Cognitive Speed in Neurodegenerative Disease: Comparing Mean Rate and Inconsistency Within and Across the Alzheimer's and Lewy Body Spectra in the COMPASS-ND Study.

Background: Alzheimer's disease (AD) and Lewy body disease (LBD) are characterized by early and gradual worsening perturbations in speeded cognitive responses. Objective: Using simple and choice reaction time tasks, we compared two indicators of cognitive speed within and across the AD and LBD spectra: mean rate (average reaction time across trials) and inconsistency (within person variability). Methods: The AD spectrum cohorts included subjective cognitive impairment (SCI, n = 28), mild cognitive impairment (MCI, n = 121), and AD (n = 45) participants. The LBD spectrum included Parkinson's disease (PD, n = 32), mild cognitive impairment in PD (PD-MCI, n = 21), and LBD (n = 18) participants. A cognitively unimpaired (CU, n = 39) cohort served as common benchmark. We conducted multivariate analyses of variance and discrimination analyses. Results: Within the AD spectrum, the AD cohort was slower and more inconsistent than the CU, SCI, and MCI cohorts. The MCI cohort was slower than the CU cohort. Within the LBD spectrum, the LBD cohort was slower and more inconsistent than the CU, PD, and PD-MCI cohorts. The PD-MCI cohort was slower than the CU and PD cohorts. In cross-spectra (corresponding cohort) comparisons, the LBD cohort was slower and more inconsistent than the AD cohort. The PD-MCI cohort was slower than the MCI cohort. Discrimination analyses clarified the group difference patterns. Conclusions: For both speed tasks, mean rate and inconsistency demonstrated similar sensitivity to spectra-related comparisons. Both dementia cohorts were slower and more inconsistent than each of their respective non-dementia cohorts.

Machine learning analyses identify multi-modal frailty factors that selectively discriminate four cohorts in the Alzheimer's disease spectrum: a COMPASS-ND study.

BACKGROUND: Frailty indicators can operate in dynamic amalgamations of disease conditions, clinical symptoms, biomarkers, medical signals, cognitive characteristics, and even health beliefs and practices. This study is the first to evaluate which, among these multiple frailty-related indicators, are important and differential predictors of clinical cohorts that represent progression along an Alzheimer's disease (AD) spectrum. We applied machine-learning technology to such indicators in order to identify the leading predictors of three AD spectrum cohorts; viz., subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD. The common benchmark was a cohort of cognitively unimpaired (CU) older adults. METHODS: The four cohorts were from the cross-sectional Comprehensive Assessment of Neurodegeneration and Dementia dataset. We used random forest analysis (Python 3.7) to simultaneously test the relative importance of 83 multi-modal frailty indicators in discriminating the cohorts. We performed an explainable artificial intelligence method (Tree Shapley Additive exPlanation values) for deep interpretation of prediction effects. RESULTS: We observed strong concurrent prediction results, with clusters varying across cohorts. The SCI model demonstrated excellent prediction accuracy (AUC = 0.89). Three leading predictors were poorer quality of life ([QoL]; memory), abnormal lymphocyte count, and abnormal neutrophil count. The MCI model demonstrated a similarly high AUC (0.88). Five leading predictors were poorer QoL (memory, leisure), male sex, abnormal lymphocyte count, and poorer self-rated eyesight. The AD model demonstrated outstanding prediction accuracy (AUC = 0.98). Ten leading predictors were poorer QoL (memory), reduced olfaction, male sex, increased dependence in activities of daily living (n = 6), and poorer visual contrast. CONCLUSIONS: Both convergent and cohort-specific frailty factors discriminated the AD spectrum cohorts. Convergence was observed as all cohorts were marked by lower quality of life (memory), supporting recent research and clinical attention to subjective experiences of memory aging and their potentially broad ramifications. Diversity was displayed in that, of the 14 leading predictors extracted across models, 11 were selectively sensitive to one cohort. A morbidity intensity trend was indicated by an increasing number and diversity of predictors corresponding to clinical severity, especially in AD. Knowledge of differential deficit predictors across AD clinical cohorts may promote precision interventions.

Identifying key multi-modal predictors of incipient dementia in Parkinson's disease: a machine learning analysis and Tree SHAP interpretation.

Background: Persons with Parkinson's disease (PD) differentially progress to cognitive impairment and dementia. With a 3-year longitudinal sample of initially non-demented PD patients measured on multiple dementia risk factors, we demonstrate that machine learning classifier algorithms can be combined with explainable artificial intelligence methods to identify and interpret leading predictors that discriminate those who later converted to dementia from those who did not. Method: Participants were 48 well-characterized PD patients (Mbaseline age = 71.6; SD = 4.8; 44% female). We tested 38 multi-modal predictors from 10 domains (e.g., motor, cognitive) in a computationally competitive context to identify those that best discriminated two unobserved baseline groups, PD No Dementia (PDND), and PD Incipient Dementia (PDID). We used Random Forest (RF) classifier models for the discrimination goal and Tree SHapley Additive exPlanation (Tree SHAP) values for deep interpretation. Results: An excellent RF model discriminated baseline PDID from PDND (AUC = 0.84; normalized Matthews Correlation Coefficient = 0.76). Tree SHAP showed that ten leading predictors of PDID accounted for 62.5% of the model, as well as their relative importance, direction, and magnitude (risk threshold). These predictors represented the motor (e.g., poorer gait), cognitive (e.g., slower Trail A), molecular (up-regulated metabolite panel), demographic (age), imaging (ventricular volume), and lifestyle (activities of daily living) domains. Conclusion: Our data-driven protocol integrated RF classifier models and Tree SHAP applications to selectively identify and interpret early dementia risk factors in a well-characterized sample of initially non-demented persons with PD. Results indicate that leading dementia predictors derive from multiple complementary risk domains.

Dementia Risk Prediction in a Longitudinal Geriatric Parkinson's Disease Cohort: Evaluation and Application of the Montreal Parkinson Risk of Dementia Scale.

Background: Parkinson's disease (PD) increases risk for dementia and cascading adverse outcomes. The eight-item Montreal Parkinson Risk of Dementia Scale (MoPaRDS) is a rapid, in-office dementia screening tool. We examine predictive validity and other characteristics of the MoPaRDS in a geriatric PD cohort by testing a series of alternative versions and modelling risk score change trajectories. Methods: Participants were 48 initially non-demented PD patients (Mage = 71.6 years, range = 65-84) from a three-year, three-wave prospective Canadian cohort study. A dementia diagnosis at Wave 3 was used to stratify two baseline groups: PD with Incipient Dementia (PDID) and PD with No Dementia (PDND). We aimed to predict dementia three years prior to diagnosis using baseline data for eight indicators that harmonized with the original report, plus education. Results: Three MoPaRDS items (age, orthostatic hypotension, mild cognitive impairment [MCI]) discriminated the groups both independently and as a composite three-item scale (area under the curve [AUC] = 0.88). The eight-item MoPaRDS reliably discriminated PDID from PDND (AUC = 0.81). Education did not improve predictive validity (AUC = 0.77). Performance of the eight-item MoPaRDS varied across sex (AUCfemales = 0.91; AUCmales = 0.74), whereas the three-item configuration did not (AUCfemales = 0.88; AUCmales = 0.91). Risk scores of both configurations increased over time. Conclusions: We report new data on the application of the MoPaRDS as a dementia prediction tool for a geriatric PD cohort. Results support the viability of the full MoPaRDS, and indicate that an empirically determined brief version is a promising complement.

Bridging Integrator 1 (BIN1, rs6733839) and Sex Are Moderators of Vascular Health Predictions of Memory Aging Trajectories.

BACKGROUND: A promising risk loci for sporadic Alzheimer's disease (AD), Bridging Integrator 1 (BIN1), is thought to operate through the tau pathology pathway. OBJECTIVE: We examine BIN1 risk for a moderating role with vascular health (pulse pressure; PP) and sex in predictions of episodic memory trajectories in asymptomatic aging adults. METHODS: The sample included 623 participants (Baseline Mean age = 70.1; 66.8% female) covering a 44-year longitudinal band (53-97 years). With an established memory latent variable arrayed as individualized trajectories, we applied Mplus 8.5 to determine the best fitting longitudinal growth model. Main analyses were conducted in three sequential phases to investigate: 1) memory trajectory prediction by PP, 2) moderation by BIN1 genetic risk, and 3) stratification by sex. RESULTS: We first confirmed that good vascular health (lower PP) was associated with higher memory level and shallower decline and males were more severely affected by worsening PP in both memory performance and longitudinal decline. Second, the PP prediction of memory trajectories was significant for BIN1 C/C and C/T carriers but not for persons with the highest AD risk (T/T homozygotes). Third, when further stratified by sex, the BIN1 moderation of memory prediction by PP was selective for females. CONCLUSION: We observed a novel interaction whereby BIN1 (linked with tauopathy in AD) and sex sequentially moderated a benchmark PP prediction of differential memory decline in asymptomatic aging. This multi-modal biomarker interaction approach, disaggregated by sex, can be an effective method for enhancing precision of AD genetic risk assessment.

Data-Driven Analyses of Longitudinal Hippocampal Imaging Trajectories: Discrimination and Biomarker Prediction of Change Classes.

BACKGROUND: Hippocampal atrophy is a well-known biomarker of neurodegeneration, such as that observed in Alzheimer's disease (AD). Although distributions of hippocampal volume trajectories for asymptomatic individuals often reveal substantial heterogeneity, it is unclear whether interpretable trajectory classes can be objectively detected and used for prediction analyses. OBJECTIVE: To detect and predict hippocampal trajectory classes in a computationally competitive context using established AD-related risk factors/biomarkers. METHODS: We used biomarker/risk factor and longitudinal MRI data in asymptomatic adults from the AD Neuroimaging Initiative (n = 351; Mean = 75 years; 48.7% female). First, we applied latent class growth analyses to left (LHC) and right (RHC) hippocampal trajectory distributions to identify distinct classes. Second, using random forest analyses, we tested 38 multi-modal biomarkers/risk factors for their relative importance in discriminating the lower (potentially elevated atrophy risk) from the higher (potentially reduced risk) class. RESULTS: For both LHC and RHC trajectory distribution analyses, we observed three distinct trajectory classes. Three biomarkers/risk factors predicted membership in LHC and RHC lower classes: male sex, higher education, and lower plasma Aß1-42. Four additional factors selectively predicted membership in the lower LHC class: lower plasma tau and Aß1-40, higher depressive symptomology, and lower body mass index. CONCLUSION: Data-driven analyses of LHC and RHC trajectories detected three classes underlying the heterogeneous distributions. Machine learning analyses determined three common and four unique biomarkers/risk factors discriminating the higher and lower LHC/RHC classes. Our sequential analytic approach produced evidence that the dynamics of preclinical hippocampal trajectories can be predicted by AD-related biomarkers/risk factors from multiple modalities.

Subjective memory concerns, poor vascular health, and male sex predict exacerbated memory decline trajectories: An integrative data-driven class and prediction analysis.

OBJECTIVE: Subjective memory decline (SMD) has been identified as a potential early marker of nonnormal and accelerated cognitive decline. We performed data-driven analyses that integrated trajectory classification with prediction modeling to test declining trajectory class prediction by SMD facets, pulse pressure (PP; i.e., a robust proxy for vascular health), and sex. METHOD: The longitudinal design featured memory trajectories across a 40-year band (55-95 years) of nondemented aging (N = 580; Mage = 70.2 years; 65% female) from the Victoria Longitudinal Study. First, latent class growth analyses identified distinct classes of memory trajectories. Second, we used the three-step method (R3STEP) to predict membership in the declining memory classes using six measures: memory complaints, memory concerns, memory compensation, memory self-efficacy, PP, and sex. RESULTS: First, we identified four classes of memory aging trajectories: (a) stable memory aging (STABLE), (b) typical memory aging (TYPICAL), (c) slowly declining memory aging (SLOW), and (d) rapidly declining memory aging (RAPID). Second, more memory concerns predicted membership in the SLOW and RAPID classes. Higher PP predicted membership in the SLOW class. Male sex predicted membership in the declining (TYPICAL, SLOW, RAPID) classes. CONCLUSION: Among SMD facets, memory concerns represent the most severe degree of apprehension about subjectively experienced memory losses. The present integrative data-driven analysis indicated that such concerns predicted membership in declining memory trajectory classes in addition to worse vascular health (higher PP) and sex (male). In nondemented aging, concerns about increasing memory failures may be veridical indicators of memory loss, especially when coupled with vascular comorbidity and being male. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Differential Cognitive Decline in Alzheimer's Disease Is Predicted by Changes in Ventricular Size but Moderated by Apolipoprotein E and Pulse Pressure.

BACKGROUND: Differential cognitive trajectories in Alzheimer's disease (AD) may be predicted by biomarkers from multiple domains. OBJECTIVE: In a longitudinal sample of AD and AD-related dementias patients (n = 312), we tested whether 1) change in brain morphometry (ventricular enlargement) predicts differential cognitive trajectories, 2) further risk is contributed by genetic (Apolipoprotein E [APOE] ɛ4+) and vascular (pulse pressure [PP]) factors separately, and 3) the genetic + vascular risk moderates this pattern. METHODS: We applied a dynamic computational approach (parallel process models) to test both concurrent and change-related associations between predictor (ventricular size) and cognition (executive function [EF]/attention). We then tested these associations as stratified by APOE (ɛ4-/ɛ4+), PP (low/high), and APOE+ PP (low/intermediate/high) risk. RESULTS: First, concurrently, higher ventricular size predicted lower EF/attention performance and, longitudinally, increasing ventricular size predicted steeper EF/attention decline. Second, concurrently, higher ventricular size predicted lower EF/attention performance selectively in APOEɛ4+ carriers, and longitudinally, increasing ventricular size predicted steeper EF/attention decline selectively in the low PP group. Third, ventricular size and EF/attention associations were absent in the high APOE+ PP risk group both concurrently and longitudinally. CONCLUSION: As AD progresses, a threshold effect may be present in which ventricular enlargement in the context of exacerbated APOE+ PP risk does not produce further cognitive decline.

A Multimodal Risk Network Predicts Executive Function Trajectories in Non-demented Aging.

Background: Multiple modalities of Alzheimer's disease (AD) risk factors may operate through interacting networks to predict differential cognitive trajectories in asymptomatic aging. We test such a network in a series of three analytic steps. First, we test independent associations between three risk scores (functional-health, lifestyle-reserve, and a combined multimodal risk score) and cognitive [executive function (EF)] trajectories. Second, we test whether all three associations are moderated by the most penetrant AD genetic risk [Apolipoprotein E (APOE) ε4+ allele]. Third, we test whether a non-APOE AD genetic risk score further moderates these APOE × multimodal risk score associations. Methods: We assembled a longitudinal data set (spanning a 40-year band of aging, 53-95 years) with non-demented older adults (baseline n = 602; Mage = 70.63(8.70) years; 66% female) from the Victoria Longitudinal Study (VLS). The measures included for each modifiable risk score were: (1) functional-health [pulse pressure (PP), grip strength, and body mass index], (2) lifestyle-reserve (physical, social, cognitive-integrative, cognitive-novel activities, and education), and (3) the combination of functional-health and lifestyle-reserve risk scores. Two AD genetic risk markers included (1) APOE and (2) a combined AD-genetic risk score (AD-GRS) comprised of three single nucleotide polymorphisms (SNPs; Clusterin[rs11136000], Complement receptor 1[rs6656401], Phosphatidylinositol binding clathrin assembly protein[rs3851179]). The analytics included confirmatory factor analysis (CFA), longitudinal invariance testing, and latent growth curve modeling. Structural path analyses were deployed to test and compare prediction models for EF performance and change. Results: First, separate analyses showed that higher functional-health risk scores, lifestyle-reserve risk scores, and the combined score, predicted poorer EF performance and steeper decline. Second, APOE and AD-GRS moderated the association between functional-health risk score and the combined risk score, on EF performance and change. Specifically, only older adults in the APOEε4- group showed steeper EF decline with high risk scores on both functional-health and combined risk score. Both associations were further magnified for adults with high AD-GRS. Conclusion: The present multimodal AD risk network approach incorporated both modifiable and genetic risk scores to predict EF trajectories. The results add an additional degree of precision to risk profile calculations for asymptomatic aging populations.

Data-driven approaches to executive function performance and structure in aging: Integrating person-centered analyses and machine learning risk prediction.

Objective: Executive function (EF) performance and structure in nondemented aging are frequently examined with variable-centered approaches. Person-centered analytics can contribute unique information about classes of persons by simultaneously considering EF performance and structure. The risk predictors of these classes can then be determined by machine learning technology. Using data from the Victoria Longitudinal Study we examined two goals: (a) detect different underlying subgroups (or classes) of EF performance and structure and (b) test multiple risk predictors for best discrimination of these detected subgroups. Method: We used a classification sample (n = 778; Mage = 71.42) for the first goal and a prediction subsample (n = 570; Mage = 70.10) for the second goal. Eight neuropsychological measures represented three EF dimensions (inhibition, updating, shifting). Fifteen predictors represented five domains (genetic, functional, lifestyle, mobility, demographic). Results: First, we observed two distinct classes: (a) lower EF performance and unidimensional structure (Class 1) and (b) higher EF performance and multidimensional structure (Class 2). Second, Class 2 was predicted by younger age, more novel cognitive activity, more education, lower body mass index, lower pulse pressure, female sex, faster balance, and more physical activity. Conclusions: Data-driven modeling approaches tested the possibility of an EF aging class that displayed both preserved EF performance levels and sustained multidimensional structure. The two observed classes differed in both performance level (lower, higher) and structure (unidimensional, multidimensional). Machine learning prediction analyses showed that the higher performing and multidimensional class was associated with multiple brain health-related protective factors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Portals to frailty? Data-driven analyses detect early frailty profiles.

BACKGROUND: Frailty is an aging condition that reflects multisystem decline and an increased risk for adverse outcomes, including differential cognitive decline and impairment. Two prominent approaches for measuring frailty are the frailty phenotype and the frailty index. We explored a complementary data-driven approach for frailty assessment that could detect early frailty profiles (or subtypes) in relatively healthy older adults. Specifically, we tested whether (1) modalities of early frailty profiles could be empirically determined, (2) the extracted profiles were differentially related to longitudinal cognitive decline, and (3) the profile and prediction patterns were robust for males and females. METHODS: Participants (n = 649; M age = 70.61, range 53-95) were community-dwelling older adults from the Victoria Longitudinal Study who contributed data for baseline multi-morbidity assessment and longitudinal cognitive trajectory analyses. An exploratory factor analysis on 50 multi-morbidity items produced 7 separable health domains. The proportion of deficits in each domain was calculated and used as continuous indicators in a data-driven latent profile analysis (LPA). We subsequently examined how frailty profiles related to the level and rate of change in a latent neurocognitive speed variable. RESULTS: LPA results distinguished three profiles: not-clinically-frail (NCF; characterized by limited impairment across indicators; 84%), mobility-type frailty (MTF; characterized by impaired mobility function; 9%), and respiratory-type frailty (RTF; characterized by impaired respiratory function; 7%). These profiles showed differential neurocognitive slowing, such that MTF was associated with the steepest decline, followed by RTF, and then NCF. The baseline frailty index scores were the highest for MTF and RTF and increased over time. All observations were robust across sex. CONCLUSIONS: A data-driven approach to early frailty assessment detected differentiable profiles that may be characterized as morbidity-intensive portals into broader and chronic frailty. Early inventions targeting mobility or respiratory deficits may have positive downstream effects on frailty progression and cognitive decline.

Integrating Three Characteristics of Executive Function in Non-Demented Aging: Trajectories, Classification, and Biomarker Predictors.

OBJECTIVE: With longitudinal executive function (EF) data from the Victoria Longitudinal Study, we investigated three research goals pertaining to key characteristics of EF in non-demented aging: (a) examining variability in EF longitudinal trajectories, (b) establishing trajectory classes, and (c) identifying biomarker predictors discriminating these classes. METHOD: We used a trajectory analyses sample (n = 781; M age = 71.42) for the first and second goals and a prediction analyses sample (n = 570; M age = 70.10) for the third goal. Eight neuropsychological EF measures were used as indicators of three EF dimensions: inhibition, updating, and shifting. Data-driven classification analyses were applied to the full trajectory distribution. Machine learning prediction analyses tested 15 predictors from genetic, functional, lifestyle, mobility, and demographic risk domains. RESULTS: First, we observed: (a) significant variability in EF trajectories over a 40-year band of aging and (b) significantly variable patterns of EF decline. Second, a four-class EF trajectory model was observed, characterized with classes differentiated by an algorithm of level and slope information. Third, the highest group class was discriminated from lowest by several prediction factors: more education, more novel cognitive activity, lower pulse pressure, younger age, faster gait, lower body mass index, and better balance. CONCLUSION: First, with longitudinal variability in EF aging, the data-driven approach showed that long-term trajectories can be differentiated into separable classes. Second, prediction analyses discriminated class membership by a combination of multiple biomarkers from demographic, lifestyle, functional, and mobility domains of risk for brain and cognitive aging decline.

In multiple facets of subjective memory decline sex moderates memory predictions.

INTRODUCTION: Two established subjective memory decline facets (SMD; complaints, concerns) are early indicators of memory decline and Alzheimer's disease. We report (1) a four-facet SMD inventory (memory complaints, concerns, compensation, self-efficacy) and (2) prediction of memory change and moderation by sex. METHODS: The longitudinal design featured 40 years (53 to 97) of non-demented aging (n = 580) from the Victoria Longitudinal Study. Statistical analyses included confirmatory factor analyses and conditional latent growth modeling. RESULTS: The four-facet SMD Inventory was psychometrically confirmed. Longitudinal analyses revealed significant variability in level and change for SMD and memory. Prediction analyses showed complaints and concerns predicted lower level and steeper memory decline; however, follow-up moderation analyses revealed selective predictions for females. Memory compensation predicted decline overall. Lower memory self-efficacy predicted steeper decline selectively for males. DISCUSSION: Although traditional and novel SMD facets predicted memory decline, differential sex moderation was observed. SMD research benefits from conceptual complementarity and precision prediction.

Body mass index predicts cognitive aging trajectories selectively for females: Evidence from the Victoria Longitudinal Study.

OBJECTIVE: Elevated body weight in midlife is an established risk factor for accelerated cognitive decline, impairment, and dementia. Research examining the impact of later-life body mass index (BMI) on normal cognitive aging has produced mixed results. There is a need for longitudinal designs, replication across multiple cognitive domains, and consideration of BMI effects in the context of important moderators. The present research examined (a) BMI prediction of neuropsychological performance and decline in executive function (EF), neurocognitive speed, and memory and (b) sex stratification of BMI effects. METHOD: Participants (n = 869; 573 females; M age = 71.75, range = 53-85 years) were older adults from the Victoria Longitudinal Study. Latent growth modeling was used to examine BMI as a predictor of level and change in three latent variables of cognition. The data were then stratified by sex to test whether BMI effects differed for females and males. We adjusted for selected medical, psychosocial, and demographic characteristics. RESULTS: Higher BMI predicted less decline in EF, neurocognitive speed, and memory. Interestingly, when the data were stratified by sex, higher BMI predicted less neuropsychological decline across domains for females only. BMI was unrelated to cognitive aging trajectories for males. CONCLUSIONS: We found that elevated BMI was a risk-reducing factor for cognitive decline only for females. Results may be used to enhance the precision with which intervention protocols may target specific subgroups of older adults. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A multiomics approach to heterogeneity in Alzheimer's disease: focused review and roadmap.

Aetiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer's disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput 'omics' are unbiased data-driven techniques that probe the complex aetiology of Alzheimer's disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer's disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer's disease.

Mitonuclear interactions influence Alzheimer's disease risk.

We examined the associations between mitochondrial DNA haplogroups (MT-hgs; mitochondrial haplotype groups defined by a specific combination of single nucleotide polymorphisms labeled as letters running from A to Z) and their interactions with a polygenic risk score composed of nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset (AOO) of dementia. MT-hg K (Odds ratio [OR]: 2.03 [95% CI: 1.04, 3.97]) and a 1 SD larger nMT-PRS (OR: 2.2 [95% CI: 1.68, 2.86]) were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K (OR: 0.45 [95% CI: 0.22, 0.9]) and MT-hg T (OR: 0.22 [95% CI: 0.1, 0.49]) were observed. Individual MT-hgs were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T (Hazard ratio: 0.62 [95% CI: 0.42, 0.91]) and a synergistic interaction between the nMT-PRS and MT-hg V (Hazard ratio: 2.28 [95% CI: 1.19, 4.35]). These results suggest that MT-hgs influence dementia risk and that variants in the nuclear and mitochondrial genome interact to influence the AOO of dementia.

Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis.

OBJECTIVE: High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data. METHODS: To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data. RESULTS: Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age. CONCLUSION: Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals. CLINICAL TRIALS REGISTRATION: The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.

Age, cohort, and period effects on metamemory beliefs.

Questionnaires like the Metamemory in Adulthood Questionnaire (MIA; Dixon, Hultsch, & Hertzog, 1988) have been used to examine longitudinal changes and cross-sectional age differences in multiple metamemory facets (e.g., memory self-efficacy). This study used 3 independent cross-sectional samples (N = 1,555; ages 55-85) from the Victoria Longitudinal Study collected in 1986, 1992, and 2000 to evaluate period and cohort effects on 8 MIA scales. Alternative general linear models analyzed age, cohort, and period effects, while subsequently assessing gender differences in metamemory beliefs. Period effects were detected on the MIA Internal Strategy and External Strategy scales; self-reported use of internal strategies decreased while use of external memory aids increased over the historical period. Reliable cohort (generational) differences were found for MIA Change, with the lowest levels of perceived change in individuals born between 1916 and 1925. MIA Task, measuring knowledge about memory, produced small age and cohort effects. Gender differences emerged in metamemory, especially for the Internal Strategy and External Strategy scales (women reporting higher strategy use). Gender differences were also seen for the Capacity, Locus, Anxiety, and Achievement scales, with women reporting higher perceived memory efficacy, control, memory anxiety, and greater motivation to have better memory, respectively. The historical trends in metamemory beliefs should be replicated with other measures and other populations; however, the results generally confirm conclusions from earlier cross-sectional studies regarding age sensitivity of metamemory beliefs from middle age to old age. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Association of Alzheimer's Disease Genetic Risk Loci with Cognitive Performance and Decline: A Systematic Review.

The association of Apolipoprotein E (APOE) with late-onset Alzheimer's disease (LOAD) and cognitive endophenotypes of aging has been widely investigated. There is increasing interest in evaluating the association of other LOAD risk loci with cognitive performance and decline. The results of these studies have been inconsistent and inconclusive. We conducted a systematic review of studies investigating the association of non-APOE LOAD risk loci with cognitive performance in older adults. Studies published from January 2009 to April 2018 were identified through a PubMed database search using keywords and by scanning reference lists. Studies were included if they were either cross-sectional or longitudinal in design, included at least one genome-wide significant LOAD risk loci or a genetic risk score, and had one objective measure of cognition. Quality assessment of the studies was conducted using the quality of genetic studies (Q-Genie) tool. Of 2,466 studies reviewed, 49 met inclusion criteria. Fifteen percent of the associations between non-APOE LOAD risk loci and cognition were significant. However, these associations were not replicated across studies, and the majority were rendered non-significant when adjusting for multiple testing. One-third of the studies included genetic risk scores, and these were typically significant only when APOE was included. The findings of this systematic review do not support a consistent association between individual non-APOE LOAD risk and cognitive performance or decline. However, evidence suggests that aggregate LOAD genetic risk exerts deleterious effects on decline in episodic memory and global cognition.

Frailty effects on non-demented cognitive trajectories are moderated by sex and Alzheimer's genetic risk.

BACKGROUND: Age-related frailty reflects cumulative multisystem physiological and health decline. Frailty increases the risk of adverse brain and cognitive outcomes, including differential decline and dementia. In a longitudinal sample of non-demented older adults, we examine whether (a) the level and/or change in frailty predicts trajectories across three cognitive domains (memory, speed, and executive function (EF)) and (b) prediction patterns are modified by sex or Alzheimer's genetic risk (Apolipoprotein E (APOE)). METHODS: Participants (n = 632; M age = 70.7, range 53-95; 3 waves) were from the Victoria Longitudinal Study. After computing a frailty index, we used latent growth modeling and path analysis to test the frailty effects on level and change in three latent variables of cognition. We tested two potential moderators by stratifying by sex and APOE risk (ε4+, ε4-). RESULTS: First, frailty levels predicted speed and EF performance (level) and differential memory change slopes. Second, change in frailty predicted the rate of decline for both speed and EF. Third, sex moderation analyses showed that females were selectively sensitive to (a) frailty effects on memory change and (b) frailty change effects on speed change. In contrast, the frailty effects on EF change were stronger in males. Fourth, genetic moderation analyses showed that APOE risk (e4+) carriers were selectively sensitive to frailty effects on memory change. CONCLUSION: In non-demented older adults, increasing frailty is strongly associated with the differential decline in cognitive trajectories. For example, higher (worse) frailty was associated with more rapid memory decline than was lower (better) frailty. These effects, however, are moderated by both genetic risk and sex.