Heterogeneous effects of genetic risk for Alzheimer's disease on the phenome

Here we report how four major forms of Alzheimer's disease (AD) genetic risk-APOE-epsilon 4, APOE-epsilon 2, polygenic risk and familial risk-are associated with 273 traits in similar to 500,000 individuals in the UK Biobank. The traits cover blood biochemistry and cell traits, metabolic and general health, psychosocial health, and cognitive function. The difference in the profile of traits associated with the different forms of AD risk is striking and may contribute to heterogenous presentation of the disease. However, we also identify traits significantly associated with multiple forms of AD genetic risk, as well as traits showing significant changes across ages in those at high risk of AD, which may point to their potential roles in AD etiology. Finally, we highlight how survivor effects, in particular those relating to shared risks of cardiovascular disease and AD, can generate associations that may mislead interpretation in epidemiological AD studies. The UK Biobank provides a unique opportunity to powerfully compare the effects of different forms of AD genetic risk on the phenome in the same cohort.

Automated summary

This study reveals the association of different forms of Alzheimer's disease genetic risk with various traits, contributing to the heterogeneous presentation of the disease. Significant traits associated with multiple forms of AD genetic risk and changes in traits across ages in high-risk individuals are identified. The study highlights the potential for survivor effects and shared risks to generate misleading associations in epidemiological AD studies.