Cognitive resilience polygenic risk score sensitive to preclinical disease changes

Abstract

AbstractBackgroundAlzheimer’s disease (AD) polygenic risk scores (PRS) are often derived from case/control GWAS, which are typically not sensitive to preclinical disease changes, limiting their clinical utility. To overcome this pitfall, we built and evaluated the performance of multiple PRS of AD‐related endophenotypes, including resilience to cognitive impairment in the presence of amyloid.MethodFour PRS were derived from GWAS of baseline memory, memory decline, cognitive resilience (Dumitrescu et al., 2021), and AD (Kunkle et al. 2019). PRS were built in an independent cohort that was free of dementia, the Vanderbilt Memory and Aging Project (N=255). We used linkage disequilibrium clumping on TOPMed‐imputed genotypes, and a threshold of P=0.01. We ran linear models with baseline memory score as the outcome, and baseline age, sex, and PRS as predictors. Linear mixed effects models, with identical predictors, were used when longitudinal memory was the outcome, letting individual slope and intercept vary. Finally, we tested a CSF Aβ42‐by‐PRS interaction term to assess if PRS modified associations between amyloid and cognition. Sensitivity analyses excluded APOE from PRS calculations.ResultAs expected, the baseline memory PRS related to baseline memory (β=0.12, P=0.04), and the memory decline PRS related to longitudinal memory (β=0.04, P=0.001). Without APOE, the baseline memory PRS and the memory decline PRS results attenuated. The AD PRS related to both baseline memory (β=‐0.19, P=0.002) and longitudinal memory (β=‐0.03, P=0.01), but results attenuated without APOE. The resilience PRS did not have a main effect on baseline or longitudinal memory. However, interestingly, the resilience PRS interacted with CSF Aβ42 on baseline memory (β=‐0.001, P=0.02; Figure 1), whereby the resilience PRS related to memory among amyloid‐positive individuals (β=0.44, P=0.01) but not amyloid‐negative individuals (β=0.06, P=0.46). No other PRS was predictive of memory among amyloid‐positive individuals, and resilience PRS results remained consistent without APOE.ConclusionOur results demonstrate that a resilience PRS appears to be predictive of individual cognitive performance downstream of amyloidosis. Future work is needed to replicate this finding, but our preliminary findings highlight the potential utility of resilience PRS for predicting individual risk for AD‐related cognitive impairment during the preclinical stages of disease.