Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers

TL;DR

A protective PLCG2 gene variant delays Alzheimer’s onset in people with a specific APOE gene form, suggesting a potential therapeutic target.

Contribution

Identifies PLCG2 variants as protective against Alzheimer’s in APOE ε4 carriers and links them to elevated ghrelin levels.

Findings

PLCG2-P522R and PLCG2-3’UTR variants delay Alzheimer’s onset in APOE ε4 carriers.

PLCG2-P522R carriers have higher plasma ghrelin levels.

TREM2-R62H variant is linked to earlier Alzheimer’s onset in APOE ε4 carriers.

Abstract

The PLCG2-P522R variant, which encodes a mildly hyperactive form of the PLCγ2 enzyme, has been identified as a protective genetic factor against Alzheimer’s disease (AD). Many recently discovered AD-associated microglial risk genes converge on the TREM2-PLCγ2 signaling pathway, emphasizing the importance of characterizing this signaling pathway to uncover potential therapeutic targets and biomarkers. In this study, we investigated the effects of AD-associated PLCG2 and TREM2 variants, particularly in individuals carrying the APOE ε4 allele, and explored plasma biomarker profiles associated with these variants.

Using genotype and clinical endpoint data from the FinnGen genomic research project, we conducted Kaplan–Meier survival analyses and Cox proportional hazards models to assess the ages of onset for AD, anxiety, and type 2 diabetes. The key findings were replicated in the UK Biobank datasets. Additionally, we assessed several metabolic and inflammatory plasma biomarkers in relation to PLCG2 and TREM2 variants among participants in the FINGER multi-domain lifestyle intervention cohort.

In FinnGen, both the PLCG2-P522R and PLCG2-3’UTR variants associated independently with a delayed age of AD onset, including among heterozygous APOE ε4 carriers. Also, carriers of the PLCG2-P522R variant showed significantly elevated plasma levels of ghrelin. Conversely, APOE ε4 carriers with the TREM2-R62H variant exhibited an earlier AD onset age. Similar trends for AD onset age were observed in the UK Biobank data.

These findings indicate that protective PLCG2 variants may mitigate APOE ε4-associated AD risk in the Finnish population. Moreover, the elevated plasma ghrelin levels observed in the carriers of the PLCG2-P522R variant suggest a potential connection between this metabolic hormone and beneficial anti-inflammatory or cognitive effects, although its specific role in AD remains uncertain. Collectively, our results highlight the need for additional studies to further elucidate the mechanisms and biomarkers through which protective PLCG2 variants interact with APOE ε4.

The online version contains supplementary material available at 10.1186/s13195-026-01957-1.

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