Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s Disease

We generated a proxy Alzheimer9s disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer9s disease. We identified four genes significantly associated with the proxy phenotype, three of which have been previously associated with clinically diagnosed Alzheimer9s disease (SORL1, TREM2, and TOMM40). We identified one gene (HEXA) which has not been previously associated with Alzheimer9s disease but is known to contribute to neurodegenerative disease. Here we show that proxy Alzheimer9s disease can capture some of the rare variant association signal for Alzheimer9s disease and can be used to highlight genes and variants of interest. The proxy phenotype allows for the utilisation of large genetic databases without clinically diagnosed Alzheimer9s disease patients to uncover variants and genes that contribute to Alzheimer9s disease.