Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer’s Disease
Open accessAbstract
Background: Alzheimer’s disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. Objective: We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. Methods: We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer’s Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer’s Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. Results: We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year progression to AD from MCI significantly increased the predictive accuracy. Conclusion: Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.
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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 [9]
The Results section discusses two other PLCG2 variants, rs4073828 and rs4369658, and mentions five previously reported AD-associated variants without identifying M28L. Searches for M28L, rs61749044, and an odds ratio near 1.16 found no passage in our copy supporting the specific claim. (LLM, conf=0.76)
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- Authors
- Li, H., Initiative, F. T. A. D. N., Liu, H., Lutz, M. W., & Luo, S.
- Affiliations
- Duke University (US)
- Corresponding author
- Luo, Sheng
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2023-01-31
- Volume
- 91
- Issue
- 3
- Pages
- 977-987
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC9905310
- OpenAlex
- W4311344417
- Cited by
- 17
- References
- 51
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 5
- FWCI
- 2.12
- 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
- U.S. Department of Defense (U01 AG024904, P50 AG005138, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Alzheimer's Association (P30 AG013854, P30AG010124, P50 AG023501, U01 AG016976, P50 AG025688, AG010129, P30AG035982, P50 AG005681, P30 AG053760, P30 AG010161, U01 AG024904, P30 AG062421, P50 AG008702, P30 AG062422, P30 AG049638, P30 AG010133, P50 AG005136, W81XWH-12-2-0012, P50 AG005146)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
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- University of Southern California (P50AG005142, W81XWH-12-2-0012, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, P30 AG010129)
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- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012, P30 AG010129)
- National Institute on Aging (U01-AG-024904, AG062429, AG 005138, AG-028383, AG010133, AG 016976, P30AG053760, P30AG010129, P30AG010133, AG062421, AG-016573, AG008051, P30-AG062428, P30AG049638, AG047366, W81XWH-12-2–0012, AG-010124, P30AG028383, P30AG012300, AG-005133, AG 025688, R01AG064803, AG008017, P50AG005133, AG 024904, U01AG016976, AG-013854, AG035982, AG049638, P50AG005138, AG062715, AG019610, AG010161, P30AG010124, AG047266, P50AG016573, P50AG047366, AG010129, P30AG008017, P30 AG062428‐01, P30AG010161, P30AG008051, P50AG008702, AG023501, P30AG035982, AG013846, P50AG005681, P50AG005142, P50AG047270, P30AG019610, P50AG005146, AG047270, P30AG013846, P50AG005136, AG062422, P30AG013854, AG053760, P50AG025688, P50AG047266, AG005681, P30AG062429, P30AG062422, P30AG028716, P30AG072958, P30AG062715, U24AG072122, P30AG072947, P30AG062421, P50AG023501)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, mild cognitive impairment
- MeSH terms
- Alzheimer Disease, Bayes Theorem, Humans, Nerve Growth Factors, Transcription Factors, Biomarkers, Amyloid beta-Peptides, tau Proteins, Disease Progression, Neurodegenerative Diseases, Class Ia Phosphatidylinositol 3-Kinase, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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