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

Abstract

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.

Brain atrophy trajectories predict differential functional performance in Alzheimer's disease: Moderations with apolipoprotein E and sex

“…Functional decline is accelerated in AD compared to prodromal stages of dementia (ie, mild cognitive impairment [MCI]), 8 and has been linked with several risk factors 9 including cognitive impairment, 10 brain atrophy, 11 increased white-matter hyperintensity, 12 genetics, 13 sex, 14 and dementia status. 15 A multimodal risk approach integrating multiple domains 16,17 with modifiable and non-modifiable risk factors is currently pursued in the field to predict accelerated cognitive trajectories in older adults 18 and dementia patients. 16 We apply a similar multimodal approach and extend previous work on cognitive changes to study differential functional trajectories in AD as predicted by three important and commonly studied risk domains (brain morphometry, genetics, and sex).…”

Vascular Risk Predicts Plasma Amyloid β 42/40 Through Cerebral Amyloid Burden in Apolipoprotein E ε4 Carriers

“… 7 , 9 Determining whether and how established modifiable risk factors impact the relationship between amyloid in the brain versus plasma will be necessary to understand their overall contribution to a larger heterogenous multifactorial risk network. 10 …”

“…7,9 Determining whether and how established modifiable risk factors impact the relationship between amyloid in the brain versus plasma will be necessary to understand their overall contribution to a larger heterogenous multifactorial risk network. 10 One key modifiable risk domain that we examine in the present study is vascular risk. Vascular risk factors have been directly linked to cerebral amyloid burden in older adults, 11,12 and synergistic associations of vascular risk and amyloid burden has been associated with cognitive decline.…”