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Two New Genetic Risk Factors for Alzheimer’s Disease

This study was published as a preprint and has not yet been peer reviewed.

Key Takeaways

  • Variants in ATP8B4 and ABCA1 were identified as novel risk factors for Alzheimer’s disease (AD), and there is evidence that rare variants in ADAM10 may also confer risk.

  • This study supports previous work identifying damaging variants in the SORL1, TREM2, and ABCA1 genes.

  • The RIN3, CLU, ZCWPW1, and ACE genes also had suggestive signals and may be driver genes in genome-wide association studies loci.

Why This Matters

  • AD is the most common cause of dementia, and genetic variation can contribute to disease risk.

  • Previous studies have identified genetic risk factors for AD. However, many of these variants have low effect sizes individually, and a better understanding of risk factors is still needed.

  • Large studies comparing sequencing data from thousands of patients with AD and healthy controls can yield more insight into risk factors.

  • Understanding risk factors and disease pathophysiology can have clinical implications as treatments for AD become available.

Study Design

  • The authors of this large collaborative multistage gene burden analysis examined exome sequencing data from patients with AD and healthy controls collected from multiple studies in the United States and Europe.

  • Quality control procedures helped to account for site-specific technical biases from data collected at different centers using different methods.

  • The stage 1 analysis compared gene-based rare-variant burdens in patients with AD and controls.

  • The stage 2 analysis examined an independent dataset using the same analysis model in patients to confirm stage 1 findings.

  • Characteristics of identified rare damaging variants were further analyzed to understand how they may contribute to AD risk.

Key Results

  • The study analyzed exome sequencing data from 32,558 individuals, including 16,036 patients with AD and 16,522 controls.

  • The stage 1 analysis compared gene-based rare-variant burdens in patients with AD (n = 12,652) and controls (n = 8693).

  • The stage 2 analysis examined an independent dataset of patients with AD (n = 3384) and controls (n = 7829).

  • Analysis supported previous identification of rare damaging variants in the SORL1, TREM2, and ABCA1 genes.

  • Damaging variants were suggested in ATP8B4, ABCA1, and ADAM10. However, likely due to rarity, the ADAM10 signal was not significant exome-wide, and a larger dataset is needed to confirm.

  • The RIN3, CLU, ZCWPW1, and ACE genes also had suggestive signals, were enriched in early-onset AD cases, and may act as drivers in GWAS loci.

  • Identified genes may play a role in AD pathology, including through APP processing, lipid metabolism, Aβ aggregation, or neuroinflammatory processes.

Limitations

  • Data were collected at different centers using different methods that may collectively contribute to site-specific technical biases. The authors employed quality control procedures to help correct for these biases.

Disclosures

  • The authors declared no conflicts of interest.

  • The research was supported through numerous grants and funding sources, including the Clinical Research Hospital Program from the French Ministry of Health, Fondation Alzheimer, and Stichting Alzheimer Nederland. Supplemental materials contain full funding acknowledgments.

This is a summary of a preprint research study, “Exome Sequencing Identifies Rare Damaging Variants in ATP8B4 and ABCA1 As Novel Risk Factors for Alzheimer’s Disease,” written by Henne Holstege from Amsterdam University Medical Center and colleagues. This study from medRxiv is provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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