A COMMON ALLELE IN SPI1 LOWERS RISK AND DELAYS AGE AT ONSET FOR ALZHEIMER'S DISEASE

The age at onset of late-onset Alzheimer’s disease (AD) spans at least 4 decades but its modifying genetic factors remain largely unknown. We conducted a genome-wide survival analysis on 39,855 samples of European ancestry from the International Genomics of Alzheimer’s Project (IGAP) Consortium to discover genetic variants associated with age at onset. We then validated the suggestive locus through CSF biomarker associations, and further investigated the underlying mechanisms with eQTL and gene expression analysis. Rs1057233, located in a previously reported AD risk locus near CELF1/SPI1, was associated with lower age at onset (p=8.3x10-6), higher cerebrospinal fluid Aβ42 levels (p=1.2x10-4), and lower expression of SPI1 in human monocytes (p=6.39x10-102). SPI1, a transcription factor involved in myeloid and B-lymphoid cell differentiation and function, is co-expressed with multiple known AD microglial expressed genes including TYROBP, MS4A4A and CD33, and binds to the DNA at these loci. We nominate SPI1 as a new AD risk gene that affect CSF abeta and age at onset of AD. Therapeutics that lower SPI1 levels or modulate genes downstream of SPI1 may be effective in reducing risk for AD.