G. Peggy McFall

Testing Covariates of Type 2 Diabetes-Cognition Associations in Older Adults: Moderating or Mediating Effects?

OBJECTIVE The general goal of this study was to advance our understanding of Type 2 diabetes (T2D)-cognition relationships in older adults by linking and testing comprehensive sets of potential moderators, potential mediators, and multiple cognitive outcomes. METHOD We identified in the literature 13 health-related (but T2D-distal) potential covariates, representing four informal domains (i.e., biological vitality, personal affect, subjective health, lifestyle activities). Cross-sectional data from the Victoria Longitudinal Study (age range = 53-90 years; n = 41 T2D and n = 458 control participants) were used. We first examined whether any of the 13 potential covariates influenced T2D-cognition associations, as measured by a comprehensive neuropsychological battery (15 measures). Next, using standard regression-based moderator and mediator analyses, we systematically tested whether the identified covariates would significantly alter observed T2D-cognition relationships. RESULTS Six potential covariates were found to be sensitive to T2D associations with performance on seven cognitive measures. Three factors (systolic blood pressure, gait-balance composite, subjective health) were significant mediators. Each mediated multiple cognitive outcomes, especially measures of neurocognitive speed, executive functioning, and episodic memory. CONCLUSIONS Our findings offer a relatively comprehensive perspective of T2D-related cognitive deficits, comorbidities, and modulating influences. The implications for future research reach across several fields of study and application. These include (1) neuropsychological research on neural and biological bases of T2D-related cognitive decline, (2) clinical research on intervention and treatment strategies, and (3) larger-scale longitudinal studies examining the potential multilateral and dynamic relationships among T2D status, related comorbidities, and cognitive outcomes.

IDE (rs6583817) Polymorphism and Pulse Pressure are Independently and Interactively Associated with Level and Change in Executive Function in Older Adults

OBJECTIVE We report a gene × environment (health) study focusing on concurrent performance and longitudinal change in a latent-variable executive function (EF) phenotype. Specifically, we tested the independent and interactive effects of a recently identified insulin degrading enzyme genetic polymorphism (IDE rs6583817) and pulse pressure (PP; one prominent aging-related vascular health indicator) across up to 9 years of EF data in a sample of older adults from the Victoria Longitudinal Study. Both factors vary across a continuum of risk-elevating to risk-reducing and have been recently linked to normal and impaired cognitive aging. METHOD We assembled a genotyped and typically aging group of older adults (n = 599, M age = 66 years at baseline), following them for up to 3 longitudinal waves (M interval = 4.4 years). We used confirmatory factor analyses, latent growth modeling, and path analyses to pursue 3 main research goals. RESULTS First, the EF single factor model was confirmed comprising 4 executive function tasks and it demonstrated measurement invariance across the waves. Second, older adults with the major IDE G allele exhibited better EF outcomes than homozygotes for the minor A allele at the centering age of 75 years. Adults with higher PP performed more poorly on EF tasks at age 75 years and exhibited greater EF longitudinal decline. Third, gene × health interaction analyses showed that worsening vascular health (higher PP) differentially affected EF performance in older adults with the IDE G allele. CONCLUSION Genetic interaction analyses can reveal differential and magnifying effects on cognitive phenotypes in aging. In the present case, pulse pressure is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across the risk and protective allelic distribution of this IDE gene.

IDE (rs6583817) polymorphism and type 2 diabetes differentially modify executive function in older adults

We tested independent and interactive contributions of a recently noted and promising insulin degrading enzyme polymorphism (IDE; rs6583817) and type 2 diabetes (T2D) to executive function performance, concurrently and longitudinally. Regarding normal neurocognitive decline and Alzheimers disease, T2D is a known risk factor and this IDE variant might contribute risk or risk reduction via the minor (A) or major (G) allele. We compared normal aging and T2D groups (baseline n = 574; ages 53-95 years) over 2 longitudinal waves (mean interval = 4.4 years). We used confirmatory factor analysis, latent growth curve modeling, and path analysis. A confirmed single-factor model of 4 executive function tasks established the cognitive phenotype. This IDE variant predicted concurrent group differences and differential change in cognitive performance. Furthermore, the IDE major allele reduced risk of cognitive decline. T2D predicted performance only concurrently. Both IDE and T2D are associated with executive function levels in older adults, but only IDE moderated 2-wave change. Previously linked to Alzheimers disease, this IDE variant should be further explored for its potential influence on cognitive phenotypes of normal aging.

ApoE and Pulse Pressure Interactively Influence Level and Change in the Aging of Episodic Memory: Protective Effects Among ε2 Carriers

OBJECTIVE We tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study. METHOD We assembled a sample of older adults (n = 570, baseline M age = 71, age range = 53-95) and used latent growth modeling to test 4 research goals. RESULTS First, the best fitting memory model was 2 single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE ε2 allele than the ε3 or ε4 alleles. CONCLUSIONS PP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene.

Alzheimer's genetic risk intensifies neurocognitive slowing associated with diabetes in nondemented older adults

We examine interactive and intensification effects of type 2 diabetes (T2D) with APOE and an Alzheimers disease genetic risk score (GRS) on neurocognitive speed performance and change in nondemented older adults.

Genetic factors moderate everyday physical activity effects on executive functions in aging: Evidence from the Victoria Longitudinal Study.

OBJECTIVE Everyday physical activity (EPA) is an important modifiable contributor to age-related variability in executive functioning (EF). However, its role may be moderated by nonmodifiable genetic factors. We tested independent and interactive effects of brain-derived neurotrophic factor (BDNF rs6265) and insulin degrading enzyme (IDE rs6583817) on EF and EPA-EF relationships. METHOD The sample consisted of genotyped older adults (N = 577; M age = 70.47 years) over 3 waves (∼9 years) of the Victoria Longitudinal Study. Analyses included (a) confirmatory factor analysis establishing a single latent EF factor from 4 standard EF tasks, (b) latent growth modeling over a 40-year band of aging (ages 53 to 95), and (c) structural regression to investigate the independent and interactive effects of BDNF, IDE, and EPA. RESULTS First, higher levels of EPA were associated with better EF performance at the centering age (75 years) and less EF decline. Second, IDE G+ (protective) carriers exhibited better EF performance at Age 75 than their G- (nonprotective) peers. Third, within the IDE G+ carrier group, those with higher EPA exhibited better EF performance and slower decline over time than those with lower EPA. Fourth, for the BDNF homozygote Val group, higher EPA was associated with better EF performance and more gradual EF change; however, this beneficial effect was not seen for Met carriers. CONCLUSION The effect of modifiable physical health factors on EF is moderated by biological mechanisms associated with risk-protection genetic polymorphisms.

Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles.

Objectives Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimers disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Method Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). Results For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Discussion Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied.

Alzheimer’s Disease Biomarkers Interactively Influence Physical Activity, Mobility, and Cognition Associations in a Non-Demented Aging Population

BACKGROUND Alzheimers disease (AD) risk-reduction strategies (e.g., increasing physical activity, improving mobility) have garnered increasing attention in the literature. However, the effect of such modifiable factors on the preclinical trajectories of brain and cognitive health may be moderated by non-modifiable biomarkers associated with AD. OBJECTIVE In a longitudinal sample of non-demented older adults, we examine the independent predictors everyday physical activity (EPA) and mobility on executive function (EF) performance and change. Next, we test whether these predictions are modified by interactions between age and AD genetic risk. METHODS This accelerated longitudinal design included adults (n = 532, M age = 70.4, age range 53-95) from the Victoria Longitudinal Study. We tested the independent effects of EPA and Mobility (i.e., gait, balance), moderation by Apolipoprotein E (i.e., APOEɛ4+, ɛ4-) and age (young-old, middle-old, old-old), and interactions between APOE and age on performance and 9-year change in an EF latent variable. RESULTS First, higher levels of both EPA and Mobility were associated with better EF performance and less decline. Second, the interaction between age and APOE showed that low EPA and older age was associated with poorer EF performance and steeper EF decline for APOEɛ4 + carriers, and low mobility was associated with poorer EF performance and steeper EF decline for APOEɛ4 + carriers than the non-risk carriers. CONCLUSION In non-demented older adults, age moderated the effects of both EPA and Mobility on EF performance and change. However, this moderation occurs differentially across APOE4 status.

An Alzheimer's genetic risk composite, but not ApoE, intensifies diabetes-related neurocognitive slowing in nondemented older adults

Background:Risk factors (and their synergistic interactions) associated with Alzheimer’s disease (AD) may predict normal or preclinical deficits and decline. Although ApoE (rs429358, rs7412) is the gene most consistently linked with AD risk, genome-wide association studies have identified others, including CLU (rs11136000), CR1 (rs6656401), and PICALM (rs541458). Type 2 diabetes (T2D) is a risk factor for AD and for increased cognitive deficits in nondemented older adults. We examined if the effect of diabetes on neurocognitive speed performance (level) and longitudinal change was intensified by (a) genetic risk from each of the four variants independently or (b) an AD Genetic Risk Composite (AGRC) representing combined risk from all four variants. Methods: This longitudinal design included non-demented older adults (n1⁄4591, baseline M age1⁄469, age range 53–91, 68% women, 8% with T2D) followed over 9 years. Saliva was processed with standard procedures from Oragene-DNA Genotek. Genotyping was carried out using a PCR-RFLP strategy. The AGRC was created by summing allelic risk across the four specified genotypes: 01⁄4no risk, 11⁄4moderate risk, 21⁄4full risk and then grouped into low and high risk using median split (Mdn1⁄43.0). Statistical analyses included latent growth modeling testing independent and interactive effects on level (centering age1⁄475) and change using a confirmed neurocognitive speed latent variable consisting of choice reaction time, sentence verification, and lexical decision measures. Results:First, adults with T2D exhibited slower speed performance at age 75 than adults without T2D (b1⁄4.494, p1⁄4.007). Second, none of the genetic risk variants showed independent effects on speed performance or change. Third, interaction analyses (e.g., T2D x ApoE) showed no magnification of speed decrements. Fourth, intensification interaction analyses (T2D x AGRC) showed that adults in the high risk AGRC group with T2D exhibited significantly greater 9-year decline in speed (b1⁄4.048, p1⁄4.004). Finally, education and pulse pressure where significant covariates but did not alter the observed effects. Conclusions: Independently, as expected, diabetes was associated with cognitive slowing in nondemented aging. Only the AD Genetic Risk Composite, not ApoE or other variants, intensified the effects of T2D on neurocognitive speed in the form of exacerbated slowing over 9 years.

Alzheimer's environmental and genetic risk scores are differentially associated with 'g' and δ

Introduction We investigated the association of the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) and an AD genetic risk score (GRS) with cognitive performance. Methods The ANU-ADRI (composed of 11 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1,061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modelling was used to evaluate the association of the ANU-ADRI and GRS with: 1) general cognitive ability (g) 2) dementia related variance in cognitive performance (δ) and 3) verbal ability, episodic memory, executive function and processing speed. Results A worse ANU-ADRI score was associated with poorer performance in ‘g’, δ, and each cognitive domain. A worse GRS was associated with poorer performance in δ and episodic memory. Discussion The ANU-ADRI was broadly associated with worse cognitive performance, validating its further use in early dementia risk assessment. Highlights An environmental/lifestyle dementia risk index is broadly associated with cognitive performance An Alzheimer’s genetic risk score is associated with dementia severity and episodic memory The environmental risk index is more strongly associated with dementia severity than genetic risk Research in Context Systematic Review The authors reviewed the literature using online databases (e.g. PubMed). Previous research has highlighted the need for dementia risk assessment tools to be evaluated on outcomes prior to dementia onset, such as cognitive performance. The relevant citations have been appropriately cited. Interpretation The Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) was more broadly associated with cognitive performance than Alzheimer’s genetic risk. For the ANU-ADRI, stronger effects were observed for dementia-related variance in cognitive task performance that for variance in general cognitive function. This suggests that ANU-ADRI is more specifically associated with dementia-related processes and further validates its use in early risk assessment for dementia. Future Directions Accordingly, future studies should seek to evaluate the association of the ANU-ADRI and genetic risk with AD biomarkers and longitudinal cognitive performance to evaluate differential trajectories in ‘g’ and δ.