Brain somatic mutations associated with aging contribute to the initiation of Tau pathology in Alzheimer's disease

Abstract

Brain somatic mutations arising from the neural stem cell niche appear to underlie several neurodevelopmental disorders and brain tumors. Studies, however, have yet to shed light on the significance and pathogenic roles of brain somatic mutations in Alzheimer’s disease (AD). Here, we performed deep whole-exome sequencing (average read depth 584X) in 111 postmortem hippocampal formation and matched blood tissues from 52 AD patients and 11 non-demented individuals. We found an average of 11.96 and 12.91 somatic single nucleotide variations (SNVs) in brain tissue from AD patients and controls, respectively, and 59.31 and 59.17 SNVs from blood. The number of somatic mutations in brain specimens increased significantly with aging, and the rate of mutation accumulation in the brain was 4.8-fold slower than that in blood. The pathogenic somatic mutations identified in 26.9% (14 of 52) of AD individuals were enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of Tau. Further, we discovered that a pathogenic brain somatic mutation in PIN1 leads to a loss of function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increased the phosphorylation and aggregated form of Tau. Altogether, this study provides new insights into the genetic architecture underlying the pathogenesis of AD, demonstrating that brain somatic mutations associated with aging contribute to the initial appearance of Tau pathology in the hippocampal formation of the AD brain.