Decoding the educational impact on Alzheimer's risk: an umbrella review of Mendelian randomization evidence

Alzheimer's disease (AD) remains a major global health challenge. The objective of this umbrella review is to synthesize Mendelian Randomization (MR) evidence evaluating the causal relationship between educational attainment (EA) and AD risk, thereby addressing the inherent limitations of observational studies.

We conducted a comprehensive literature search in PubMed, Embase, and Web of Science up to July 6, 2023. MR studies investigating the causal relationship between EA and AD risk were included. We assessed study quality using the STROBE-MR checklist and graded evidence strength. Due to heterogeneity in genetic instruments, a qualitative synthesis was performed.

Eleven publications examining 41 distinct associations were included. Most studies reported a consistent protective effect of EA on AD risk. However, this protective effect was attenuated when mediated by cognitive traits, which independently protected against AD. Quality assessment revealed variability in adherence to reporting guidelines, notably concerning study pre-registration and broad generalizability.

Findings highlight a complex interplay between EA, cognitive traits, and AD risk, aligning with the cognitive reserve hypothesis. Ultimately, EA exhibits a protective effect against AD, largely mediated by cognitive traits, and likely explained by multiple structural and lifestyle mechanisms. Future research must prioritize longitudinal designs and gene-environment interactions.