Polygenic score analysis identifies distinct genetic risk profiles in Alzheimer’s disease comorbidities

Alzheimer's disease (AD) is usually accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH) that can significantly affect patient management and progression. As AD, these comorbidities have their own cumulative common genetic risk component that can be explored in a single individual through polygenic scores. Utilizing data from the UK Biobank, we investigated the correlation between polygenic scores (PGS) for these comorbidities and their actual presentation in AD patients. We show that individuals with higher PGS values showed an elevated risk of developing T2D (OR 2.1, p = 1.07 × 10^-11) and epilepsy (OR 1.5, p = 0.0176). High T2D-PGS is also associated with an earlier AD onset in individuals at high genetic risk for AD (AD-PGS). In contrast, no significant genetic associations were found for MDD and MH. Our findings show distinct common genetic risk factors for T2D and epilepsy carried by AD patients that are associated with increased prevalence and earlier disease onset. These results highlight the contribution of common genetic variation to the broader clinical landscape of AD and will contribute to future tailored patient management strategies for individuals at high genetic risk.