Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementias.

This study identified 91 genetic loci associated with Alzheimer's disease risk, including 16 new loci, but further validation is needed to confirm their clinical relevance.

Summary and findings

This meta-analysis examined the genetic architecture of Alzheimer's disease (AD) and related dementias (ADRD) in a population of 128,681 cases and 849,833 controls. It identified 91 genetic loci associated with ADRD risk, including 16 new loci, and reported a polygenic score linked to increased risk of AD pathology. No therapeutic claims are made.

Abstract

To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.

Key findings

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Limitations

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Elsewhere in the IGF-1 DES (Des(1-3) IGF-1) corpus