Examination of the Effect of Rare Variants in TREM2 , ABI3 , and PLCG2 in LOAD Through Multiple Phenotypes
Open accessAbstract
Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer’s disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2 , ABI3 , and TREM2 with LOAD risk and their effect at different time points of the disease. Methods: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ 42 , tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.
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PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer's disease and with longevity.
“PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer’s disease (AD) and with longevity.”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [10]
The Results (page unavailable) report that PLCG2 p.P522R was associated with reduced Alzheimer’s disease risk, and the Discussion (page unavailable) links it to enrichment in healthy centenarians. The Results attribute increased Alzheimer’s risk to variants in TREM2 and ABI3, not PLCG2; the cited paper does not support the claim that PLCG2 polymorphisms are associated with increased risk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPLCG2 M28L variant was also identified in a reanalysis of a European-American cohort database (OR=1.25, p=0.054).
“This variant was also identified in a reanalysis of a European-American cohort database (OR=1.25 p=0.054) 25 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [25]
The Genetic data and Statistical analyses sections describe an analysis of European-American cohorts, and the Results describe a reanalysis excluding overlapping samples. But the paper identifies the PLCG2 variant analyzed as p.P522R, not M28L; our copy does not report OR=1.25 or p=0.054 for M28L. No page numbers are available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredHuman genetics studies of Alzheimer's disease have identified the ABI3 gene or locus as a risk gene or risk variant for late-onset Alzheimer's disease.
“Human genetics studies of Alzheimer’s disease (AD) have identified the ABI3 gene as a candidate risk gene for AD.”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [17]
The association of the ABI3 variant with LOAD was replicated by independent groups.
“Subsequently, this association was replicated by independent groups (9, 10).”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [10]
ABI3 and its downstream pathways may be promising therapeutic targets.
“Given our functional data shown in this study and its significant genetic association with AD (8–10), ABI3 and its downstream pathways may be promising therapeutic targets.”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [10]
Human genetics studies of AD identified a coding variant of ABI3, p.Ser209Phe (rs616338), associated with late-onset AD.
“Human genetics studies of AD identified a coding variant of ABI3, p.Ser209Phe (rs616338), associated with late-onset AD158–161 (Table 2y).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [161]
PLCG2 P522R protection against AD was validated in a European-American cohort (OR=0.63, p=0.002).
“This finding was validated in a European-American cohort (OR=0.63, p=0.002) 25”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [25]
The PLCG2 M28L variant confers a modest increased risk of AD (OR ≈ 1.16).
“other rare PLCG2 variants, such as M28L (rs61749044) that confers a modest increased risk of AD (OR ≈ 1.16) [1, 4, 7–13]”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [13]
The Methods and Results passages discuss PLCG2 p.P522R, not M28L (rs61749044). Searches for M28L and OR 1.16 found no passage in our copy addressing the claimed risk estimate; the protective finding for p.P522R concerns a different variant. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSeveral other TREM2 variants (R62H, T66M, H157Y, D87N) increase the risk of AD.
“Several other TREM2 variants that affect the expression of TREM2 also increased the risk of AD, including R62H, T66M, H157Y, and D87N.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [168]
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References 54 · Cited by 32
Part of this paper’s reference list could not be split into single entries.
Research works printed but not linked: 3
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- Authors
- Olive, C., Ibanez, L., Farias, F. H. G., Wang, F., Budde, J. P., Norton, J. B., Gentsch, J., Morris, J. C., Li, Z., Dube, U., Del-Aguila, J., Bergmann, K., Bradley, J., Benitez, B. A., Harari, O., Fagan, A., Ances, B., Cruchaga, C., & Fernandez, M. V.
- Affiliations
- Washington University School of Medicine
- Washington University in St. Louis (US)
- ORCID
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2020-09-04
- Volume
- 77
- Issue
- 4
- Pages
- 1469-1482
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC7927150
- OpenAlex
- W3082995946
- Cited by
- 32
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 2
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (175.010.200, 047.017.043)
- National Institutes of Health (n01hc085082-026, n01hc085081-021, n01hc085079-024, n01hc085083-027, n01hc085080-026, n01hc085086-022, 5u01hl096899-08, n01hc25195-41-0-1, n01hc55222-0-0-0, 5u01hl096902-08)
- National Institute on Aging (R01AG064877, RF1AG044546, U01AG049505, U01AG016976, RF1AG053303, U01AG052409, R01AG020098, U01AG052410, K99AG061281, R01AG054076, U01AG057659, U01AG032984, R01AG049607, R01AG033040, UF1AG047133, U01AG049506, R01AG044546, P50AG005681, P01AG003991, R01AG064614, R01AG023629, U01AG049507, U01AG058922, RF1AG058501, U01AG049508, R01AG033193, R01AG015928, U01AG052411, R01AG057777, U54AG052427, U24AG056270, U24AG041689, P30AG066444, P01AG026276, U24AG021886)
- National Heart, Lung, and Blood Institute (HHSN268201 100012C, HHSN268201100007I, N01 HC085086, HHSN268201100007C, HHSN2682 01100008C, HH-SN-268201100006C, HHSN268201100011C, HHSN2682011-00005I, N01 HC085079, N01 HC085083, HHSN268201500001I, HHSN2682011-00009I, N01 HC085080, HHSN268201100005C, HHSN 268200800007C, HHSN268201500001C, HHSN268201100005G, HHSN268201100010C, U01HL130114, HHSN268201100011I, U01HL096814, N01-HC-025195, U01-HL-096899, HHSN268201200036C, HHSN26820 1100009C, N01HC085082, U01-HL-096902, R01HL105756, U01HL080295, N01 HC055222, HHSN2682011-00008I, U01HL096917, N01 HC085081, R01HL070825, RC2HL102419, U01HL096812)
- National Human Genome Research Institute (U54HG003067, U54HG003079, U54HG003273)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- late-onset Alzheimer's disease, rare variants
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Membrane Glycoproteins, Phenotype, Receptors, Immunologic, Genetic Variation, Cohort Studies, Databases, Genetic, Adaptor Proteins, Signal Transducing, Phospholipase C gamma
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