The original paywalled research paperAn analysis of exome sequencing data from more than 10,000 individuals with late onset Alzheimer’s disease (AD; LOAD) suggests that natural variants in tyrosine phosphatase genes may protect against the neurodegenerative disorder by impacting on the PI3K/Akt/GSK-3β signaling pathway. This pathway is important for cell survival. ...
https://onlinelibrary.wiley.com/doi/ful ... /ahg.12375
Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways
David Curtis, Kaushiki Bakaya, Leona Sharma, Sreejan Bandyopadhyay
Annals of human genetics
First published: 05 February 2020
DOI: 10.1111/ahg.12375
Unfortunately, I don't see an open access discussion regarding which alleles provide protection.Abstract
Previous studies have implicated common and rare genetic variants as risk factors for late‐onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome‐sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7, and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because PIK3R1 variants are expected to impair PI3K/Akt/GSK‐3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease.
