.
CITATION:
R. Raman ; K. Hussen ; M.C. Donohue ; K. Ernstrom ; K.C. Holdridge ; O. Langford ; D.P. Molina-Henry ; A.L. Pierce ; J.R. Sims ; A. Smith ; R. Yaari ; P.S. Aisen ; R. Sperling ; J.D. Grill ; and the A4 Study Team (2024): Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer’s Disease Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.136
LEFT FRONTOPARIETAL CONTROL NETWORK CONNECTIVITY MODERATES THE EFFECT OF AMYLOID ON COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE: THE A4 STUDY
R. Boyle, H.M. Klinger, Z. Shirzadi, G.T. Coughlan, M. Seto, M.J. Properzi, D.L. Townsend, Z. Yuan, C. Scanlon, R.J. Jutten, K.V. Papp, R.E. Amariglio, D.M. Rentz, J.P. Chhatwal, M.C. Donohue, R.A. Sperling, A.P. Schultz, R.F. Buckley, and on behalf of the A4 Study Team
J Prev Alz Dis 2024;4(11):881-888
Show summaryHide summaryBACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer’s disease related pathology and neurodegeneration in smaller cohort studies.
OBJECTIVES: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).
DESIGN: Longitudinal mixed.
SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.
PARTICIPANTS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).
MEASUREMENTS: Global cognitive performance (Preclinical Alzheimer’s Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.
RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.
CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.
CITATION:
R. Boyle ; H.M. Klinger ; Z. Shirzadi ; G.T. Coughlan ; M. Seto ; M.J. Properzi ; D.L. Townsend ; Z. Yuan ; C. Scanlon ; R.J. Jutten ; K.V. Papp ; R.E. Amariglio ; D.M. Rentz ; J.P. Chhatwal ; M.C. Donohue ; R.A. Sperling ; A.P. Schultz ; R.F. Buckley ; and on behalf of the A4 Study Team ; (2024): Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer’s Disease: The A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.140
MAXIMIZING THE UTILITY OF ALZHEIMER’S DISEASE TRIAL DATA: SHARING OF BASELINE A4 AND LEARN DATA
G.A. Jimenez-Maggiora, A.P. Schulz, M.C. Donohue, H. Qiu, S.N. Jaiswal, O. Adegoke, R. Gallardo, O. Baryshnikava, R.A. Rissman, S. Abdel-Latif, R.A. Sperling, P.S. Aisen, for the A4 and LEARN Study Teams
J Prev Alz Dis 2024;4(11):889-894
Show summaryHide summaryBACKGROUND: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies were conducted between 2014 and 2023, with enrollment completed in 2017 and final study results reported in 2023. The study screening process involved the collection of initial clinical, cognitive, neuroimaging, and genetic measures to determine eligibility. Once randomized, enrolled participants were assessed every four weeks over a 4.5-year follow-up period during which longitudinal clinical, cognitive, and neuroimaging measures were collected. A large number of longitudinal fluid biospecimens were also collected and banked. Consistent with the NIH data sharing policy and the principles of Open Science, the A4/LEARN investigators aimed to share data as broadly and early as possible while still protecting participant privacy and confidentiality and the scientific integrity of the studies.
OBJECTIVES: We describe the approach, methods, and platforms used to share the A4 and LEARN pre-randomization study data for secondary research use. Preliminary results measuring the impact of these efforts are also summarized. We conclude with a discussion of lessons learned and next steps.
DESIGN: The materials shared included de-identified quantitative and image data, analysis software, instruments, and documentation.
SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan, and Australia.
PARTICIPANTS: The A4 study screened (n=6763), enrolled, and randomized (n=1169) participants between the ages of 65 and 85 with a blinded follow-up period of 240 weeks followed by an open-label period of variable length. The LEARN study screened and enrolled individuals (n=538) who were ineligible for the A4 study based on nonelevated measures of amyloid accumulation using positron emission tomography imaging (amyloid PET).
MEASUREMENTS: We provide descriptive measures of the data shared and summarize the frequency, characteristics, and status of all data access requests submitted to date. We evaluate the scientific impact of the data-sharing effort by conducting a literature search to identify related publications.
RESULTS: The A4 and LEARN pre-randomization study data were released in December 2018. As of May 8, 2024, 1506 requests have been submitted by investigators and citizen scientists from more than 50 countries. We identified 49 peer-reviewed publications that acknowledge the A4/LEARN study.
CONCLUSIONS: Our initial results provide evidence supporting the feasibility and scientific utility of broad and timely sharing of Alzheimer’s disease trial data.
CITATION:
G.A. Jimenez-Maggiora ; A.P. Schulz ; M.C. Donohue ; H. Qiu ; S.N. Jaiswal ; O. Adegoke ; R. Gallardo ; O. Baryshnikava ; R.A. Rissman ; S. Abdel-Latif ; R.A. Sperling ; P.S. Aisen ; for the A4 and LEARN Study Teams (2024): Maximizing the Utility of Alzheimer’s Disease Trial Data: Sharing of Baseline A4 and LEARN Data . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.120
EDITORIAL: ON THE 2024 ALZHEIMER’S ASSOCIATION CRITERIA: STILL NOT READY FOR CLINICAL USE
R.Z. Zhou, A. Wimo, B. Winblad
J Prev Alz Dis 2024;4(11):895-896
Show summaryHide summary
CITATION:
R.Z. Zhou ; A. Wimo ; B. Winblad ; (2024): Editorial: On the 2024 Alzheimer’s Association Criteria: Still Not Ready for Clinical Use. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.141
NOVEL BLOOD-BASED BIOMARKERS AND DISEASE MODIFYING THERAPIES FOR ALZHEIMER’S DISEASE. ARE WE READY FOR THE NEW ERA?
R. Korologou-Linden, J. Kalsi, D. Kafetsouli, A. Olawale, D. Wingfield, D. Mummery, B. Hayhoe, O. Robinson, A. Majeed, L.T. Middleton
J Prev Alz Dis 2024;4(11):897-902
Show summaryHide summaryRecent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer’s disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer’s disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer’s disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.
CITATION:
R. Korologou-Linden ; J. Kalsi ; D. Kafetsouli ; A. Olawale ; D. Wingfield ; D. Mummery ; B. Hayhoe ; O. Robinson ; A. Majeed ; L.T. Middleton (2024): Novel Blood-Based Biomarkers and Disease Modifying Therapies for Alzheimer’s Disease. Are We Ready for the New Era?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.83
EXAMINING THE DIAGNOSTIC ACCURACY OF A NOVEL PERFORMANCE-BASED TEST FOR ALZHEIMER’S DISEASE SCREENING
A.M. Reed, K. Duff, L.E. Dibble, S.S. Paul, A. Hooyman, S.Y. Schaefer
J Prev Alz Dis 2024;4(11):903-907
Show summaryHide summaryAffordable, rapid methods for identifying mild Alzheimer’s disease (AD) are needed. A simple, brief performance-based test involving the learning of functional upper-extremity movements has been developed and is associated with AD pathology and functional decline. However, its specificity to AD relative to other neurodegenerative diseases that present with motor impairment is unknown. This study examined whether this novel test could distinguish between 34 participants diagnosed with mild AD (Clinical Dementia Rating Scale = 0.5-1) from 23 participants with mild-to-moderate Parkinson’s disease (PD) (Hoehn & Yahr = 2-3) using Receiver Operating Characteristic analysis of secondary data from two separate clinical trials. Indicators of diagnostic accuracy demonstrated that the test identified participants with AD, who had worse scores than those with PD, suggesting it may be a viable screening tool for mild AD. Exploratory analyses with a control group (n=52) further showed that test scores were not sensitive to motor dysfunction.
CITATION:
A.M. Reed ; K. Duff ; L.E. Dibble ; S.S. Paul ; A. Hooyman ; S.Y. Schaefer (2024): Examining the Diagnostic Accuracy of a Novel Performance-Based Test for Alzheimer’s Disease Screening. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.93
PREDICTING COGNITIVE DECLINE FOR NON-DEMENTED ADULTS WITH HIGH BURDEN OF TAU PATHOLOGY, INDEPENDENT OF AMYLOID STATUS
H.-S. Wu, L. Li, Q.-Q. Sun, C.-C. Tan, L. Tan, W. Xu, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):908-916
Show summaryHide summaryBACKGROUND: Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population.
METHOD: Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer’s disease were examined during an extended 8-year follow-up.
RESULT: Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer’s Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer’s dementia (HR= 6.21, 95% CI= 3.61-10.66, p< 0.001 ).
CONCLUSION: APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.
CITATION:
H.-S. Wu ; L. Li ; Q.-Q. Sun ; C.-C. Tan ; L. Tan ; W. Xu ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): Predicting Cognitive Decline for Non-Demented Adults with High Burden of Tau Pathology, Independent of Amyloid Status. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.82
NON-GENETIC RISK FACTORS OF ALZHEIMER’S DISEASE: AN UPDATED UMBRELLA REVIEW
S.-Y. He, W.-M. Su, X.-J. Wen, S.-J. Lu, B. Cao, B. Yan, Y.-P. Chen
J Prev Alz Dis 2024;4(11):917-927
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by intricate genetic and environmental etiology. The objective of this study was to identify robust non-genetic risk factors for AD through an updated umbrella review.
METHODS: We conducted a comprehensive search of meta-analyses and systematic reviews on non-genetic risk factors associated with AD in PubMed, Cochrane, Embase, and Ovid Medline up to June 30, 2023. After collecting data, we estimated the summary effect size and their 95% confidence intervals. The degree of heterogeneity between studies was assessed using I2 statistics and a 95% prediction interval was determined. Additionally, we evaluated potential excess significant bias and small study effects within the selected candidate studies.
RESULTS: The umbrella review encompassed a total of 53 eligible papers, which included 84 meta-analyses covering various factors such as lifestyle, diet, environmental exposures, comorbidity or infections, drugs, and biomarkers. Based on the evidence classification criteria employed in this study, two factors as convincing evidence (Class I), including rheumatoid arthritis (RA), potentially reduced the risk of AD, but diabetes significantly increased the risk of AD. Furthermore, three factors as highly suggestive evidence (Class II), namely depression, high homocysteine, and low folic acid level, potentially increased the risk of AD.
CONCLUSION: Our findings highlight several risk factors associated with AD that warrant consideration as potential targets for intervention. However, it is crucial to prioritize the identified modifiable risk factors, namely rheumatoid arthritis, diabetes, depression, elevated homocysteine levels, and low folic acid levels to effectively address this complex neurodegenerative disorder.
CITATION:
S.-Y. He ; W.-M. Su ; X.-J. Wen ; S.-J. Lu ; B. Cao ; B. Yan ; Y.-P. Chen (2024): Non-Genetic Risk Factors of Alzheimer’s Disease: An Updated Umbrella Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.100
OPTIMISING ALZHEIMER’S DISEASE DIAGNOSIS AND TREATMENT: ASSESSING COST-UTILITY OF INTEGRATING BLOOD BIOMARKERS IN CLINICAL PRACTICE FOR DISEASEMODIFYING TREATMENT
S. Aye, R. Handels, B. Winblad, L. Jönsson
J Prev Alz Dis 2024;4(11):928-942
Show summaryHide summaryBACKGROUND: Recent developments in blood biomarkers (BBM) have shown promising results in diagnosing amyloid pathology in Alzheimer’s Disease (AD). However, information on how these BBMs can best be used in clinical settings to optimise clinical decision-making and long-term health outcomes for individuals with AD is still lacking.
OBJECTIVES: We aim to assess the potential value of BBM in AD diagnosis within the context of disease-modifying treatment (DMT).
DESIGN: We developed a decision analytic model to evaluate the long-term health outcomes using BBM in AD diagnosis. We compared standard of care (SOC) diagnosis workflow to the integration of BBM as a (1) referral decision tool in primary health center (PHC) and (2) triaging tool for invasive CSF examination in specialist memory clinic (MC). We combined a decision tree and a Markov model to simulate the patient’s diagnostic journey, treatment decisions following diagnosis and long-term health outcomes. Input parameters for the model were identified from published literature and registry data analysis. We conducted a cost-utility analysis from the societal perspective using a one-year cycle length and a 30-year (lifetime) horizon.
MEASUREMENTS: We reported the simulated outcomes in the percentage of correct diagnosis, costs (in 2022 Euros), quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICER) associated with each diagnosis strategy.
RESULTS: Compared to SOC, integrating BBM in PHC increased patient referrals by 8% and true positive AD diagnoses by 10.4%. The lifetime costs for individuals diagnosed with AD were € 249,685 and €250,287, and QALYs were 9.5 and 9.52 in SOC and PHC pathways, respectively. The cost increments were €603, and QALYs gained were 0.01, resulting in an ICER of €48,296. Using BBM in MC reduced the exposure to invasive CSF procedures and costs but also reduced true positive AD diagnoses and QALYs.
CONCLUSIONS: Using BBM at PHC to make referral decisions might increase initial diagnostic costs but can prevent high costs associated with disease progression, providing a cost-effective DMT is available, whereas using BBM in MC could reduce the initial evaluation cost but incur high costs associated with disease progression.
CITATION:
S. Aye ; R. Handels ; B. Winblad ; L. Jönsson (2024): Optimising Alzheimer’s Disease Diagnosis and Treatment: Assessing Cost-Utility of Integrating Blood Biomarkers in Clinical Practice for Disease-Modifying Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.67
PREDICTING BRAIN AMYLOID STATUS USING THE NATIONAL INSTITUTE OF HEALTH TOOLBOX (NIHTB) FOR ASSESSMENT OF NEUROLOGICAL AND BEHAVIORAL FUNCTION
Y. Cheng, E. Ho, S. Weintraub, D. Rentz, R. Gershon, S. Das, H.H. Dodge
J Prev Alz Dis 2024;4(11):943-957
Show summaryHide summaryBACKGROUND: Amyloid-beta (Aβ) plaque is a neuropathological hallmark of Alzheimer’s disease (AD). As anti-amyloid monoclonal antibodies enter the market, predicting brain amyloid status is critical to determine treatment eligibility.
OBJECTIVE: To predict brain amyloid status utilizing machine learning approaches in the Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study.
DESIGN: ARMADA is a multisite study that implemented the National Institute of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in older adults with different cognitive ability levels (normal, mild cognitive impairment, early-stage dementia of the AD type).
SETTING: Participants across various sites were involved in the ARMADA study for validating the NIHTB.
PARTICIPANTS: 199 ARMADA participants had either PET or CSF information (mean age 76.3 ± 7.7, 51.3% women, 42.3% some or complete college education, 50.3% graduate education, 88.9% White, 33.2% with positive AD biomarkers).
MEASUREMENTS: We used cognition, emotion, motor, sensation scores from NIHTB, and demographics to predict amyloid status measured by PET or CSF. We applied LASSO and random forest models and used the area under the receiver operating curve (AUROC) to evaluate the ability to identify amyloid positivity.
RESULTS: The random forest model reached AUROC of 0.74 with higher specificity than sensitivity (AUROC 95% CI:0.73 – 0.76, Sensitivity 0.50, Specificity 0.88) on the held-out test set; higher than the LASSO model (0.68 (95% CI:0.68 – 0.69)). The 10 features with the highest importance from the random forest model are: picture sequence memory, cognition total composite, cognition fluid composite, list sorting working memory, words-in-noise test (hearing), pattern comparison processing speed, odor identification, 2-minutes-walk endurance, 4-meter walk gait speed, and picture vocabulary. Overall, our model revealed the validity of measurements in cognition, motor, and sensation domains, in associating with AD biomarkers.
CONCLUSION: Our results support the utilization of the NIH toolbox as an efficient and standardizable AD biomarker measurement that is better at identifying amyloid negative (i.e., high specificity) than positive cases (i.e., low sensitivity).
CITATION:
Y. Cheng ; E. Ho ; S. Weintraub ; D. Rentz ; R. Gershon ; S. Das ; H.H. Dodge (2024): Predicting Brain Amyloid Status Using the National Institute of Health Toolbox (NIHTB) for Assessment of Neurological and Behavioral Function . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.77
VALUE OF KNOWING: HEALTH-RELATED BEHAVIOR CHANGES FOLLOWING AMYLOID PET RESULTS DISCLOSURE IN MILD COGNITIVE IMPAIRMENT
Y. Wang, D. Ren, J.S. Roberts, L.K. Tamres, J.H. Lingler
J Prev Alz Dis 2024;4(11):958-965
Show summaryHide summaryBACKGROUND: Growing evidence supports the clinical utility of amyloid PET, however, whether patients at risk for dementia use knowledge of their brain amyloid status to alter their health behaviors remains unclear.
OBJECTIVES: To explore the effect of amyloid PET results disclosure on self-reported health behaviors in patients with mild cognitive impairment.
DESIGN: Self-reported health behaviors were a secondary outcome of the Return of Amyloid Imaging Scan Results (RAISR) randomized clinical trial of amyloid PET results disclosure for individuals with mild cognitive impairment.
SETTING: Academic medical center.
PARTICIPANTS: RAISR study participants included 82 patients with mild cognitive impairment who were 92% non-Hispanic white, 59% male, and, on average, 73 ± 8.61 years old with 16.25 ± 2.49 years of education.
INTERVENTION: Participants were assigned to a scan group with the opportunity to have an amyloid PET scan and learn their results or to a control group consisting only of a mild cognitive impairment education session and no opportunity for an amyloid PET scan.
MEASUREMENTS: A 14-item health behavior questionnaire supplemented with qualitative data from the open-ended text entries to describe “other” health behaviors and follow-up semi-structured interviews. Baseline assessments were conducted prior to group assignment. For the present analysis, 71 participants had available data and scan group participants were divided by amyloid status, creating three groups for comparison: amyloid positive, amyloid negative, and control (no scan).
RESULTS: Over 12 months of follow-up, no significant differences were observed in lifestyle, vitamin/supplement use, stress reduction activities, cognitive stimulation, or advance directive completion. Amyloid-negative participants were less likely than controls to consider long-term care insurance (63.6% vs. 89.2%; P = .025), and to endorse behaviors classified as “other” (36.4% vs. 64.9%; P = 0.037). After adjusting for education level, gender, and Mini-Mental State Exam score, logistic regression showed that amyloid-negative patients were 74% less likely than controls to report “other” behaviors (OR = 0.26, 95% CI [0.08, 0.85], P = 0.025), and 78% less likely to consider long-term care insurance (OR= 0.22, 95% CI [0.06, 0.86], P = 0.03). Qualitative analysis of open-ended questionnaire data and supplemental interviews with scan group participants revealed “other” activities to include changes in areas like employment, driving, and residential status, and engagement in other non-medical activities (e.g., pursuing bucket lists).
CONCLUSIONS: This exploratory analysis of health-related behavior changes following amyloid PET disclosure suggests that the value of knowing one’s brain amyloid status may differ by scan result and encompass actions that focus more on maximizing quality of life than promoting cognitive health.
CITATION:
Y. Wang ; D. Ren ; J.S. Roberts ; L.K. Tamres ; J.H. Lingler ; (2024): Value of Knowing: Health-Related Behavior Changes following Amyloid PET Results Disclosure in Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.50
LONGITUDINAL EVOLUTION OF FINANCIAL CAPACITY AND CEREBRAL TAU AND AMYLOID BURDEN IN OLDER ADULTS WITH NORMAL COGNITION OR MILD COGNITIVE IMPAIRMENT
K.J. Mimmack, E.H. Sprague, R.E. Amariglio, P. Vannini, G.A. Marshall, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):966-974
Show summaryHide summaryBackground: Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer’s disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid—hallmarks of AD pathology.
Objectives: This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time.
Design: Participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument–Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline).
Setting: Multi-center international cohort study.
Participants: Sample size was 507—322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data.
Measurements: Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons.
Results: Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03).
Conclusions: Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.
CITATION:
K.J. Mimmack ; E.H. Sprague ; R.E. Amariglio ; P. Vannini ; G.A. Marshall ; for the Alzheimer’s Disease Neuroimaging Initiative (2023): Longitudinal Evolution of Financial Capacity and Cerebral Tau and Amyloid Burden in Older Adults with Normal Cognition or Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.121
SAFETY, EFFICACY AND CLINICAL APPLICATIONS OF FOCUSED ULTRASOUND-MEDIATED BLOOD BRAIN BARRIER OPENING IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW
A. Patwardhan, T. Wilkinson, Y. Meng, I. Alhashyan, S.E. Black, N. Lipsman, M. Masellis
J Prev Alz Dis 2024;4(11):975-982
Show summaryHide summaryAlzheimer’s disease is a neurodegenerative disorder marked by cognitive decline and brain pathology involving amyloid plaques and neurofibrillary tangles. Current drug development focuses on disease-modifying therapies, primarily antibodies targeting amyloid or tau. However, the blood-brain barrier (BBB) poses a challenge for drug delivery to the brain. Pre- and early clinical data suggests that Focused Ultrasound (FUS) technology safely enhances BBB permeability without damaging brain tissue, enabling drug delivery. This systematic review discusses the application of FUS to open the BBB for the treatment of Alzheimer’s disease (AD). We review the safety, efficacy, and potential biological effects of FUS-mediated BBB opening in AD patients.
CITATION:
A. Patwardhan ; T. Wilkinson ; Y. Meng ; I. Alhashyan ; S.E. Black ; N. Lipsman ; M. Masellis (2024): Safety, Efficacy and Clinical Applications of Focused Ultrasound-Mediated Blood Brain Barrier Opening in Alzheimer’s Disease: A Systematic Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.85
ECONOMIC IMPACT OF PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER DISEASE IN THE UNITED STATES
F.H. Frech, G. Li, T. Juday, Y. Ding, S. Mattke, A. Khachaturian, A.S. Rosenberg, C. Ndiba-Markey, A. Rava, R. Batrla, S. De Santi, H. Hampel
J Prev Alz Dis 2024;4(11):983-991
Show summaryHide summaryBACKGROUND: Limited evidence exists on the economic burden of individuals who progress from mild cognitive impairment (MCI) to Alzheimer disease and related dementia disorders (ADRD).
OBJECTIVES: To assess the all-cause health care resource utilization and costs for individuals who develop ADRD following an MCI diagnosis compared to those with stable MCI.
DESIGN: This was a retrospective cohort study from January 01, 2014, to December 31, 2019.
SETTING: The Merative MarketScan Commercial and Medicare Databases were used.
PARTICIPANTS: Individuals were included if they: (1) were aged 50 years or older; (2) had ≥1 claim with an MCI diagnosis based on the International Classification of Diseases, Ninth Revision (ICD-9) code of 331.83 or the Tenth Revision (ICD-10) code of G31.84; and had continuous enrollment. Individuals were excluded if they had a diagnosis of Parkinson’s disease or ADRD or prescription of ADRD medication.
MEASUREMENTS: Outcomes included all-cause utilization and costs per patient per year in the first 12 months following MCI diagnosis, in total and by care setting: inpatient admissions, emergency department (ED) visits, outpatient visits, and pharmacy claims.
RESULTS: Out of the total of 5185 included individuals, 1962 (37.8%) progressed to ADRD (MCI-to-ADRD subgroup) and 3223 (62.2%) did not (Stable MCI subgroup). Adjusted all-cause utilization was higher for all care settings in the MCI-to-ADRD subgroup compared with the Stable MCI subgroup. Adjusted all-cause mean total costs ($34 599 vs $24 541; mean ratio [MR], 1.41 [95% CI, 1.31-1.51]; P<.001), inpatient costs ($47 463 vs $38 004; MR, 1.25 [95% CI, 1.08-1.44]; P=.002), ED costs ($4875 vs $3863; MR, 1.26 [95% CI, 1.11-1.43]; P<.001), and outpatient costs ($16 652 vs $13 015; MR, 1.28 [95% CI, 1.20-1.37]; P<.001) were all significantly higher for the MCI-to-ADRD subgroup compared with the Stable MCI subgroup.
CONCLUSIONS: Individuals who progressed from MCI to ADRD had significantly higher health care costs than individuals with stable MCI. Early identification of MCI and delaying its progression is important to improve patient and economic outcomes.
CITATION:
F.H. Frech ; G. Li ; T. Juday ; Y. Ding ; S. Mattke ; A. Khachaturian ; A.S. Rosenberg ; C. Ndiba-Markey ; A. Rava ; R. Batrla ; S. De Santi ; H. Hampel (2024): Economic Impact of Progression from Mild Cognitive Impairment to Alzheimer Disease in the United States. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.68
EVALUATION OF CLINICAL MEANINGFULNESS OF FORTASYN CONNECT IN TERMS OF “TIME SAVED”
S.P. Dickson, A. Solomon, M. Kivipelto, T. Hartmann, A.M.J. van Hees, A. Brownlee, B. Haaland, C.H. Mallinckrodt, S.B. Hendrix
J Prev Alz Dis 2024;4(11):992-997
Show summaryHide summaryAssessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer’s disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.
CITATION:
S.P. Dickson ; A. Solomon ; M. Kivipelto ; T. Hartmann ; A.M.J. van Hees ; A. Brownlee ; B. Haaland ; C.H. Mallinckrodt ; S.B. Hendrix ; (2024): Evaluation of Clinical Meaningfulness of Fortasyn Connect in Terms of “Time Saved”. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.55
EFFECTIVENESS OF RESISTANCE EXERCISE ON COGNITIVE FUNCTION IN ANIMAL MODELS OF ALZHEIMER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
F.O. de Andrade Santos, A.A. Passos, R.M. Arida, L. Teixeira-Machado
J Prev Alz Dis 2024;4(11):998-1012
Show summaryHide summaryAIM: Alzheimer’s disease (AD) is among common cause of dementia. Complementary therapies, such as resistance exercise (RE), have been proposed as an alternative for the treatment of AD. We performed a systematic review and meta-analysis to investigate the effects of RE on the cognitive function of AD animal models and their physiological mechanisms.
METHODS: This review was submitted to PROSPERO (CRD42019131266) and was done according to PRISMA checklist. Four databases were used in the search: MEDLINE/PUBMED, SCOPUS, Web of Science and Google Scholar. We used SYRCLE and CAMAREDES to assess the risk of bias and methodological quality. We calculated the standardized mean difference using 95% confidence intervals and considered the random effects model and p < 0.05 to determine significance.
KEY FINDINGS: A total of 1,807 studies were founded, and after the selection process, only 11 studies were included in this review and 8 studies were included for meta-analysis. Four studies applied RE before AD induction, 7 studies applied RE after AD induction or in the AD condition. All studies included 550 adult and older animals weighing 25-280g. Our analysis revealed that RE had a positive effect on memory in AD animal models but did not show a significant impact on anxiety.
CONCLUSION: RE performed four or six weeks, more than three days a week, had a significant protective effect on memory. The included studies had a high risk of bias and moderate methodological quality. Therefore, RE can be a potential strategy for preventing cognitive decline in animal models.
CITATION:
F.O. de Andrade Santos ; A.A. Passos ; R.M. Arida ; L. Teixeira-Machado (2024): Effectiveness of Resistance Exercise on Cognitive Function in Animal Models of Alzheimer Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.75
GLOBAL BURDEN OF DEMENTIA DEATH FROM 1990 TO 2019, WITH PROJECTIONS TO 2050: AN ANALYSIS OF 2019 GLOBAL BURDEN OF DISEASE STUDY
Z. Li, N. Yang, L. He, J. Wang, Y. Yang, F. Ping, L. Xu, H. Zhang, W. Li, Y. Li
J Prev Alz Dis 2024;4(11):1013-1021
Show summaryHide summaryBACKGROUND: Dementia is a growing global health challenge. Quantifying the current burden and predicting the future increases of dementia-related deaths are necessary to enhance effective policy decisions and health system planning.
METHODS: Data on dementia mortality was derived from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 study. The 2020-2050 dementia-related deaths were forecasted using the Bayesian age-period-cohort model.
RESULTS: Globally, the number of dementia-related death increased from 0.56 million in 1990 to 1.62 million in 2019 and were estimated to increase to 4.91 million by the year 2050. Metabolic risk factors would become the most important modifiable risk factors affecting dementia death which account for 28.10% of dementia related death by the year 2050. For different Socio-demographic Index (SDI) regions, the low SDI region would have the highest age-standardized mortality rate (ASMR) (29.16 per 100,000) by 2050. Moreover, the number of dementia-related deaths under the age of 70 years was predicted to reach 0.18 million by 2050.
CONCLUSIONS: Dementia related death remains a global health problem, and health policies targeting metabolic risk factors may be an important way to alleviate this problem.
CITATION:
Z. Li ; N. Yang ; L. He ; J. Wang ; Y. Yang ; F. Ping ; L. Xu ; H. Zhang ; W. Li ; Y. Li ; (2024): Global Burden of Dementia Death from 1990 to 2019, with Projections to 2050: An Analysis of 2019 Global Burden of Disease Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.21
ESTIMATED INVESTMENT NEED TO INCREASE ENGLAND’S CAPACITY TO DIAGNOSE ELIGIBILITY FOR AN ALZHEIMER’S TREATMENT TO G7 AVERAGE CAPACITY LEVELS
S. Mattke, Z. Shi, M. Hanson, S. Mitchell, C. Lynch, K. MacLean Kalonji, L. Lanman
J Prev Alz Dis 2024;4(11):1022-1029
Show summaryHide summaryBACKGROUND: As disease-modifying Alzheimer’s (AD) treatments are becoming available, concerns have been raised that even high-income countries lack the diagnostic capacity to accurately identify eligible patients in a timely manner.
OBJECTIVES: We analyze how much NHS England would have to invest in capacity for AD specialists, biomarker testing with PET scans or CSF testing and MRI scans to reach G7 average levels and estimate the effect on wait times in the diagnostic process.
DESIGN: Desk research and expert interviews for cost and capacity data. Markov model to estimate wait times.
SETTING: NHS England.
MEASUREMENTS: AD specialists, and PET and MRI scanners per capita in G7 countries and wait times in England under different investment scenarios.
RESULTS: England has the lowest number of PET and MRI scanners and the second-lowest of AD specialists per capita among the G7 countries. An investment of GBP 14 billion over ten years would be needed to reach G7 average levels, of which 31%, 22%, 10%, 37% would be devoted to capacity for memory assessment services, PET scanning, CSF analysis, and MRI scanning, respectively. This investment would reduce estimated average wait times by around 87% between 2023 and 2032.
CONCLUSIONS: The NHS England has large gaps in diagnostic capacity for AD. Without substantial investments, AD patients in England would experience substantial wait times and avoidable disease progression.
CITATION:
S. Mattke ; Z. Shi ; M. Hanson ; S. Mitchell ; C. Lynch ; K. MacLean Kalonji ; L. Lanman ; (2024): Estimated Investment Need to Increase England’s Capacity to Diagnose Eligibility for an Alzheimer’s Treatment to G7 Average Capacity Levels. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.24
“BACK TO BRAAK”: ROLE OF NUCLEUS REUNIENS AND SUBCORTICAL PATHWAYS IN ALZHEIMER’S DISEASE PROGRESSION
S. Censi, C. Sestieri, M. Punzi, A. Delli Pizzi, A. Ferretti, F. Gambi, V. Tomassini, S. Delli Pizzi, S.L. Sensi, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):1030-1040
Show summaryHide summaryBACKGROUND: Patients with Alzheimer’s Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD.
OBJECTIVES: To characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI).
DESIGN: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum.
SETTING: Prodromal and clinical stages of AD.
PARTICIPANTS: We analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis.
MEASUREMENTS: A multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach.
RESULTS: AD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69.
CONCLUSIONS: In line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.
CITATION:
S. Censi ; C. Sestieri ; M. Punzi ; A. Delli Pizzi ; A. Ferretti ; F. Gambi ; V. Tomassini ; S. Delli Pizzi ; S.L. Sensi ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): “Back to Braak”: Role of Nucleus Reuniens and Subcortical Pathways in Alzheimer’s Disease Progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.42
MAGNETIC RESONANCE IMAGING-NEGATIVE CEREBRAL AMYLOID ANGIOPATHY: CEREBROSPINAL FLUID AMYLOID-Β42 OVER AMYLOID POSITRON EMISSION TOMOGRAPHY
J.-M. Pyun, M.J. Kang, S.J. Baek, K. Lee, Y.H. Park, S.Y. Kim, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):1041-1046
Show summaryHide summaryBACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer’s disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed.
METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer’s Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level.
RESULTS: NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606).
CONCLUSIONS: CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.
CITATION:
J.-M. Pyun ; M.J. Kang ; S.J. Baek ; K. Lee ; Y.H. Park ; S.Y. Kim ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.49
ASSOCIATION BETWEEN COMORBIDITY INDICES AND FUNCTIONAL AUTONOMY IN INDIVIDUALS WITH COGNITIVE IMPAIRMENT: A SYSTEMATIC REVIEW
M.N. Temedda, A. Garnier-Crussard, C. Mouchoux, V. Dauphinot
J Prev Alz Dis 2024;4(11):1047-1054
Show summaryHide summaryThis systematic review aimed to examine whether higher comorbidity burden, as assessed by comorbidity indices, was associated with a functional autonomy decline in individuals with cognitive impairment. The search was conducted in the following databases: PubMed/MEDLINE, ScienceDirect, Cochrane, and Embase. Both cross-sectional and longitudinal studies that examined the relationship between comorbidity indices and scales measuring activities of daily living (ADL) in individuals with cognitive impairment were included. The quality assessment tool for observational cohort and cross-sectional studies of the National Institutes of Health (NIH) was used. Overall, 12 studies were included, among which three were longitudinal. Significant association was frequently reported by cross-sectional designs (n=7 studies) and only one study reported a significant longitudinal association. This longitudinal study repeatedly assessed both comorbidity burden and functional autonomy, and considered comorbidity burden as a time-varying covariate. Considering comorbidity burden as a time varying covariate may deal with the dynamic nature of comorbidity burden over time, and conducting repeated assessments during the follow-up using both comorbidity index and ADL scales may increase their sensitivity to reliably measure comorbidity burden and functional autonomy decline over time. In conclusion, a higher comorbidity index was associated with a lower level of functional autonomy in people with cognitive impairment. This relationship seems to be dynamic over time and using comorbidity indices and ADL scales only once may not deal with the fluctuation of both comorbidity burden and functional autonomy decline. To cope with complexity of this relationship this review highlights some methodological approaches to be considered.
CITATION:
M.N. Temedda ; A. Garnier-Crussard ; C. Mouchoux ; V. Dauphinot (2024): Association between Comorbidity Indices and Functional Autonomy in Individuals with Cognitive Impairment: A Systematic Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.51
PREDICTION OF ALZHEIMER’S DISEASE BASED ON 3D GENOME SELECTED CIRCRNA
R. Chi, K. Li, K. Su, L. Liu, M. Feng, X. Zhang, J. Wang, X. Li, G. He, Y. Shi
J Prev Alz Dis 2024;4(11):1055-1062
Show summaryHide summaryAlzheimer’s disease (AD) is a neurodegenerative disease and there is by far no effective treatment for it, especially in its late stage. Circular RNAs (circRNAs), known as a class of non-coding RNAs are widely observed in eukaryotic transcriptomes, and are reported to play an important role in neurodegenerative diseases including AD. circRNAs usually act as microRNA (miRNA) inhibitors or «sponges» to regulate the function of miRNAs, leading to subsequent changes in protein activities and functions. Accumulating evidence indicates that circRNAs can serve as potential biomarker in AD early prediction. The functional roles of circRNAs are very versatile including miRNAs binding - thus affecting downstream gene expression, generating abnormally translated protein peptides, and affecting epigenetic modifications which subsequently affect AD related gene expressions. Therefore, identifying AD-related circRNAs can contribute to AD early diagnosis and intervention. In this work, we collected and curated an AD-related circRNA dataset; by exploring the circRNAs’ corresponding DNA loci distribution in chromatin 3D conformation (3D genome) and utilize the such 3D genome information, we were able to selected a concise yet predictively effective circRNA panel, based on which, significantly better AD prediction machine learning models were achieved.
CITATION:
R. Chi ; K. Li ; K. Su ; L. Liu ; M. Feng ; X. Zhang ; J. Wang ; X. Li ; G. He ; Y. Shi ; (2024): Prediction of Alzheimer’s Disease Based on 3D Genome Selected circRNA. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.52
FEMALE REPRODUCTIVE FACTORS AND RISK OF MILD COGNITIVE IMPAIRMENT AND DEMENTIA: THE HUNT STUDY
Y. Wedatilake, C. Myrstad, S.E. Tom, B.H. Strand, S. Bergh, G. Selbæk
J Prev Alz Dis 2024;4(11):1063-1072
Show summaryHide summaryBACKGROUND: More women are living with dementia than men worldwide and there is a need to investigate causes for this female preponderance. While reproductive factors have been investigated as risk factors, the results are conflicting. We aim to clarify this using a large cohort with a long observation time, adjusting for multiple health and lifestyle variables and encompassing a wider range of cognitive impairment.
OBJECTIVE: To study the association between menopause age, menarche age and risk of and risk of mild cognitive impairment (MCI) and dementia.
SETTING: The Trøndelag Health study (HUNT), a longitudinal population health study in Norway (1984-2019).
Participants: Women who were ≥70 years in 2017-2019 were assessed for cognitive impairment.
MEASUREMENTS: Data on menopause age and menarche age were obtained from questionnaires. Diagnosis of MCI or dementia was set using a standardised procedure by a diagnostic group of nine physicians. Multinomial logistic regression was used to study the association between menopause age, menarche age and risk of MCI and dementia with adjustment for birth year, education, smoking, ApoE4, number of children, diabetes, body mass index, alcohol use and physical inactivity.
RESULTS: We evaluated 5314 women where 900 (16.9%) had dementia, and 1747 (32.8%) had MCI. Multiple adjusted relative risk ratio (RRR) and 95% confidence intervals (CI) for dementia were: 0.96(95%CI 0.95-0.98) (p<0.001) for menopause age, 0.97(95%CI 0.94-0.99) (p=0.007) for natural menopause age (excluding hysterectomy and/or oophorectomy<55 years) and 0.97(95%CI 0.95-0.99) (p<0.001) for reproductive span (menopause age minus menarche age). Menopause age <45years was associated with a 56% higher risk compared to mean menopause age 50 years. We found no significant associations between menarche age and dementia and no associations with MCI.
CONCLUSIONS: Older menopause age and longer reproductive span corresponding to longer oestrogen exposure were associated with a lower dementia risk. Future studies should explore therapeutical options to offset this risk in women.
CITATION:
Y. Wedatilake ; C. Myrstad ; S.E. Tom ; B.H. Strand ; S. Bergh ; G. Selbæk (2024): Female Reproductive Factors and Risk of Mild Cognitive Impairment and Dementia: The HUNT Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.46
PERFORMANCE OF FULLY-AUTOMATED HIGH-THROUGHPUT PLASMA BIOMARKER ASSAYS FOR ALZHEIMER’S DISEASE IN AMNESTIC MILD COGNITIVE IMPAIRMENT SUBJECTS
G.M. Giuffrè, D. Quaranta, M.G. Vita, E.M. Costantini, S. Citro, C. Carrozza, G. De Ninno, P. Calabresi, C. Marra
J Prev Alz Dis 2024;4(11):1073-1078
Show summaryHide summaryINTRODUCTION: Novel plasma biomarkers are promising for identifying Alzheimer’s disease (AD) pathological processes in vivo, but most currently employed assays have limitations precluding widespread use.
METHODS: CSF and plasma samples were collected from seventy amnestic mild cognitive impairment (aMCI) subjects, stratified as A+ and A-. CSF Aβ40, Aβ42, p-tau181 and t-tau and plasma Aβ40, Aβ42 and p-tau181 quantification were conducted using the Lumipulse G assays (Fujirebio), to evaluate the diagnostic performance of plasma biomarkers and assess their associations with CSF biomarkers.
RESULTS: All plasma biomarkers except Aβ40 showed a very good accuracy in distinguishing A+ aMCI from A- aMCI, Aβ42/p-tau181 ratio being the most accurate (AUC 0.895, sensitivity 95.1%, specificity 82.8%). Plasma biomarkers levels were significantly associated with CSF biomarkers concentration.
DISCUSSION: High-throughput and fully-automated plasma assays could be helpful in discriminating with high accuracy between aMCI in the AD continuum and aMCI unlikely due to AD in clinical settings.
CITATION:
G.M. Giuffrè ; D. Quaranta ; M.G. Vita ; E.M. Costantini ; S. Citro ; C. Carrozza ; G. De Ninno ; P. Calabresi ; C. Marra (2024): Performance of Fully-Automated High-Throughput Plasma Biomarker Assays for Alzheimer’s Disease in Amnestic Mild Cognitive Impairment Subjects. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.58
INTEREST IN AND EXPERIENCE WITH GENETIC TESTING FOR LATE-ONSET MEDICAL CONDITIONS: RESULTS FROM THE NATIONAL POLL ON HEALTHY AGING
S.J. Feldman, D. Blasco, M. Mones, J. Scott Roberts
J Prev Alz Dis 2024;4(11):1079-1086
Show summaryHide summaryBACKGROUND: The increasing availability of genetic testing for late-onset diseases such as Alzheimer’s disease necessitates understanding public perceptions and experiences of such testing among at-risk populations.
OBJECTIVES: To assess (a) prior uptake of genetic testing (both in medical and direct-to-consumer settings), (b) future interest in genetic testing for late-onset conditions (e.g., Alzheimer’s disease, Parkinson’s disease), and (c) perceptions of testing pros and cons among middle-to-older aged adults.
DESIGN: Online, cross-sectional survey study.
SETTING: The National Poll on Healthy Aging at the University of Michigan is a recurring biannual survey of a nationally representative sample of adults aged 50-80. This study reports on a March 2018 fielding of the survey that included a genetic testing module administered to adults aged 50-64.
PARTICIPANTS: Study participants were 991 community-dwelling adults aged 50-64.
MEASUREMENTS: Survey measures assessed (a) prior use of genetic testing, (b) reasons for engaging in genetic testing, (c) interest in different types of genetic testing, including for Alzheimer’s disease, Parkinson’s disease, and macular degeneration, and (d) perceived benefits, risks, and limitations of testing.
RESULTS: Previous uptake of genetic testing was limited (medical use: 5.1%; direct-to-consumer: 10.8%), with direct-to-consumer test uptake higher among respondents with household incomes of $100,000 or more. Over half of adults endorsed interest in genetic testing for estimation of disease risk (58.9%), ancestry knowledge (58%), and informing medical care (53.8%). Interest in genetic testing for specific late-onset conditions was even higher, including Alzheimer’s disease (70%), Parkinson’s disease (65.3%), and macular degeneration (64.3%). Multivariable logistic regression models showed that older adults more likely to be interested in genetic testing for medical or disease risk purposes were those with higher levels of education (college degree or higher) and who endorsed the benefits of genetic testing, whereas respondents who endorsed testing risks and limitations were less likely to express interest.
CONCLUSION: While prior use of genetic testing among the middle-to-older age population was low, interest in testing for Alzheimer’s disease and other late-onset conditions was high. This high interest may translate into increased uptake given expanded access to testing and recent treatment advances for Alzheimer’s disease.
CITATION:
S.J. Feldman ; D. Blasco ; M. Mones ; J. Scott Roberts ; (2024): Interest in and Experience with Genetic Testing for Late-Onset Medical Conditions: Results from the National Poll on Healthy Aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.69
ASSOCIATION BETWEEN CEREBROSPINAL FLUID STREM2 LEVELS AND DEPRESSION: THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE STUDY
Y. Wang, M. Ye, Q. Ji, Q. Liu, X. Xu, Y. Zhan
J Prev Alz Dis 2024;4(11):1087-1092
Show summaryHide summaryOBJECTIVE: Previous studies demonstrated a significant protective effect of elevated cerebrospinal fluid (CSF) sTREM2 levels on brain structure and cognitive decline. Nonetheless, the role of sTREM2 in the depression progression remains unclear. This study aimed to investigate the association between CSF sTREM2 levels and longitudinal trajectories of depression.
METHODS: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Study were used. CSF sTREM2 levels and depression were measured using an ELISA-based assay and the Geriatric Depression Scale (GDS-15), respectively. Linear mixed-effect models were employed to assess the relationships between CSF sTREM2 levels and GDS scores.
RESULTS: A total of 1,017 participants were enrolled at baseline, with a mean follow-up time of 4.65 years. Baseline CSF sTREM2 levels were negatively correlated with GDS scores (β=-0.21, P=0.022) after adjustment for age, gender, race/ethnicity, education, APOE ε4 carrier status, TREM2 rare variant carrier status, marital status, smoking, and clinical cognitive status.
CONCLUSION: Our findings suggested that a higher level of CSF sTREM2 was associated with a lower risk of depression.
CITATION:
Y. Wang ; M. Ye ; Q. Ji ; Q. Liu ; X. Xu ; Y. Zhan ; (2024): Association between Cerebrospinal Fluid sTREM2 Levels and Depression: The Alzheimer’s Disease Neuroimaging Initiative Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.70
BIOMARKERS AND COGNITION STUDY, SINGAPORE (BIOCIS): PROTOCOL, STUDY DESIGN, AND PRELIMINARY FINDINGS
Y.J. Leow, J.D.J. Wang, A. Vipin, G.K. Sandhu, S.A. Soo, D. Kumar, A.A. Mohammed, F.Z.B. Zailan, F.P.H.E. Lee, S. Ghildiyal, S.Y. Liew, C. Dang, P. Tanoto, I.Y.Z. Tan, W.F.W. Chong, N. Kandiah
J Prev Alz Dis 2024;4(11):1093-1105
Show summaryHide summaryBACKGROUND: The focus of medicine is shifting from treatment to preventive care. The expression of biomarkers of dementia and Alzheimer’s disease (AD) appear decades before the onset of observable symptoms, and evidence has emerged supporting pharmacological and non-pharmacological interventions to treat modifiable risk factors of dementia. However, there is limited research on the epidemiology, clinical phenotypes, and underlying pathobiology of cognitive diseases in Asian populations.
OBJECTIVES: The objectives of the Biomarkers and Cognition Study, Singapore(BIOCIS) are to characterize the underlying pathobiology of Cognitive Impairment through a longitudinal study incorporating fluid biomarker profiles, neuroimaging, neuropsychological and clinical outcomes in a multi-ethnic Southeast Asian population.
DESIGN, SETTING, PARTICIPANTS: BIOCIS is a 5-year longitudinal study where participants are assessed annually. 2500 participants aged 30 to 95 will be recruited from the community in Singapore. To investigate how pathology presents with or without minimal clinical symptoms and vice versa, CI and unimpaired individuals will be recruited. Participants will undergo assessments to characterise biomarkers of dementia through neuroimaging, fluid biomarkers, cognitive assessments, behavioural and lifestyle profiles, retinal scans and microbiome indicators.
RESULTS: Since commencement of recruitment in February 2022, 1148 participants have been enrolled, comprising 1012 Chinese, 62 Indian, and 35 Malay individuals. Mean age and education is 61.32 years and 14.34 years respectively with 39.8% males. 47.9 % of the cohort are employed and 32.06% have a family history of dementia. The prevalence of cerebral small vessel disease is 90.2% with a mean modified Fazekas white matter hyperintensity score of 4.1.
CONCLUSION: The BIOCIS cohort will help identify novel biomarkers, pathological trajectories, epidemiology of dementia, and reversible risk factors in a Southeast Asian population. Completion of BIOCIS longitudinal data could provide insights into risk-stratification of Asians populations, and potentially inform public healthcare and precision medicine for better patient outcomes in the prevention of Alzheimer’s disease and dementia.
CITATION:
Y.J. Leow ; J.D.J. Wang ; A. Vipin ; G.K. Sandhu ; S.A. Soo ; D. Kumar ; A.A. Mohammed ; F.Z.B. Zailan ; F.P.H.E. Lee ; S. Ghildiyal ; S.Y. Liew ; C. Dang ; P. Tanoto ; I.Y.Z. Tan ; W.F.W. Chong ; N. Kandiah (2024): Biomarkers and Cognition Study, Singapore (BIOCIS): Protocol, Study Design, and Preliminary Findings. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.89
ALZHEIMER’S DISEASE PREDICTION USING FLY-OPTIMIZED DENSELY CONNECTED CONVOLUTION NEURAL NETWORKS BASED ON MRI IMAGES
R. Sampath, M. Baskar
J Prev Alz Dis 2024;4(11):1106-1121
Show summaryHide summaryAlzheimer’s is a degenerative brain cell disease that affects around 5.8 million people globally. The progressive neurodegenerative disease known as Alzheimer’s Disease (AD), affects the frontal cortex, the part of the brain in charge of memory, language, and cognition. As a result, researchers are utilizing a variety of machine-learning techniques to create an automated method for AD detection. The massive data collected during ROI and biomarker identification takes longer to handle using current methods. This study uses metaheuristic-tuned deep learning to detect the AD-affected region. The research utilizes advanced deep learning and image processing techniques to enhance early and accurate diagnosis of Alzheimer’s disease, potentially enhancing patient outcomes and prompt therapy. The capacity of deep neural networks to extract complex patterns from magnetic resonance imaging (MRI) scans makes them indispensable in the diagnosis of AD since they allow the detection of minor aberrations and complex alterations in brain structure and composition. An adaptive histogram approach processes the collected photographs, and a weighted median filter is used in place of the noisy pixels. The next step is to identify the issue region using a deep convolution network-based clustering segmentation process. A correlated information theory approach is used to extract various textural and statistical features from the separated regions. Lastly, the selected features are probed by the fly-optimized densely linked convolution neural networks. The method surpasses state-of-the-art techniques in sensitivity (15.52%), specificity (15.62%), accuracy (9.01%), error rate (11.29%), and F-measure (10.52%) for recognizing AD-impacted regions in MRI scans using the Kaggle dataset.
CITATION:
R. Sampath ; M. Baskar ; (2024): Alzheimer’s Disease Prediction Using Fly-Optimized Densely Connected Convolution Neural Networks Based on MRI Images. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.66
THE INSULIN SENSITIZER KBP-336 PREVENTS DIABETESINDUCED COGNITIVE DECLINE IN ZDF RATS
A.T. Larsen, K.E. Mohamed, E.A. Petersen, M.A. Karsdal, K. Henriksen
J Prev Alz Dis 2024;4(11):1122-1131
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown.
DESIGN AND INTERVENTION: Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment.
RESULTS: When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213.
CONCLUSION: In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.
CITATION:
A.T. Larsen ; K.E. Mohamed ; E.A. Petersen ; M.A. Karsdal ; K. Henriksen (2024): The Insulin Sensitizer KBP-336 Prevents Diabetes-Induced Cognitive decline in ZDF Rats. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.74
SEX DIFFERENCE IN THE ASSOCIATION BETWEEN PRIOR FRACTURE AND SUBSEQUENT RISK OF INCIDENT DEMENTIA: A LONGITUDINAL COHORT STUDY
D. Gao, W. Rong, C. Li, J. Liang, Y. Wang, Y. Pan, W. Zhang, F. Zheng, W. Xie
J Prev Alz Dis 2024;4(11):1132-1139
Show summaryHide summaryBackground: A history of fracture has been associated with increased risk of dementia; however, it is uncertain whether sex difference exists in the association between prior fracture and subsequent risk of incident dementia.
OBJECTIVES: To investigate whether sex modified the relationship between prior fracture and subsequent risk of dementia.
DESIGN: Prospective cohort study.
SETTING: UK Biobank.
PARTICIPANTS: 496,331 participants (54.6% women) free of dementia at baseline.
MEASUREMENTS: History of fracture was self-reported via touchscreen questionnaires at baseline. The primary outcome was all-cause dementia.
RESULTS: Both any fracture and fragility fracture were significantly associated with an increased risk of subsequent all-cause dementia in men (adjusted hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.14-1.43; adjusted HR: 1.48; 95% CI: 1.18-1.87, respectively), but not in women (adjusted HR: 1.04; 95% CI 0.95-1.15; adjusted HR: 1.01; 95% CI: 0.87-1.18, respectively); and these sex-differences were significant (P interaction = 0.006; P interaction = 0.007, respectively). The sex differences in the impacts of different fracture sites (including upper limb, lower limb, spine, and multiple sites) were consistent on all-cause dementia.
CONCLUSIONS: This study demonstrated that prior fracture was associated with an increased risk of dementia in men but not in women, and the sex difference was significant. Previous fracture may be an important marker for identifying subsequent dementia in middle-aged and older men.
CITATION:
D. Gao ; W. Rong ; C. Li ; J. Liang ; Y. Wang ; Y. Pan ; W. Zhang ; F. Zheng ; W. Xie (2024): Sex Difference in the Association between Prior Fracture and Subsequent Risk of Incident Dementia: A Longitudinal Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.56
ASSOCIATION BETWEEN RESTING HEART RATE AND MACHINE LEARNING-BASED BRAIN AGE IN MIDDLE- AND OLDER-AGE
J. Wang, H. Huang, W. Yang, A. Dove, X. Ma, W. Xu
J Prev Alz Dis 2024;4(11):1140-1147
Show summaryHide summaryBACKGROUND: Resting heart rate (RHR), has been related to increased risk of dementia, but the relationship between RHR and brain age is unclear.
OBJECTIVE: We aimed to investigate the association of RHR with brain age and brain age gap (BAG, the difference between predicted brain age and chronological age) assessed by multimodal Magnetic Resonance Imaging (MRI) in mid- and old-aged adults.
DESIGN: A longitudinal study from the UK Biobank neuroimaging project where participants underwent brain MRI scans 9+ years after baseline.
SETTING: A population-based study.
PARTICIPANTS: A total of 33,381 individuals (mean age 54.74 ± 7.49 years; 53.44% female).
MEASUREMENTS: Baseline RHR was assessed by blood pressure monitor and categorized as <60, 60–69 (reference), 70–79, or ≥80 beats per minute (bpm). Brain age was predicted using LASSO through 1,079 phenotypes in six MRI modalities (including T1-weighted MRI, T2-FLAIR, T2*, diffusion-MRI, task fMRI, and resting-state fMRI). Data were analyzed using linear regression models.
RESULTS: As a continuous variable, higher RHR was associated with older brain age (β for per 1-SD increase: 0.331, 95% [95% confidence interval, CI]: 0.265, 0.398) and larger BAG (β: 0.263, 95% CI: 0.202, 0.324). As a categorical variable, RHR 70-79 bpm and RHR ≥80 bpm were associated with older brain age (β [95% CI]: 0.361 [0.196, 0.526] / 0.737 [0.517, 0.957]) and larger BAG (0.256 [0.105, 0.407] / 0.638 [0.436, 0.839]), but RHR< 60 bpm with younger brain age (-0.324 [-0.500, -0.147]) and smaller BAG (-0.230 [-0.392, -0.067]), compared to the reference group. These associations between elevated RHR and brain age were similar in both middle-aged (<60) and older (≥60) adults, whereas the association of RHR< 60 bpm with younger brain age and larger BAG was only significant among middle-aged adults. In stratification analysis, the association between RHR ≥80 bpm and older brain age was present in people with and without CVDs, while the relation of RHR 70-79 bpm to brain age present only in people with CVD.
CONCLUSION: Higher RHR (>80 bpm) is associated with older brain age, even among middle-aged adults, but RHR< 60 bpm is associated with younger brain age. Greater RHR could be an indicator for accelerated brain aging.
CITATION:
J. Wang ; H. Huang ; W. Yang ; A. Dove ; X. Ma ; W. Xu (2024): Association between Resting Heart Rate and Machine Learning-Based Brain Age in Middle- and Older-Age. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.76
PERIODONTAL DISEASE AND ALZHEIMER’S: INSIGHTS FROM A SYSTEMATIC LITERATURE NETWORK ANALYSIS
A. Villar, S. Paladini, J. Cossatis
J Prev Alz Dis 2024;4(11):1148-1165
Show summaryHide summaryThis study investigated the relationship between periodontal disease (PD) and Alzheimer’s Disease (AD) through a Systematic Literature Network Analysis (SLNA), combining bibliometric analysis with a Systematic Literature Review (SLR). Analyzing 328 documents from 2000 to 2023, we utilized the Bibliometrix R-package for multiple bibliometric analysis. The SLR primarily centered on the 47 most globally cited papers, highlighting influential research. Our study reveals a positive correlation between Periodontal Disease (PD) and Alzheimer’s Disease (AD), grounded in both biological plausibility and a comprehensive review of the literature, yet the exact causal relationship remains a subject of ongoing scientific investigation. We conducted a detailed analysis of the two main pathways by which PD could contribute to brain inflammation: (a) the Inflammatory Cascade, and (b) Microbial Involvement. The results of our SLNA emphasize the importance of oral health in reducing Alzheimer’s risk, suggesting that managing periodontal health could be an integral part of Alzheimer’s prevention and treatment strategies. The insights from this SLNA pave the way for future research and clinical practices, underscoring the necessity of interdisciplinary methods in both the investigation and treatment of neurodegenerative diseases like Alzheimer’s. Furthermore, our study presents a prospective research roadmap to support ongoing advancement in this field.
CITATION:
A. Villar ; S. Paladini ; J. Cossatis (2024): Periodontal Disease and Alzheimer’s: Insights from a Systematic Literature Network Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.79
THE SHAPE TRAIL TEST IS SENSITIVE IN DIFFERENTIATING OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT: A CULTURE-NEUTRAL FIVE-MINUTE TEST
Z. Ding, A.S. Chan
J Prev Alz Dis 2024;4(11):1166-1176
Show summaryHide summaryINTRODUCTION: The Shape Trail Test (STT) was developed based upon the Trail Making Test, as a culture-neutral test for measuring processing speed and mental flexibility. This study aims to evaluate the accuracy and validity of this five-minute test for differentiating individuals with normal cognition (NC), subjective memory impairment (SMI), and mild cognitive impairment (MCI).
METHOD: The study included 210 participants aged 50-80 years, with 70 participants in each group matched for age, education, and gender.
RESULTS: No significant difference in STT measures was found between the NC and SMI groups. In contrast, both the NC and SMI groups exhibited significantly better performance (shorter completion time in STT-A and STT-B and fewer STT-B errors) than the MCI group. No significant group differences were found in STT-A errors. Stepwise regression analysis identified three significant predictors for classifying the MCI group from the NC and/or SMI groups, including the STT-B completion time, the STT-A errors, and the interaction between STT-B completion time and STT-B errors. The composite score of these three predictors demonstrated good discriminatory power for classifying the MCI group from the other groups, with area under the curves (AUCs) of 0.76 – 0.79 (p < 0.001), sensitivities of 78.6% - 80%, and specificities of 60% - 61.4%. However, none of the STT measures or their interactions were significant predictors for differentiating the SMI group from the NC group. Besides, the STT measures were significantly correlated with age, education, and executive function measures.
DISCUSSION: The STT could be a culture- and language-free, reliable test for assessing executive function and a sensitive test for predicting MCI.
CITATION:
Z. Ding ; A.S. Chan (2024): The Shape Trail Test Is Sensitive in Differentiating Older Adults with Mild Cognitive Impairment: A Culture-neutral Five-minute Test. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.80
LETTER TO THE EDITOR: HYPNOTICS AND INCIDENT DEMENTIA: A RISK ASSESSMENT
T. Kawada
J Prev Alz Dis 2024;4(11):1177
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CITATION:
T. Kawada (2024): Letter to the Editor: Hypnotics and Incident Dementia: A Risk Assessment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.73
LETTER TO THE EDITOR: UPDATE TO: TWO RANDOMIZED PHASE 3 STUDIES OF ADUCANUMAB IN EARLY ALZHEIMER’S DISEASE
C. Rubel, T. Chen, G. Dent
J Prev Alz Dis 2024;4(11):1178-1179
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CITATION:
C. Rubel ; T. Chen ; G. Dent ; (2024): Letter to the Editor: Update to: Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.147