Polygenic risk score analysis suggests hypothyroidism as a risk factor for Alzheimer’s disease

Utilizing the All of Us cohort, this study explores the relationship between clinical conditions, and AD risk, shedding light on potential preventative measures. We selected a subset of non-AD affected individuals aged 60 and older (n = 72,044). Polygenic Risk Scores (PRS) were calculated to assess AD risk, which were then associated with medical conditions. A replication study was conducted in the UK Biobank to validate the findings. We found significant association between AD-PRS and nine conditions, with the most significant being hypothyroidism (adj-p < 1.3 ^-06 ). The AD-PRS was significantly lower in participants with hypothyroidism, and was further confirmed in a replication study using the UK Biobank data (n=390,543; p= 1.3 ^-23 ). Our results demonstrate that the absence of hypothyroidism might be a factor enhancing AD resilience since it can balance the genetic risk factors, as non-affected individuals exhibited a significantly higher AD-PRS than individuals with hypothyroidism.