Genetics of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the leading cause of neurodegeneration in the elderly and is clinically characterized by slowly progressing cognitive decline, which most commonly affects episodic memory function. This eventually leads to difficulties in activities of daily living. Biomarker studies show that the underlying pathology of AD begins 20 years before clinical symptoms. This results in the need to define specific targets and preclinical stages in order to address the problems of this disease at an earlier point in time. Genetic studies are indispensable for gaining insight into the etiology of neurodegenerative diseases and can play a major role in the early definition of the individual disease risk. This review provides an overview of the currently known genetic features of AD.

Keywords: Dementia; Genetic profiling; Neurodegeneration; Neurogenetics; Risk variants.

Fig. 1

Risk genes associated with AD. Previously identified genetic variants, represented by the frequency of risk alleles and the strength of the genetic effect. Colors in the legend indicate pathways in which the genes are involved. (Adapted from Lane et al. European Journal of Neurology, 2018 Risk genes associated with AD)

Fig. 2

Simplified, schematic representation of the ApoE signaling pathway, which controls APP transcription and Aβ production by activating a MAP kinase cascade. ApoE increases the risk of AD by causing a gradual increase in APP abundance and Aβ secretion, with ApoE4 being more and ApoE2 less efficient than ApoE3, in parallel with its effects on AD risk. (Adapted from Huang et al., Cell, 2017 Stimulation of APP transcription and Aβ secretion by ApoE)