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Genomic variation in educational attainment modifies Alzheimer disease risk
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Abstract
Objective To determine the putative protective relationship of educational attainment on Alzheimer’s disease (AD) risk using Mendelian randomization, and to test the hypothesis that by using genetic regions surrounding individually associated SNPs as the instrumental variable we can identify genes that contribute to the relationship. Methods We performed Mendelian randomization using genome-wide association study summary statistics from studies of educational attainment and AD in two stages. Our instrumental variable comprised of i) 1,271 SNPs significantly associated with educational attainment and ii) individual 2Mb regions surrounding the genome-wide significant SNPs. Results A causal inverse relationship between educational attainment and AD was identified by the 1,271 SNPs (odds ratio = 0.63; 95% CI, 0.54-0.74; p =4.08×10 −8 ). Analysis of individual loci identified six regions that significantly replicated the causal relationship. Genes within these regions included LRRC2 , SSBP2 , and NEGR1 ; the latter a regulator of neuronal growth. Conclusions Educational attainment is an important protective factor for AD. Genomic regions that significantly paralleled the overall causal relationship contain genes expressed in neurons or involved in the regulation of neuronal development.
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“As previous studies and our results suggest, EduYears shows phenotypic correlations and shares genetic components with multiple traits and diseases relevant to medical research, including cognitive function, neurodegeneration and psychiatric disorders43–46”
From Shared genetic architectures of educational attainment in East Asian and European populations (2024) · cites this paper as [45]
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“Several studies have provided evidence that Negr1 is involved in Alzheimer disease (AD) [69, 70], autism spectrum disorder (ASD) [27], and schizophrenia (SCZ) [71].”
BackgroundThe Role of IgLON Cell Adhesion Molecules in Neurodegenerative Diseases
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“These findings were expanded by a study identifying statistically significant associations with the protective efficacy of SNPs located in the NEGR1 gene to mediate the protective role of educational attainment in Alzheimer’s disease [90].”
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“In addition, a contribution to Alzheimer’s disease risk has also been reported, supporting the relevant role of Negr1 in neuronal health and disease [8,9].”
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Chen, T.-T., Kim, J., Lam, M., Chuang, Y.-F., Chiu, Y.-L., Lin, S.-C., Jung, S.-H., Kim, B., Kim, S., Cho, C., et al. (2024) · Nature Human Behaviour · doi:10.1038/s41562-023-01781-9 · Cited by 18
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“Furthermore,arecentstudyused Mendelianrandomizationanalysiswith1,271SNPs previouslyassociatedwitheducationalattainmentto confirmthecausalrelationshipofeducationwithAD [15].”
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“decreased Alzheimer’s disease risk with more years in education (Raghavan et al., 2019).”
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“Recent studies have also indicated the involvement of IgLON4 and IgLON5 in the progression of neurodegenerative disorders 19–21 .”
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Mapping Causal Biology: Mendelian Randomization in the Era of Big Data
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“Similar protective effects were observed in studies by Raghavan et al. (2019) (OR: 0.63, 95% CI: 0.54–0.74) and Hu et al. (2022) (OR: 0.72, 95% CI: 0.66–0.78).”
InfluentialLuo, J., Li, X.-L., Wang, X., & Yuan, J. (2025) · Medicine · doi:10.1097/md.0000000000045331 · Cited by 1
“[33] SNPs showing linkage disequilibrium were filtered out based on R 2 0.001 and a window size of 10,000 kb. [34] If a selected IV was not present in the outcome summary data, SNPs with high linkage disequilibrium (i.e., R 2 > 0.8) were sought as proxy SNPs for replacement.”
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“(3 ) sNPs with linkage disequilibrium (lD) were excluded according to the criteria of R 2 < 0.001 and window size = 10,000 kb criteria [29]. if a screened iV was not present in the summary data of the outcome, sNPs with high lD (R 2 > 0.8) with the iV were searched for as a surrogate sNP to be…”
InfluentialHopkins, L. N., Avgan, N., Sutherland, H. G. E., Fernandez, F., Knowles, E. E. M., Haupt, L. M., Blangero, J., Glahn, D. C., Shum, D., Lea, R. A., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-32828-8
“NEGR1 has also been reported to be associated with MDD 100,101 and AD 102,103 , with its role in neuronal development, cognition, and learning widely studied in murine models 104–106 .”
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“SNPs in linkage disequilibrium (LD) were pruned to minimize bias from correlated genetic variants based on R 2 0.001 and a window size of 10,000 kb [28].”
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“Evidence shows a shared genetic architecture between cognitive performance, AD, and educational attainment 19,75 .”
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“Third, the SNPs were filtered based on a linkage disequilibrium (LD) threshold of R 2 0.001 and a window size of 10,000 kb [31].”
Influential
Metadata
- Authors
- Raghavan, N. S., Vardarajan, B., & Mayeux, R.
- Affiliations
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Mayeux, Richard
- Venue
- Neurology Genetics
- Published
- 2019-04
- Volume
- 5
- Issue
- 2
- Pages
- e310-e310
- ISSN
- 2376-7839 (ISSN-L)
- PMC
- PMC6395060
- OpenAlex
- W2903298416
- Cited by
- 33
- References
- 17
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 7 · 2019: 2
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Neurology Genetics (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (TL1TR001875)
- National Institute on Aging (U01AG032984, U24AG056270, U24AG021886)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, educational attainment, genetic risk factors, Mendelian randomization, single nucleotide polymorphisms, causal relationship, SSBP2, NEGR1, neuronal development, protective factors
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