PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

AbstractA rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer ’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and A β1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that ofAPOE- ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low A β1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of thePLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connectingPLCG2 toAPOE andTREM2 using unsupervised...
Source: Acta Neuropathologica - Category: Neurology Source Type: research