Gene–Environment Interactions for Alzheimer's Disease Pathology in Cognitively Normal Adults: The <scp>CABLE</scp> Study

BACKGROUND: Characterizing the gene-environment interactions with early pathological changes in Alzheimer's disease (AD) is critical to precision medicine. METHODS: We recruited 1007 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Multiple linear regression models were applied to explore the associations between polygenic risk scores (PRSs) and cerebrospinal fluid (CSF) biomarkers of AD, the interactions between PRSs and potentially modifiable risk factors, and the relationships between lifestyle categories and CSF AD biomarkers. RESULTS: A higher AD-PRS was associated with more severe amyloidosis, as indicated by pTau/Aβ42 (β = 0.091, p = 0.005) and tTau/Aβ42 (β = 0.092, p = 0.004). There were significant interactions between AD-PRS and three modifiable risk factors (anemia, gingivitis, and anxiety) in AD biomarker ratios. Stratified analyses by AD-PRS indicated that anemia was associated with higher pTau/Aβ42 and tTau/Aβ42 in the first and second quartiles, while gingivitis and anxiety correlated with amyloidosis in the fourth quartile (all p < 0.05). Additionally, a favorable lifestyle was associated with milder amyloidosis in the high genetic risk group. CONCLUSIONS: AD-PRS was associated with amyloidosis severity. The associations between modified risk factors (anemia, gingivitis, and anxiety) and biomarker ratios differed by genetic risk strata. Moreover, a healthy lifestyle was associated with less amyloid burden in individuals with high genetic risk. These findings can be used to generate hypotheses for future longitudinal studies to investigate whether targeted management of these factors influences AD pathological progression.