Genetic Risk Factors for Complex Forms of Alzheimer’s Disease

Abstract

The most frequent forms of Alzheimer’s disease (AD) are complex, and their distribution within families cannot be explained by a Mendelian model of inheritance. In fact, these forms of AD result from a combination of genetic and environmental factors, with the estimated heritability ranging from 58 to 79%. This chapter reviews the large body of research on genetic risk factors in AD. Linkage analyses and candidate gene association studies have notably identified APOE (the major genetic risk factor for AD) and SORL1. Most of the other loci known to be associated with AD have been identified in genome-wide association studies and (more recently) analyses of rare variants. These AD-associated loci and genes have highlighted a number of underlying biological mechanisms, which will be discussed briefly. Although some of these pathways (e.g., amyloid precursor protein (APP) metabolism and tau pathology) fit with the amyloid cascade hypothesis, others point out innate immunity and microglia.