Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

  • Neha Raghavan
  • Giuseppe TostoEmail author
Dementia (K S Marder, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Dementia


Purpose of Review

We aimed to summarize the recent advances in genetic findings of Alzheimer’s disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components.

Recent Findings

Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components.


We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.


GWAS Next-generation sequencing Polygenic risk score Epistasis 



Dr. Tosto is supported by NIH grant R21AG054832

Compliance with Ethical Standards

Conflict of Interest

Neha Raghavan and Giuseppe Tosto each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.The Gertrude H. Sergievsky Center, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  2. 2.Department of Neurology, Columbia University College of Physicians and SurgeonsNew York Presbyterian HospitalNew YorkUSA
  3. 3.Institute for Genomic MedicineColumbia UniversityNew YorkUSA
  4. 4.The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

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