02/2023 journal articles
THE EFFECTS OF SUBJECTIVE COGNITIVE DECLINE ON APOE GENOTYPE DISCLOSURE IN THE BUTLER HOSPITAL ALZHEIMER’S PREVENTION REGISTRY
A.K.W. Lee, M.K. Collier, L.I. Thompson, D. Popescu, E. Arthur, S. Correia, S.P. Salloway, J. Alber
J Prev Alz Dis 2023;2(10):152-161Show summaryHide summary
Background: Subjective cognitive decline (SCD) and APOE genotyping are both instrumental in identifying high-risk individuals for Alzheimer’s disease (AD) prevention trials.
Objective: This study examined the relationship between SCD and the impact of APOE disclosure on the psychological and behavioral health of cognitively unimpaired individuals.
Design/Setting/Participant: We recruited 189 trial volunteers (mean age 66, 65% female, 96% White), from the Butler Hospital Alzheimer’s Prevention Registry. Participants completed screening for cognitive impairment and a psychological readiness assessment before learning their APOE genotype, and were followed for 6 months after.
Results: SCD had a modest, temporary impact on mood and event-related distress following APOE disclosure, specifically on those who were ε4 carriers. The presence of SCD (SCD+) did not compound the AD genetic test-specific distress related to learning that one was an ε4 carrier. SCD also did not moderate changes in perceived AD risk, with all non-carriers showing a more rapid decrease in perceived risk over time than carriers. Counterintuitively, those without SCD (SCD-) reported taking more steps in future-directives than the SCD+ group at baseline and after disclosure, potentially suggesting that those with SCD may have subtle executive declines that limit future-oriented actions or fear-avoidance behaviors. Further, the SCD- group was more accurate in recalling their APOE status and the recall accuracy correlated with their broad knowledge about APOE as a risk gene for AD.
Conclusion: Our findings support the safety and tolerability of APOE disclosure in research volunteers regardless of their SCD statuses, but further studies are warranted to include diverse individuals and those pursuing testing through direct-to-consumer services outside of traditional research settings.
A.K.W. Lee ; M.K. Collier ; L.I. Thompson ; D. Popescu ; E. Arthur ; S. Correia ; S.P. Salloway ; J. Alber ; (2023): The Effects of Subjective Cognitive Decline on APOE Genotype Disclosure in the Butler Hospital Alzheimer’s Prevention Registry. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.12
MEDICAL JOURNEY OF PATIENTS WITH MILD COGNITIVE IMPAIRMENT AND MILD ALZHEIMER’S DISEASE DEMENTIA: A CROSS-SECTIONAL SURVEY OF PATIENTS, CARE PARTNERS, AND NEUROLOGISTS
J.J. Pruzin, S. Brunton, S. Alford, C. Hamersky, A. Sabharwal, G. Gopalakrishna
J Prev Alz Dis 2023;2(10):162-170Show summaryHide summary
Background: Alzheimer’s disease (AD) is a progressive, neurodegenerative disease presenting along a continuum ranging from asymptomatic disease to mild cognitive impairment (MCI), followed by dementia characterized as mild, moderate, or severe.
Objectives: To better understand the medical journey of patients with all-cause MCI or mild AD dementia from the perspective of patients, care partners, and physicians.
Design: Cross-sectional study.
Setting: Online surveys in the United States between February 4, 2021, and March 1, 2021.
Participants: 103 patients with all-cause MCI or mild AD dementia and 150 care partners participated in this survey. 301 physicians (75 of whom were neurologists) completed a survey.
Measurements: The surveys included questions regarding attitudes, experiences, and behaviors related to diagnosis and management of MCI and mild AD dementia. For the patient and care partner surveys, questions regarding healthcare received for MCI and mild AD dementia were only asked of care partners.
Results: Most patients (73%) had a similar medical journey. The majority (64%) initially consulted a primary care physician on average 15 months after symptom onset, with symptoms primarily consisting of forgetfulness and short-term memory loss. About half (51%) of patients in the typical medical journey were diagnosed by a neurologist. Upon diagnosis, most neurologists reported having discussions with patients and care partners about the potential causes of MCI or mild AD dementia (83%); of these physicians, 83% explained the effect other conditions have on the risk of the diagnoses and symptom progression. Neurologists (52%) consider themselves the coordinator of care for patients with MCI or mild AD dementia. Amongst patients and care partners, about one-third (35%) perceive the neurologists to be the coordinating physician.
Conclusions: Neurologists commonly diagnose MCI and mild AD dementia but are typically not the first point of contact in the medical journey, and patients do not consult with a physician for over a year after symptom onset. Neurologists play a key role in the medical journey for patients and care partners, and could help ensure earlier diagnosis and treatment, and improve clinical outcomes by coordinating MCI and mild AD dementia care and collaborating with primary care physicians.
J.J. Pruzin ; S. Brunton ; S. Alford ; C. Hamersky ; A. Sabharwal ; G. Gopalakrishna (2023): Medical Journey of Patients with Mild Cognitive Impairment and Mild Alzheimer’s Disease Dementia: A Cross-sectional Survey of Patients, Care Partners, and Neurologists. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.21
INVESTIGATING PARTIALLY DISCORDANT RESULTS IN PHASE 3 STUDIES OF ADUCANUMAB
C. Mallinckrodt, Y. Tian, P.S. Aisen, F. Barkhof, S. Cohen, G. Dent, O. Hansson, K. Harrison, T. Iwatsubo, C.J. Mummery, K.K. Muralidharan, I. Nestorov, L. Nisenbaum, R. Rajagovindan, C. von Hehn, C.H. van Dyck, B. Vellas, S. Wu, Y. Zhu, A. Sandrock, T. Chen, S. Budd Haeberlein
J Prev Alz Dis 2023;2(10):171-177Show summaryHide summary
Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer’s disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies.
Design: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies.
Setting: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries.
Participants: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE.
Intervention: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks.
Measurements: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab.
Results: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms.
Conclusions: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.
C. Mallinckrodt ; Y. Tian ; P.S. Aisen ; F. Barkhof ; S. Cohen ; G. Dent ; O. Hansson ; K. Harrison ; T. Iwatsubo ; C.J. Mummery ; K.K. Muralidharan ; I. Nestorov ; L. Nisenbaum ; R. Rajagovindan ; C. von Hehn ; C.H. van Dyck ; B. Vellas ; S. Wu ; Y. Zhu ; A. Sandrock ; T. Chen ; S. Budd Haeberlein ; (2023): Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.6
PREDICTIVE UTILITY OF PLASMA AMYLOID AND TAU FOR COGNITIVE DECLINE IN COGNITIVELY NORMAL ADULTS
Y.-J. Lee, S.-Y. Lin, S.-W. Peng, Y.-C. Lin, T.-B. Chen, P.-N. Wang, I.H. Cheng
J Prev Alz Dis 2023;2(10):178-185Show summaryHide summary
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting mostly elderly adults. Recent diagnostic criteria for AD recommend the use of imaging and/or cerebrospinal fluid (CSF) biomarkers together with clinical presentation for a more persuasive diagnosis. The invasiveness and expense of such examinations have led to the search for blood-based biomarkers. The plasma levels of amyloid-β (Aβ) protein and tau peptides have been found to correlate with CSF levels and imaging findings in patients with AD. This study was conducted to explore the predictive utility of plasma Aβ1-42 and total tau (t-tau) levels for cognitive decline in healthy adults.
Methods: In this prospective longitudinal study, we enrolled adults aged ≥ 50 years with normal cognition at Taipei Veterans General Hospital from November 2016 to April 2019. Blood samples were collected on recruitment, and plasma Aβ1-42 and t-tau levels were quantified through immunomagnetic reduction. Thorough neurophysiological assessment was performed at baseline and at the annual follow-up visit. The participants were divided into two groups according to cognitive decline. The predictive utility of Aβ1-42 and t-tau levels was evaluated by receiver operating characteristic curve analysis.
Results: Of 60 participants recruited, seven participants progressed to mild cognitive impairment and 53 retained normal cognition on follow-up (average 1.07 ± 0.2 years). The baseline levels of plasma biomarkers (Aβ1-42, t-tau, and Aβ1-42 × t-tau) were significantly higher in the progressive than in the stable group (p = 0.005, p = 0.007, and p = 0.005, respectively). Higher plasma biomarker levels (Aβ1-42 ≥ 16.96 pg/ml and Aβ1-42 × t-tau ≥ 382 pg2/ml2) predicted more cognitive decline on annual follow-up visits.
Conclusion: Plasma Aβ1-42 and t-tau levels have predictive utility for cognitive decline, even in subjects with normal cognition. Higher baseline plasma Aβ1-42 and t-tau levels may indicate a higher risk of cognitive decline in cognitively normal adults.
Y.-J. Lee ; S.-Y. Lin ; S.-W. Peng ; Y.-C. Lin ; T.-B. Chen ; P.-N. Wang ; I.H. Cheng ; (2023): Predictive Utility of Plasma Amyloid and Tau for Cognitive Decline in Cognitively Normal Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.15
FRUCTOSE CONSUMPTION IS ASSOCIATED WITH A HIGHER RISK OF DEMENTIA AND ALZHEIMER’S DISEASE: A PROSPECTIVE COHORT STUDY
J. Yan, K. Zheng, X. Zhang, Y. Jiang
J Prev Alz Dis 2023;2(10):186-192Show summaryHide summary
Background: This study aimed to investigate the association between fructose consumption and all-cause dementia, and Alzheimer’s disease (AD) dementia.
Methods: We used data from the Framingham Offspring Study (FOS) Cohort exams 5 through 9. Fructose consumption was quantified using a food-frequency questionnaire (FFQ) at cohort examinations 5 and participants were dementia-free at baseline. Surveillance for incident events commenced at examination 9 through 2014. Multivariable Cox proportional hazards regression was used to estimate the hazard ratios for the association between fructose consumption and incidence of all-cause dementia and AD dementia.
Results: Over a mean follow-up of 15.2 (interquartile range, 12.3-17.1) years (31715.1 person-years), there were 233 dementia events of which 163 were AD dementia (70.0%). After multivariate adjustments, individuals with the highest consumption of fructose had a higher risk of all-cause dementia, and AD dementia when comparing daily cumulative consumption to 0 per week (reference), with HRs of 1.49 (95% 1.14-1.84, P for trend < 0.001) for all-cause dementia, and 1.60 (95%CI 1.22-2.01, P-trend < 0.001) for AD dementia. And the comparable results were shown in the subgroups for individuals with median consumption of fructose.
Conclusion: Fructose consumption was associated with a higher risk of all-cause dementia and AD dementia.
J. Yan ; K. Zheng ; X. Zhang ; Y. Jiang ; (2023): Fructose Consumption is Associated with a Higher Risk of Dementia and Alzheimer’s Disease: A Prospective Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.7
A LARGE RETROSPECTIVE COHORT STUDY ON THE RISK OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS IN ASSOCIATION WITH VASCULAR DISEASES AND CANCER THERAPY IN MEN WITH PROSTATE CANCER
X.L. Du, L. Song
J Prev Alz Dis 2023;2(10):193-206Show summaryHide summary
Background: No study was conducted on the long-term risk of Alzheimer’s disease (AD) and related dementias (ADRD) in association with vascular diseases in men with prostate cancer.
Objectives: To determine the 26-year risk of ADRD in association with cardiovascular disease (CVD), stroke, hypertension, and diabetes in a nationwide cohort of men with prostate cancer.
Design: Retrospective cohort study.
Setting: Surveillance, Epidemiology, and End Results (SEER) areas of the United States.
Participants: 351,571 men diagnosed with prostate cancer at age ≥65 years.
Measurements: Main exposures were CVD, stroke, hypertension, and diabetes. Main outcome was the incidence of ADRD.
Results: The crude 26-year cumulative incidence of any ADRD was higher in those with versus without CVD (33.80% vs 29.11%), stroke (40.70% vs 28.03%), hypertension (30.88% vs 27.31%), and diabetes (32.23% vs 28.68%). Men with CVD (adjusted hazard ratio: 1.17, 95% CI: 1.15-1.20), stroke (1.59, 1.56-1.61), hypertension (1.13, 1.11-1.14), and diabetes (1.25, 1.23-1.27) were significantly more likely to develop ADRD than those without. Patients with 4 of these vascular diseases were 161% more likely to develop ADRD (2.61, 2.47-2.76) than those without. The risk of AD (0.89, 0.87-0.91) and ADRD (0.91, 0.90-0.93) became significantly lower in men with prostate cancer who received androgen deprivation therapy as compared to those who did not after considering death as a competing risk.
Conclusions: In men with prostate cancer, vascular diseases were associated with significantly higher risks of developing ADRD. Androgen deprivation therapy was associated with a significantly decreased risk of AD in men with prostate cancer.
X.L. Du ; L. Song ; (2023): A Large Retrospective Cohort Study on the Risk of Alzheimer’s Disease and Related Dementias in Association with Vascular Diseases and Cancer Therapy in Men with Prostate Cancer . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.8
THE GERAS SOLUTIONS COGNITIVE TEST FOR ASSESSING COGNITIVE IMPAIRMENT: NORMATIVE DATA FROM A POPULATION-BASED COHORT
V. Bloniecki, J. Ulfvarson, K. Javanshiri, G. Hagman, Y. Freund-Levi, A. Nordström
J Prev Alz Dis 2023;2(10):207-211Show summaryHide summary
Background: There is a need for the development of accurate, accessible and efficient screening instruments, focused on early-stage detection of neurocognitive disorders. The Geras Solutions cognitive test (GSCT) has showed potential as a digital screening tool for cognitive impairment but normative data are needed.
Objective: The aim of this study was to obtain normative data for the GSCT in cognitively healthy patients, investigate the effects of gender and education on test scores as well as examine test-retest reliability.
Methods: The population in this study consisted of 144 cognitively healthy subjects (MMSE>26) all at the age of 70 who were earlier included in the Healthy Aging Initiative Study conducted in Umeå, Sweden. All patients conducted the GSCT and a subset of patients (n=32) completed the test twice in order to establish test-retest reliability.
Results: The mean GSCT score was 46.0 (±4.5) points. High level of education (>12 years) was associated with a high GSCT score (p = 0.02) while gender was not associated with GSCT outcomes (p = 0.5). GSCT displayed a high correlation between test and retest (r(30) = 0.8, p <0.01).
Conclusion: This study provides valuable information regarding normative test-scores on the GSCT for cognitively healthy individuals and indicates education level as the most important predictor of test outcome. Additionally, the GSCT appears to display a good test-retest reliability further strengthening the validity of the test.
V. Bloniecki ; J. Ulfvarson ; K. Javanshiri ; G. Hagman ; Y. Freund-Levi ; A. Nordström ; (2023): The Geras Solutions Cognitive Test for Assessing Cognitive Impairment: Normative Data from a Population-Based Cohort . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.9
LONGITUDINAL EXPOSURE–RESPONSE MODELING OF MULTIPLE INDICATORS OF ALZHEIMER’S DISEASE PROGRESSION
D.G. Polhamus, M.J. Dolton, J.A. Rogers, L. Honigberg, J.Y. Jin, A. Quartino, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)***
J Prev Alz Dis 2023;2(10):212-222Show summaryHide summary
BACKGROUND: Progression in Alzheimer’s disease manifests as changes in multiple biomarker, cognitive, and functional endpoints. Disease progression modeling can be used to integrate these multiple measures into a synthesized metric of where a patient lies within the disease spectrum, allowing for a more dynamic measure over the range of the disease.
OBJECTIVES: This study aimed to combine modeling techniques from psychometric research (e.g., item response theory) and pharmacometrics (e.g., hierarchical models) to describe the multivariate longitudinal disease progression for patients with mild-to-moderate Alzheimer’s disease. Additionally, we aimed to extend the subsequent model to make it suitable for clinical trial simulation, with the inclusion of covariates, to explain variability in latent progression (i.e., disease progression) and to aid in the assessment of enrichment strategies.
DESIGN: Multiple longitudinal endpoints in the Alzheimer’s Disease Neuroimaging Initiative database were modeled. This model was validated internally using visual predictive checks, and externally by comparing data from the placebo arms of two Phase 2 crenezumab studies, ABBY (NCT01343966) and BLAZE (NCT01397578).
SETTING: The Alzheimer’s Disease Neuroimaging Initiative began in 2004: the initial 5-year study (ADNI-1) was extended by 2 years in 2009 by a Grand Opportunities grant (ADNI-GO), and in 2011 and 2016 by further competitive renewals of the ADNI-1 grant (ADNI-2 and ADNI-3, respectively). This work studies natural progression data from patients with confirmed Alzheimer’s disease. The Phase 2 ABBY and BLAZE trials evaluated the safety and efficacy of crenezumab in patients with mild-to-moderate Alzheimer’s disease.
PARTICIPANTS: From the Alzheimer’s Disease Neuroimaging Initiative database, 305 subjects who had a baseline diagnosis of mild-to-moderate Alzheimer’s disease were included in modeling. From the ABBY and BLAZE studies, 158 patients were included from the studies’ placebo arms.
MEASUREMENTS: Longitudinal cognitive and functional assessments modeled included the Clinical Dementia Rating (both as Sum of Boxes and individual item scores), the Mini-Mental State Examination, the Alzheimer’s Disease Assessment Scale – Cognitive Subscale, the Functional Activities Questionnaire, the Montreal Cognitive Assessment, and the Rey Auditory Verbal Learning Test. Also included were the imaging variable fluorodeoxyglucose-positron emission tomography and the following magnetic resonance imaging volumetrics: entorhinal, fusiform, hippocampal, intra-cranial, mid-temporal, ventricular, and whole brain.
RESULTS: Applying item response theory approaches in this longitudinal setting showed clinical assessments informing a common disease scale in the following order (from early disease to late disease): Rey Auditory Verbal Learning Test, Functional Activities Questionnaire, Montreal Cognitive Assessment, Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12, Clinical Dementia Rating – Sum of Boxes, and Mini-Mental State Examination. The Clinical Dementia Rating communication and home-and-hobbies items were most informative at earlier disease stages, while memory, orientation, and personal care informed the disease status at later stages. A clinical trial simulation model was developed and accurately described within-sample longitudinal distribution of endpoints. Simplifying the model to use only baseline age, MMSE, and APOEε4 status as predictors, out-of-sample mean progression of ADAS-Cog and CDR Sum of Boxes in the ABBY and BLAZE placebo arms was accurately described; however, the variability in these endpoints was underpredicted and suggests possibility for further model refinement when extrapolating from the ADNI sample to trial data. Clinical trial simulations were performed to exemplify use of the model to investigate hypothetical disease modification effects on the multivariate, longitudinal progression on the Alzheimer’s Disease Assessment Scale – Cognitive Subscale and the Clinical Dementia Rating – Sum of Boxes.
CONCLUSIONS: The latent variable structure of item response theory can be extended to capture a variety of scales that are common assessments and indicators of disease status in mild-to-moderate Alzheimer’s disease. These models are not intended to support causal inferences, but they do successfully characterize the observed correlation between endpoints over time and result in concise numerical indices of disease status that reflect the totality of evidence from considering the endpoints jointly. As such, the models have utility for a variety of tasks in clinical trial design, including simulation of hypothetical drug effects, interpolation of missing data, and assessment of in-sample information.
D.G. Polhamus ; M.J. Dolton ; J.A. Rogers ; L. Honigberg ; J.Y. Jin ; A. Quartino ; for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) ; (2023): Longitudinal Exposure–Response Modeling of Multiple Indicators of Alzheimer’s Disease Progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.13
UTILITY OF ENVIRONMENTAL COMPLEXITY AS A PREDICTOR OF ALZHEIMER’S DISEASE DIAGNOSIS: A BIG-DATA MACHINE LEARNING APPROACH
M. Yuan, K.M. Kennedy
J Prev Alz Dis 2023;2(10):223-235Show summaryHide summary
Background: Rural-urban differences and spatial navigation deficits have received much attention in Alzheimer’s Disease research. While individual environmental and neighborhood factors have been independently investigated, their integrative, multifactorial effects on Alzheimer’s diagnosis have not. Here we explore this “environmental complexity” for predictive power in classifying Alzheimer’s from cognitively-normal status.
Methods: We utilized data from the National Alzheimer’s Coordinating Center (NACC) uniform data set containing annual visits since 2005 and selected individuals with multiple visits and who remained in their zipcode (N = 22,553). We georeferenced each subject with 3-digit zipcodes of their residences since entering the program. We calculated environmental complexity measures using geospatial tools from street networks and landmarks for spatial navigation in subjects’ zipcode zones. Zipcode zones were grouped into two cognitive classes (Cognitively-Normal and Alzheimer’s-inclined) based on the ratios of AD and dementia subjects to all subjects in an individual zipcode zone. We randomly selected 80% of the data to train a neural network classifier model on environmental complexity measures to predict the cognitive class for each zone, controlling for salient demographic variables. The remaining 20% served as the test set for performance evaluation.
Results: Our proposed model reached excellent classification ability on the testing data: 83.87% accuracy, 95.23% precision, 83.33% recall, and 0.8889 F1-score (F1-score=1 for perfect prediction). The most salient features of “Alzheimer’s-inclined” zipcode zones included longer street-length average, higher circuity, and slightly fewer points of interest. Most “cognitively-normal” zipcode zones appeared in or near urban areas with high environmental complexity measures.
Conclusion: Environmental complexity, reflected in frequency and density of street networks and landmarks features, predicted with high precision the cognitive status of 3-digit zipcode zones based on the etiologic diagnoses and observed cognitive impairment of NACC subjects residing in these zones. The zipcode zones vary widely in size (1.6 km2 to 35,241 km2), and large zipcode zones suffer high spatial heterogeneity. Other proven AD risk factors, such as PM2.5, disperse across zones, and so do individual’s activities, leading to spatial uncertainty. Nevertheless, the model classifies diagnosis well, establishing the need for prospective experiments to quantify effects of environmental complexity on Alzheimer’s development.
M. Yuan ; K.M. Kennedy ; (2023): Utility of Environmental Complexity as a Predictor of Alzheimer’s Disease Diagnosis: A Big-Data Machine Learning Approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.18
VALIDITY OF NORMATIVE VOLUMETRIC ESTIMATES FROM OPEN ACCESS SOFTWARE IN AMNESTIC MILD COGNITIVE IMPAIRMENT
S. Fountain-Zaragoza, O. Horn, K.E. Thorn, A.Z. Kraal, A. Benitez
J Prev Alz Dis 2023;2(10):236-243Show summaryHide summary
Background: Neurodegeneration in Alzheimer’s disease (AD) is typically assessed through brain MRI. Although proprietary software can provide normative estimates of regional atrophy, such tools can be cost-prohibitive for research settings. Free software for generating normative estimates has recently been released but has yet to be validated in the context of amnestic mild cognitive impairment (aMCI).
Objectives: Determine whether normative morphometric estimates generated from open-source software replicate established patterns of neurodegeneration in aMCI, and whether these metrics correlate with episodic memory performance.
Design: Observational study of brain MRI and cognition in aging and aMCI with two identical study visits occurring approximately 1.2 years apart.
Setting: Participants were recruited from the local community and outpatient clinical settings.
Participants: Adults ages 60-85 with aMCI (n = 25) and cognitively normal controls (CN; n = 74). A subset returned for follow-up (aMCI n = 11, CN n = 52).
Measurements: Participants completed brain MRI and two neuropsychological tests of verbal episodic memory. FreeSurfer v6.0 and Normative Morphometry Image Statistics were used to generate normative morphometric estimates for AD-relevant regions (hippocampus, parahippocampus, entorhinal cortex, amygdala) and control regions (cuneus, lingual gyrus, pericalcarine gyrus), adjusting for age, sex, head size, scanner manufacturer, and field strength. We tested for baseline group differences in ROI volumes and memory and assessed their within-group associations. We also evaluated changes in ROI volumes over time and tested whether these changes corresponded to declines in memory.
Results: At baseline, the aMCI group exhibited poorer memory and smaller volumes in AD-relevant regions than the CN group. There were no group differences in control region volumes. Memory was associated with volumes in AD-relevant regions in the aMCI group only. The aMCI group exhibited greater declines than the CN group in hippocampal volume (17% vs. 8% annual decline) and entorhinal volume (54% vs. 5% annual decline). Decrease in hippocampal volume was marginally associated with decline in memory for the aMCI group.
Conclusions: Normative morphometric values generated from freely available software demonstrated expected patterns of group differences in AD-related volumes and associations with memory. Significant effects were localized to AD-relevant brain regions and only occurred in the aMCI group. These findings support the validity of these free tools as reliable and cost-effective alternatives to proprietary software for use in research settings.
S. Fountain-Zaragoza ; O. Horn ; K.E. Thorn ; A.Z. Kraal ; A. Benitez (2023): Validity of Normative Volumetric Estimates from Open Access Software in Amnestic Mild Cognitive Impairment . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.19
MEDICAL AND PSYCHIATRIC RISK FACTORS FOR DEMENTIA IN VETERANS WITH AND WITHOUT TRAUMATIC BRAIN INJURY (TBI): A NATIONWIDE COHORT STUDY
R.C. Gardner, D.E. Barnes, Y. Li, J. Boscardin, C. Peltz, K. Yaffe
J Prev Alz Dis 2023;2(10):244-250Show summaryHide summary
Background: Traumatic brain injury (TBI) is a risk factor for dementia and is common, especially among Veterans. It is unknown whether TBI exposure moderates the effect of other common medical/psychiatric comorbidities that are also risk factors for dementia. If treatable or preventable risk factors have a different impact on TBI-exposed Veterans, then this may have important public health implications for dementia prevention.
Objectives: Determine prevalence of common medical/psychiatric comorbidities and associated risk of dementia in Veterans with versus without TBI.
Design: Observational cohort.
Setting: Nationwide Veterans Health Administrative data 2001-2019.
Participants: After excluding baseline dementia, Veterans age ≥55 years with TBI (N=95,139) were age/sex/race-matched 1:2 with Veterans without TBI (N=190,278).
Measurements: We compared prevalence of hypertension, coronary artery disease (CAD), diabetes, cerebrovascular disease (CVD), epilepsy, depression, and post-traumatic stress disorder (PTSD) among Veterans with and without TBI. We calculated risk of incident dementia associated with each comorbidity using multivariable hazard ratios (HR) with Fine-Grey competing risk of death adjusted for baseline demographics. We estimated population attributable fraction (PAF) of dementia due to each comorbidity among Veterans with versus without TBI.
Results: Prevalence of all comorbidities were significantly more prevalent (5.7% to 21.5% higher) among Veterans compared to those without TBI. All comorbidities were associated with increased risk of dementia in both groups. There were significant interactions between comorbidities and TBI in which HRs were slightly lower among Veterans with TBI (adjusted HRs 1.08-1.37) compared to those without TBI (adjusted HRs 1.12-2.13). Nevertheless, PAFs for dementia due to depression, hypertension, CAD, CVD, and epilepsy were slightly higher in Veterans with TBI due to their high prevalence in this group.
Conclusions: Targeting depression, hypertension, CAD, CVD, and epilepsy may be especially important for dementia risk reduction among Veterans with TBI.
R.C. Gardner ; D.E. Barnes ; Y. Li ; J. Boscardin ; C. Peltz ; K. Yaffe (2023): Medical and Psychiatric Risk Factors for Dementia in Veterans with and without Traumatic Brain Injury (TBI): A Nationwide Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.16
CROSS-SECTIONAL AND LONGITUDINAL COMPARISON OF TAU IMAGING WITH 18F-MK6240 AND 18F-FLORTAUCIPIR IN POPULATIONS MATCHED FOR AGE, MMSE AND BRAIN BETA-AMYLOID BURDEN
P. Bourgeat, N. Krishnadas, V. Doré, R. Mulligan, R. Tyrrell, S. Bozinovski, K. Huang, J. Fripp, V.L. Villemagne, C.C. Rowe, for the Alzheimer’s Disease Neuroimaging Initiative* and the AIBL research group
J Prev Alz Dis 2023;2(10):251-258Show summaryHide summary
Objectives: Longitudinal tau quantification may provide a useful marker of drug efficacy in clinical trials. Different tau PET tracers may have different sensitivity to longitudinal changes, but without a head-to-head dataset or a carefully designed case-matching procedure, comparing results in different cohorts can be biased. In this study, we compared the tau PET tracers, 18F-MK6240 and 18F-flortaucipir (FTP), both cross-sectionally and longitudinally by case-matching subjects in the AIBL and ADNI longitudinal cohort studies.
Methods: A subset of 113 participants from AIBL and 113 from ADNI imaged using 18F-MK6240 and 18F-FTP respectively, with baseline and follow-up, were matched based on baseline clinical diagnosis, MMSE, age and amyloid (Aβ) PET centiloid value. Subjects were grouped as 64 Aβ- cognitively unimpaired (CU), 22 Aβ+ CU, 14 Aβ+ mild cognitive impairment (MCI) and 13 Aβ+ Alzheimer’s disease (AD). Tracer retention was measured in the mesial, temporoparietal, rest of the cortex, and a meta-temporal region composed of entorhinal, inferior/middle temporal, fusiform, parahippocampus and amygdala. T-tests were employed to assess group separation at baseline using SUVR Z-scores and longitudinally using SUVR%/Yr.
Results: Both tracers detected statistically significant differences at baseline in most regions between all clinical groups. Only 18F-MK6240 showed statistically significant higher rate of SUVR increase in Aβ+ CU compared to Aβ- CU in the mesial, meta-temporal and temporoparietal regions.
Conclusion: 18F-MK6240 appears to be a more sensitive tracer for change in tau level at the preclinical stage of AD.
P. Bourgeat ; N. Krishnadas ; V. Doré ; R. Mulligan ; R. Tyrrell ; S. Bozinovski ; K. Huang ; J. Fripp ; V.L. Villemagne ; C.C. Rowe ; for the Alzheimer’s Disease Neuroimaging Initiative and the AIBL research group ; (2023): Cross-Sectional and Longitudinal Comparison of Tau Imaging with 18F-MK6240 and 18F-Flortaucipir in Populations Matched for Age, MMSE and Brain Beta-Amyloid Burden. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.17
FORECASTING THE PREVALENCE OF ALZHEIMER’S DISEASE AT MILD COGNITIVE IMPAIRMENT AND MILD DEMENTIA STAGES IN FRANCE IN 2022
A. Gabelle, M. Guéry, A. Doutriaux, K. Bettayeb
J Prev Alz Dis 2023;2(10):259-266Show summaryHide summary
guidelines and future disease-modifying therapies, estimating the prevalence of Alzheimer’s disease (AD) at early stages is key.
OBJECTIVE: To estimate the number of people living with mild cognitive impairment (MCI) due to AD and mild AD dementia in France in 2022 that could be eligible to future AD therapies.
METHODS: A step-by-step approach was defined based on disease stages definition and clinical practice. In line with AD guidelines, amyloid-positive profile is considered in our estimates to enhance the diagnosis accuracy of early stages of AD. Age-stratified prevalence from French cohort and international pooled analyses were identified to feed the different steps. To consider uncertainty around mean prevalence values, low and high scenarii based on the lower and upper bounds of the 95% confidence interval were conducted.
RESULTS: We estimated that 2.5 (low scenario: 1.7 - high scenario: 3.6) million people suffer from mild cognitive impairment in France in 2022 among whom 1.65 (low: 1.5 – high: 1.8) million people meet the criteria for mild cognitive impairment due to AD i.e., with amyloid positive profile. The expected number of clinical AD dementia is estimated at 925,886 people. Among those, 379,278 people suffer from mild AD dementia based on clinical diagnosis, including 311,043 (low: 289,174 - high: 328,332) cases with amyloid positive profile.
CONCLUSION: MCI due to AD, and mild dementia stages are potentially of high prevalence. Population-based studies are needed to confirm those estimates.
A. Gabelle ; M. Guéry ; A. Doutriaux ; K. Bettayeb (2023): Forecasting the Prevalence of Alzheimer’s Disease at Mild Cognitive Impairment and Mild Dementia Stages in France in 2022. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.22
EXPLORING THE ASSOCIATIONS BETWEEN ALZHEIMER’S DISEASE AND GBM MEDIATED BY MICROGLIA BASED ON NETWORK ANALYSIS
C. Zhang, X. Zhong, L. Yi, Z. Zhao, Y. Zhang, G. Tan, Y. Zhang, Y. Zhang, Y. Xu, N. Wu
J Prev Alz Dis 2023;2(10):267-275Show summaryHide summary
Previous studies have revealed that there existed epidemic associations between Alzheimer’s disease (AD) and many types of tumors, however, the inner biological mechanism connecting these diseases was not clear currently. In this study, we explored the transcriptome associations between AD and glioblastoma multiforme (GBM) that both originate in the brain, using microglia as a bridge, from gene and network levels. Firstly, we extracted human scRNA sequencing datasets from Gene Expression Omnibus (GEO) database, and identified differentially expressed genes within microglia after cell annotation. It was observed that there were 11 common genes shared by AD and GBM dys-regulated genes. Next, we utilized DIAMOnD and Flow Centrality algorithms to identify microglia modules and mediating pathways connecting these two diseases based on global network topology. Among these candidate pathways, the mediating genes FURIN and BACE1 (from SPIKN5 to CSNK1A1) were not only related to the formation of amyloid beta plaques that accumulate in the brain of AD patients, but also involved in cancer biology. Furthermore, the biological explorations of mediating pathways connecting AD and GBM modules reveal inflammatory response, lipid metabolism disorder, and cell proliferation terms. Finally, novel signatures for early AD detection as well as risk models for glioma prognosis were identified based on mediating genes involved in these pathways. In conclusion, this study provided a novel network-based strategy for exploring microglia mediation between AD and GBM and identified candidate signatures for disease detection and prognosis.
C. Zhang ; X. Zhong ; L. Yi ; Z. Zhao ; Y. Zhang ; G. Tan ; Y. Zhang ; Y. Zhang ; Y. Xu ; N. Wu (2023): Exploring the Associations between Alzheimer’s Disease and GBM Mediated by Microglia Based on Network Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.23
THE ROLE OF THYROID DYSFUNCTION IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
A. Salehipour, M. Dolatshahi, M. Haghshomar, J. Amin
J Prev Alz Dis 2023;2(10):276-286Show summaryHide summary
Imbalances in thyroid hormones have been linked with Alzheimer’s dementia. Several studies have reported an association between thyroid disorders, such as hyper- or hypothyroidism, with Alzheimer’s disease. However, there remains no consensus about the precise role of thyroid dysfunction in Alzheimer’s disease. In this study we systematically searched PubMed, Embase and Scopus for clinical studies which reported the prevalence of hyper- or hypothyroidism in people with Alzheimer’s disease compared to controls. Meta-analysis was performed to compare thyroid disorder prevalence in Alzheimer’s disease and controls. Subgroup analysis was performed to assess the clinical and subclinical thyroid dysfunction, separately. Seven studies, including 1189 people with Alzheimer’s disease and 72711 controls, were included in our sample. Hypothyroidism was significantly more prevalent in Alzheimer’s disease compared with controls (6.4% vs 2.4%, p=0.01). Subgroup analysis showed that clinical hypothyroidism was not significantly different between Alzheimer’s disease compared to controls (10.0% vs 5.3%, p=0.35). There was no difference in the crude overall prevalence of clinical and subclinical hyperthyroidism in Alzheimer’s disease versus controls (2.4 vs 1.9%, p=0.73). Our analyses revealed a higher prevalence of hypothyroidism in Alzheimer’s disease. Whether this finding is explained by hypothyroidism being a risk factor for, or consequence of, Alzheimer’s disease requires longitudinal analysis. Our review supports further work into a potential role for treatment of hypothyroidism in the prevention or delay of Alzheimer’s disease.
A. Salehipour ; M. Dolatshahi ; M. Haghshomar ; J. Amin (2023): The Role of Thyroid Dysfunction in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.20
ENVIRONMENTAL ENRICHMENT IN MURINE MODELS AND ITS TRANSLATION TO HUMAN FACTORS IMPROVING CONDITIONS IN ALZHEIMER DISEASE
M.F. Colavitta, L. Grasso, F.J. Barrantes
J Prev Alz Dis 2023;2(10):287-300Show summaryHide summary
With the aging of the world population, there has been a notable increase in the incidence of Alzheimer disease (AD), the most prevalent neurodegenerative disease affecting the elderly. Several studies have reported a delay in the onset of AD symptoms and age-related cognitive dysfunction upon changes to a healthier lifestyle. These positive adjustments find support in the cognitive reserve hypothesis, which holds that the ability to defer disease inception and protect cognitive performance is related to healthier lifestyle habits such as cognitive and physical activity, social engagement, and sensorial stimulation. These lifestyle habits can be compounded under the umbrella of the environmental enrichment (EE) paradigm. The mechanisms underlying EE’s capacity to modulate disease expression remain unclear. Since ethical and methodological considerations rule out direct analysis of such changes in the human brain, researchers have resorted to animal models to carry out in-depth characterizations of post-EE structural and functional brain modifications using a variety of behavioral, electrophysiological, genetic, biochemical, and biophysical approaches. Moreover, given the shorter lifespan of animals compared to humans, it is possible to address the effects of aging in control and AD models. In this review we analyze and classify EE data from studies using AD murine models and compare the setup variables employed. We also delve into various aspects of neuroplasticity, under the posit that this property is the key mechanistic process underlying the benefits of EE in both animal and human subjects.
M.F. Colavitta ; L. Grasso ; F.J. Barrantes ; (2023): Environmental Enrichment in Murine Models and Its Translation to Human Factors Improving Conditions in Alzheimer Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.5
PREDICTING PROGRESSION FROM NORMAL TO MCI AND FROM MCI TO AD USING CLINICAL VARIABLES IN THE NATIONAL ALZHEIMER’S COORDINATING CENTER UNIFORM DATA SET VERSION 3: APPLICATION OF MACHINE LEARNING MODELS AND A PROBABILITY CALCULATOR
Y. Pang, W. Kukull, M. Sano, R.L. Albin, C. Shen, J. Zhou, H.H. Dodge
J Prev Alz Dis 2023;2(10):301-313Show summaryHide summary
Clinical trials are increasingly focused on pre-manifest and early Alzheimer’s disease (AD). Accurately predicting clinical progressions from normal to MCI or from MCI to dementia/AD versus non-progression is challenging. Accurate identification of symptomatic progressors is important to avoid unnecessary treatment and improve trial efficiency. Due to large inter-individual variability, biomarker positivity and comorbidity information are often insufficient to identify those destined to have symptomatic progressions. Using only clinical variables, we aimed to predict clinical progressions, estimating probabilities of progressions with a small set of variables selected by machine learning approaches. This work updates our previous work that was applied to the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set Version 2 (V2), by using the most recent version (V3) with additional analyses. We generated a user-friendly conversion probability calculator which can be used for effectively pre-screening trial participants.
Y. Pang ; W. Kukull ; M. Sano ; R.L. Albin ; C. Shen ; J. Zhou ; H.H. Dodge ; (2023): Predicting Progression from Normal to MCI and from MCI to AD Using Clinical Variables in the National Alzheimer’s Coordinating Center Uniform Data Set Version 3: Application of Machine Learning Models and a Probability Calculator. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.10
SCREENING OVER SPEECH IN UNSELECTED POPULATIONS FOR CLINICAL TRIALS IN AD (PROSPECT-AD): STUDY DESIGN AND PROTOCOL
A. König, N. Linz, E. Baykara, J. Tröger, C. Ritchie, S. Saunders, S. Teipel, S. Köhler, G. Sánchez-Benavides, O. Grau-Rivera, J.D. Gispert, S. Palmqvist, P. Tideman, O. Hansson
J Prev Alz Dis 2023;2(10):314-321Show summaryHide summary
Background: Speech impairments are an early feature of Alzheimer’s disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone.
Objectives: PROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts.
Design: PROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD ‘probability-spectrum’, i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores.
Participants: N= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months.
Measurements: The speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure.
Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum.
Conclusion: The outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.
A. König ; N. Linz ; E. Baykara ; J. Tröger ; C. Ritchie ; S. Saunders ; S. Teipel ; S. Köhler ; G. Sánchez-Benavides ; O. Grau-Rivera ; J.D. Gispert ; S. Palmqvist ; P. Tideman ; O. Hansson ; (2023): Screening over Speech in Unselected Populations for Clinical Trials in AD (PROSPECT-AD): Study Design and Protocol. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.11
MEMORY FOR SEMANTICALLY RELATED OBJECTS DIFFERENTIATES COGNITIVELY UNIMPAIRED AUTOSOMAL DOMINANT MUTATION CARRIERS FROM NON-CARRIER FAMILY MEMBERS
J.T. Fox-Fuller, J.E. Martinez, A. Baena, N. Londono, D. Munera, D. Noriega, C. Vila-Castelar, P.A. Aduen, F. Lopera, A. Cronin-Golomb, Y.T. Quiroz
J Prev Alz Dis 2023;2(10):322-327Show summaryHide summary
Early cognitive changes due to Alzheimer’s disease (AD) include difficulties in semantic access and working memory. Using a computerized cognitive test developed by our group, called the Memory for Semantically Related Objects test (MESERO), we evaluated if cognitively unimpaired carriers of an autosomal dominant AD (ADAD) mutation performed worse on this test than non-carrier family members. 35 cognitively unimpaired ADAD mutation carriers and 26 non-carrier family members from a Colombian ADAD cohort took the MESERO on a laptop computer. Cognitively unimpaired ADAD carriers had significantly worse MESERO total scores than non-carrier family members, driven by worse performance in semantically-related object sets; group performances did not differ on semantically unrelated object sets. Findings suggest that MESERO performance may be sensitive to subtle cognitive changes associated with AD. Future MESERO research should examine performances between healthy older adults and people at risk for sporadic AD.
J.T. Fox-Fuller ; J.E. Martinez ; A. Baena ; N. Londono ; D. Munera ; D. Noriega ; C. Vila-Castelar ; P.A. Aduen ; F. Lopera ; A. Cronin-Golomb ; Y.T. Quiroz ; (2023): Memory for Semantically Related Objects Differentiates Cognitively Unimpaired Autosomal Dominant Mutation Carriers from Non-Carrier Family Members. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.14