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Review
. 2021 Feb 20;13(1):e12155.
doi: 10.1002/dad2.12155. eCollection 2021.

Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants

Julie Hoogmartens  1   2 , Rita Cacace  1   2 , Christine Van Broeckhoven  1   2
Affiliations
Review

Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants

Julie Hoogmartens et al. Alzheimers Dement (Amst). .

Abstract

Early-onset Alzheimer's disease (EOAD) is generally known as a dominant disease due to highly penetrant pathogenic mutations in the amyloid precursor protein, presenilin 1 and 2. However, they explain only a fraction of EOAD patients (5% to 10%). Furthermore, only 10% to 15% of EOAD families present with clear autosomal dominant inheritance. Studies showed that only 35% to 60% of EOAD patients have at least one affected first-degree relative. Parent-offspring concordance in EOAD was estimated to be <10%, indicating that full penetrant dominant alleles are not the sole players in EOAD. We aim to summarize current knowledge of rare variants underlying familial and seemingly sporadic Alzheimer's disease (AD) patients. Genetic findings indicate that in addition to the amyloid beta pathway, other pathways are of importance in AD pathophysiology. We discuss the difficulties in interpreting the influence of rare variants on disease onset and we underline the value of carefully selected ethnicity-matched cohorts in AD genetic research.

Keywords: Alzheimer's disease; biological pathways of disease; familial AD; genetic etiology; rare variants; sporadic AD.

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Figures

FIGURE 1
FIGURE 1
Schematic presentation of Alzheimer's disease (AD) genes and implicated pathways. A, Pathways in which the AD genes are involved. B, Apolipoprotein E (APOE) is a major common AD susceptibility gene involved in nine different pathways and harbors one rare variant modifying onset age. C, Color‐coded legend indicating the different genetic pathways associated with AD
FIGURE 2
FIGURE 2
Presentation of the genes in the familial to sporadic Alzheimer's disease (AD) spectrum. Rare variants (minor allele frequency [MAF] < 1%) associated with familial or sporadic AD by multiple independent studies are shown. All listed genes include heterozygous mutations associated with autosomal dominant AD, except 12S rRNA, which includes heterozygous mtDNA mutations associated with maternal AD. Red box: de novo mutations in PSEN1 and APP have been associated with sporadic AD
See this image and copyright information in PMC

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