Key result
Each standard deviation increase in years of schooling (about 3.6 years) was significantly associated with a 29% reduced risk of clinically diagnosed Alzheimer's disease (OR 0.71).
Why the study?
The consistency of Mendelian randomization estimates for risk factors with Alzheimer's disease across GWAS, GWAX, and GWAS+GWAX datasets remained unclear.
Does genetically predicted educational attainment reduce Alzheimer's disease risk consistently across clinically diagnosed GWAS and self-report proxy GWAX datasets?
Observational (n=63,926)
Yes
Does genetically predicted educational attainment reduce Alzheimer's disease risk consistently across clinically diagnosed GWAS and self-report proxy GWAX datasets?
Odds Ratio: 0.71 (95% CI 0.6–0.84)
p-value: p=1.02E-04
Mendelian randomization estimates for the effect of educational attainment on Alzheimer's disease risk show significant genetic heterogeneity and contradictory directions of effect when comparing clinically diagnosed AD GWAS datasets with self-reported proxy phenotype GWAX datasets.
May support inverse association in clinical AD GWAS; heterogeneity with proxy datasets leaves causal effect open.
BACKGROUND: Until now, Mendelian randomization (MR) studies have investigated the causal association of risk factors with Alzheimer's disease (AD) using large-scale AD genome-wide association studies (GWAS), GWAS by proxy (GWAX), and meta-analyses of GWAS and GWAX (GWAS+GWAX) datasets. However, it currently remains unclear about the consistency of MR estimates across these GWAS, GWAX, and GWAS+GWAX datasets. METHODS: Here, we first selected 162 independent educational attainment genetic variants as the potential instrumental variables (N = 405,072). We then selected one AD GWAS dataset (N = 63,926), two AD GWAX datasets (N = 314,278 and 408,942), and three GWAS+GWAX datasets (N = 388,324, 455,258, and 472,868). Finally, we conducted a MR analysis to evaluate the impact of educational attainment on AD risk across these datasets. Meanwhile, we tested the genetic heterogeneity of educational attainment genetic variants across these datasets. RESULTS: In AD GWAS dataset, MR analysis showed that each SD increase in years of schooling (about 3.6 years) was significantly associated with 29% reduced AD risk (OR=0.71, 95% CI: 0.60-0.84, and P=1.02E-04). In AD GWAX dataset, MR analysis highlighted that each SD increase in years of schooling significantly increased 84% AD risk (OR=1.84, 95% CI: 1.59-2.13, and P=4.66E-16). Meanwhile, MR analysis suggested the ambiguous findings in AD GWAS+GWAX datasets. Heterogeneity test indicated evidence of genetic heterogeneity in AD GWAS and GWAX datasets. CONCLUSIONS: We highlighted significant difference and genetic heterogeneity in clinically diagnosed AD GWAS and self-report proxy phenotype GWAX. Our MR findings are consistent with recent findings in AD genetic variants. Hence, the GWAX and GWAS+GWAX findings and MR findings from GWAX and GWAS+GWAX should be carefully interpreted and warrant further investigation using the AD GWAS dataset.
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Liu et al. (2022) conducted an observational in Alzheimer's disease (n=63,926). Educational attainment (years of schooling) vs. Lower educational attainment was evaluated on Risk of clinically diagnosed Alzheimer's disease (OR 0.71, 95% CI 0.60-0.84, p=1.02E-04). Each standard deviation increase in years of schooling (about 3.6 years) was significantly associated with a 29% reduced risk of clinically diagnosed Alzheimer's disease (OR 0.71).
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