Loading your page…
Research Square
By Ren Y, He Z, Feng Y and 4 others.
Abstract Background: The etiology of Alzheimer’s disease (AD) is an intricate pathological mechanism. Increasing evidence has demonstrated a significant association between epilepsy and the development or progression of Alzheimer's disease.
Ward brings these articles into the same app as your cards and questions. One free account for Ward, Suture, Osler and Prognia.
Two-sample MR evaluated focal epilepsy with documented hippocampal sclerosis as the exposure and AD as the outcome. The epilepsy dataset included 803 cases and 29,677 controls, while the AD dataset comprised 39,106 clinically diagnosed cases, 46,828 proxy cases, and 401,577 controls. After linkage disequilibrium clumping, harmonization, instrument-strength assessment, and Steiger filtering, two independent variants were retained. Additional UK Biobank association analyses were performed using REGENIE, including 57,795 AD cases with approximately 283,500 controls and 4,556 epilepsy cases with 289,065 controls. Associated loci were characterized using FUMA, MAGMA, regulatory annotation, and Bayesian colocalization.
Inverse-variance weighted MR indicated that genetically predicted focal epilepsy with hippocampal sclerosis was associated with increased odds of AD (OR=3.99, 95% CI 1.17–13.61; P=0.027). No heterogeneity was detected (Cochran’s Q=0.006, P=0.939; I²=0%). In the UK Biobank epilepsy GWAS, 95 variants reached the suggestive threshold (P<5×10⁻⁶). The strongest shared signal was rs429358 in APOE, which approached genome-wide significance in epilepsy (OR=1.12, 95% CI 1.07–1.16; P=5.48×10⁻⁸) and showed a substantially stronger association with AD (OR=1.67, 95% CI 1.65–1.70; P=2.23×10⁻³⁰⁷). At P < 5 × 10⁻⁶, rs429358 was the only overlapping variant between the two GWAS results. Colocalization of 1,113 harmonized variants at the chromosome 19 APOE locus strongly supported a shared association signal (PP.H4=0.99994), with rs429358 carrying virtually all variant-level posterior probability. MAGMA identified 32 Bonferroni-significant genes and 10 significant gene sets in AD, whereas none survived correction in epilepsy.
Using large-scale datasets, including UK Biobank and IEU data, these findings provide preliminary evidence that epilepsy may increase AD susceptibility and identify rs429358 as a potential overlap SNP with shared potential biological signal pathways. Larger epilepsy datasets and independent replication are required.
This is a preprint: it has not been peer reviewed yet, and its findings may change.
Published in Research Square (preprint). The abstract is shown as published and remains the work of its authors; read the full article at the source.
Prognia lists this article for reference and education. It is not medical advice. Always read the original and follow current guidelines and local protocols before acting on it.
