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

Abstract

A 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 pTau 181 , total tau, and Aβ 1-42 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 pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 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 connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade Agustin Ruiz and Alfredo Ramirez have contributed equally to this work. The members of the Alzheimer's Disease Neuroimaging Initiative (ADNI) group are listed in Acknowledgements section. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc. edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.

Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy

“…Our results are aligned with those from a recent study of longitudinally followed clinical patients with mild cognitive impairment (MCI), where PLCG2_rs72824905-G was associated with lower cerebrospinal fluid (CSF) levels of pTau181 and cognitive decline [15]. Collectively, our study which is focused on tau neuropathology and the published work on CSF tau [15] are consistent with a model where the effect of PLCG2_rs72824905-G in suppressing hyperphosphorylated tau may be most pronounced in the early stages of tau cortical deposition.…”

“…It is possible that suppression of tau neuropathology by PLCG2 _rs72824905-G may have a protective effect in neurodegeneration in the context of other neuropathologies but not when tau is the primary proteinopathy. Consistent with this possibility is the the suppressive effect of PLCG2 _rs72824905-G on CSF pTau181, which was most pronounced in those MCI patients who also had evidence of Aß deposits based on low CSF Aß42 levels [ 15 ].…”

KL-VS heterozygosity is associated with reduced tau accumulation and lower memory impairment in Alzheimer’s disease

“…To our knowledge, the current study is the first to date that evaluated the interaction between KL-VS het and Aβ on tau accumulation and cognitive decline in humans. There is a growing literature on protective genetic variants in AD 38-40 , but only a few studies have reported genetic variants to be associated with lower tau pathology in AD 41 . For the KL-VS het variant, previous studies reported an association with reduced Aβ accumulation in elderly ApoE ε4 risk-carriers 13,16 .…”

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

“…These have been extensively reviewed elsewhere [7]. Conversely, a protective polymorphism in PLCG2 (rs72824905: p.Pro522Arg) has been associated with: decreased risk of LOAD (odds ratio = 0.68; minor allele frequency cases = 0.0059, controls = 0.0093 [1]), Dementia with Lewy Bodies and Frontotemporal Dementia, slowed disease progression, which correlated with a reduction of pTau 181 and tTau in cerebrospinal fluid (CSF) [8], and finally promotion of healthy ageing [1,8,9]. Moreover, the protective PLCγ2 variant seems to counteract the harmful effect of the APOE ε4 allele, as shown for a cognitively healthy centenarian carrying both the homozygous APOE ε4 and the PLCG2 protective polymorphism [9].…”