Background: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without apolipoprotein E (APOE) were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and global/domain-specific cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers for beta-amyloid 42 (Aβ42), Aβ42/40 ratio, total tau, and phosphorylated tau in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSs/PRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE, the p-PRSs can predict age-dependent changes in beta-amyloid, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating beta-amyloid and tau, long before the onset of clinical symptoms.

Background: Genetic scores for late-onset Alzheimer’s disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (e.g., a non-APOE polygenic risk scores [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS×APOE ε4×age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals. RESULTS: We found statistically significant PRS×APOE ε4×age interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSION: APOE ε4 can modify the association between PRS and cognition decline.

BackgroundApolipoprotein E4 (APOE‐ε4) is the strongest known risk factor for late‐onset Alzheimer’s disease (LOAD). Variation in cognitive decline patterns among cognitively unimpaired individuals suggests that additional LOAD‐related genetic factors may interact with APOE‐ε4 to influence cognitive decline during asymptomatic aging. In the present study, we aim to investigate whether any genome‐wide association studies (GWAS) and p‐value threshold (pT)‐informed non‐APOE polygenic risk scores (PRS) moderate associations between APOE‐ε4 and longitudinal cognition.MethodsWe leveraged 12 years of longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention, and we built eight PRSs under various pTs for single nucleotide polymorphism selection using summary statistics from three GWAS meta‐analyses: International Genomics of Alzheimer’s Project (IGAP) case‐control study, UK‐biobank (UKBB) AD‐by‐proxy study, and a combined sample that merges IGAP and UKBB study results. All association analyses were fitted using a linear mixed effects model and adjusted for within‐individual/family correlation among 1,190 cognitively unimpaired individuals at baseline (Table 1). A set of sensitivity analyses were performed to assess the robustness of the main findings.ResultsWe found that the adverse effect of non‐APOE PRS on overall and memory‐related cognitive domains is more evident among APOE‐ε4 carriers as people age (Figure 1). There is a gradual, statistically significant difference in the rate of overall and memory‐related cognitive decline per unit change of non‐APOE PRSs between APOE‐ε4 carriers and non‐carriers for people over the age of 70 (Figure 2). Our study findings are consistent with a relatively stringent pT (p <= 5e‐8) and more evident when the PRSs are constructed using the case‐control GWAS study results, despite the smaller sample size (“Kunkle significant variants only” in Figures 1 and 2). Our findings are also robust to various sensitivity checks when we replace the dichotomous APOE‐ε4 predictor with the APOE genotype, use different PRS clumping parameters, and exclude cognitive measurements from the last test occasion, which has a smaller sample size.ConclusionWe recommend considering the interaction between non‐APOE PRS, APOE status, and age in modeling pre‐clinical cognitive phenotypes for LOAD. We also recommend leveraging a conservative p‐value threshold and using case‐control GWAS results in constructing the LOAD PRS.

BackgroundGenetic and lifestyle factors contribute to an individual’s risk for developing Alzheimer’s disease (AD). A better understanding of interactions between these factors may help design targeted interventions. In this study, we investigated whether number of long‐term healthy lifestyles modified the effect of genetic predisposition to AD on cognitive decline during the preclinical stage of AD.MethodsWe evaluated longitudinal associations of cognitive aging with a healthy lifestyle composite score, which included physical activity, diet, smoking, cognitive activity, and alcohol consumption, and the interaction of the healthy lifestyle composite score with APOE ε4 carrier status and a non‐APOE polygenic risk score (PRS) in a sample of 848 individuals from the Wisconsin Registry for Alzheimer’s Prevention (Table 1). The primary outcome was a multi‐domain cognitive composite (PACC3); secondary outcomes were immediate/delayed memory and executive function composites. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation.ResultsFavorable lifestyles can marginally modify the age dependent influence of APOE on PACC3 (p = 0.1) and executive function (p = 0.14), and significantly mitigate the adverse effect of APOE ε4 on delayed recall as people aging (p < 0.01, Figure 1). However, we observed no statistically significant interactions between non‐APOE PRS, combined lifestyle factors, and age for all the assessed cognitive outcomes (Figure 2). When we further stratify the sample by the APOE ε4 carrier status, we found the interaction between non‐APOE PRS, age, and healthy lifestyle is statistically significant for PACC3 (p = 0.02) and delayed recall (p < 0.01) and marginally significant for immediate learning (p = 0.06) among APOE ε4 carriers (Figure 3). Among APOE ε4 noncarriers, combined lifestyle factors can only modify the age‐dependent adverse genetic influence of non‐APOE PRS on PACC3 (p = 0.01), but the protective effect is more evident at a younger age (Figure 4). These results are robust to multiple sensitivity analyses.ConclusionA favorable lifestyle can mitigate the genetic risk caused by both APOE ε4 and non‐APOE PRS, but the protective effect against non‐APOE PRS is more evident among APOE ε4 carriers.