Association of Polygenic Risk Score for 5 Diseases With Alzheimer Disease Progression, Biomarkers, and Amyloid Deposition

Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder influenced by genetic and environmental factors. Conditions such as type 2 diabetes (T2D), cardiovascular disease, obesity, depression, and obstructive sleep apnea (OSA) increase AD risk and progression. This study aimed to examine the genetic predisposition to these conditions and their effect on AD pathophysiology, risk, and progression. A retrospective analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a North American prospective cohort. Polygenic risk scores (PRSs) for OSA, T2D, coronary artery disease (CAD), major depression, and body mass index (BMI) were generated for 752 non-Hispanic White participants with whole-genome sequencing data. Logistic regression was used to evaluate associations between PRSs and progression from mild cognitive impairment (MCI) to AD. Time to progression across PRS quartiles was analyzed using Cox proportional hazards models. PET amyloid and tau deposition rates, regional neocortical atrophy, and cognitive composite score declines were compared across OSA PRS quartiles using analysis of variance (ANOVA). Among 463 ADNI participants with baseline MCI (mean age 72.6 ± 7.3 years, 43.4% female), the OSA PRS, adjusted for BMI, was significantly associated with MCI-to-AD progression. The highest OSA PRS quartile had an odds ratio of 1.86 (95% CI 1.03-3.37) at 3 years and 2.02 (95% CI 1.16-3.51) at 5 years, compared with the lowest quartile. PRSs for T2D, CAD, major depression, and BMI were not associated with MCI-to-AD progression. Participants in the highest OSA PRS quartile had higher PET amyloid deposition and greater cognitive decline. In 752 participants (mean age 74.1 ± 7.3 years, 43.6% female), OSA PRS was significantly associated with baseline levels of PET amyloid, CSF amyloid-β 42, phosphorylated tau (p-tau), visinin-like protein 1, tumor necrosis factor receptor 1, and plasma neurofilament light after multiple testing adjustments. Individuals with high polygenic susceptibility to OSA exhibited an increased risk of MCI-to-AD progression and a higher amyloid deposition rate, suggesting potential modifier effects of OSA or OSA-associated genes on AD progression and pathophysiology. However, the small sample size and lack of objective OSA diagnosis limit interpretation of these genetic effects.