Purpose of Review: This article discusses the current status of knowledge regarding the genetic basis of Alzheimer disease (AD) with a focus on clinically relevant aspects.
Recent Findings: The genetic architecture of AD is complex, as it includes multiple susceptibility genes and likely nongenetic factors. Rare but highly penetrant autosomal dominant mutations explain a small minority of the cases but have allowed tremendous advances in understanding disease pathogenesis. The identification of a strong genetic risk factor, APOE, reshaped the field and introduced the notion of genetic risk for AD. More recently, large-scale genome-wide association studies are adding to the picture a number of common variants with very small effect sizes. Large-scale resequencing studies are expected to identify additional risk factors, including rare susceptibility variants and structural variation.
Summary: Genetic assessment is currently of limited utility in clinical practice because of the low frequency (Mendelian mutations) or small effect size (common risk factors) of the currently known susceptibility genes. However, genetic studies are identifying with confidence a number of novel risk genes, and this will further our understanding of disease biology and possibly the identification of therapeutic targets.
Address correspondence to Dr John M. Ringman, Easton Center for Alzheimer’s Disease Research at UCLA, 10911 Weyburn Ave., #200, Los Angeles, CA 90095–7226 firstname.lastname@example.org.
Relationship Disclosure: Dr Ringman serves as a consultant for Avanir Pharmaceuticals, Inc; Phloronol, Inc; Takeda Pharmaceutical Company Limited; and StemCells, Inc. Dr Ringman serves as site investigator for clinical trials sponsored by Alzheimer’s Disease Cooperative Study, Bristol-Myers Squibb Company, Elan Corporation; Genentech, Inc; Janssen Alzheimer Immunotherapy; Medivation, Inc; and Pfizer Inc. Dr Coppola receives or anticipates receiving grants, personal compensation, or other support from the NIH, the John Douglas French Alzheimer’s Foundation, the Muscular Dystrophy Association, Takeda Pharmaceutical Company Limited, the Adelson Medical Research Foundation, and the Tau Consortium.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Ringman and Coppola report no disclosures.