2025 American Academy of Neurology Abstract Website

Objective:

Characterizing the gene-environment interactions with early pathological changes in Alzheimer’s disease (AD) is critical to precision medicine.

Background:

Alzheimer's disease (AD) is the leading cause of dementia, with genetics accounting for up to 80% of the risk. Lifestyle factors can modify this risk, making prevention strategies increasingly critical as effective treatments remain elusive.

Design/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, interactions between PRSs and environmental risk factors, and relationships between lifestyle subgroups and CSF biomarkers of AD.

Results:

Higher AD-PRS was associated with more severe amyloidosis, including Aβ42 (P = 0.033), pTau/Aβ42 (P = 0.013), and tTau/Aβ42 (P = 0.013). There were significant or suggestive interactions between AD-PRS and three environmental risk factors (anemia, gingivitis, and anxiety) for amyloidosis (P < 0.1). Stratified analyses by AD-PRS indicated that anemia was associated with more severe amyloidosis in the first and second quartiles (P < 0.1), while gingivitis and anxiety were associated with more severe amyloidosis in the fourth quartile (P < 0.1). Separately, a favourable lifestyle was associated with milder amyloidosis, in both the high genetic risk group and low genetic risk group.

Conclusions:

AD-PRS was associated with amyloidosis in the preclinical stages of AD. Individuals with a low genetic risk may experience greater benefits in terms of delaying amyloidosis by preventing anemia, while those with a high genetic risk may derive greater advantages by preventing gingivitis and anxiety. Irrespective of genetic risk, maintaining a healthy lifestyle can effectively delay the onset of amyloidosis.