From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Abstract

Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

“…Consistent with the downregulation of IL-10 receptor signaling in Csf1r +/microglia, its downstream signaling mediator, Stat3 and several IL-10 transcriptional targets (Ddit4, Nfil3, Tsc22d3) (Ip et al, 2017, Lang et al, 2002, Berrebi et al, 2003, Hoppstadter et al, 2015 were also downregulated ( Fig 5B, F). Other potentially relevant downregulated genes encode transcripts associated with Alzheimer's disease (Sorl1) (Nicolas et al, 2016), leukodystrophy (Abcd1 and its downstream mediator of pathology, Ch25h) (Gong et al, 2017, Jang et al, 2016 and the CSF-2 target gene Pkch, encoding protein kinase Cη, a regulator of lipid metabolism and suppressor of NO production by macrophages (Torisu et al, 2016, Ozawa et al, 2016 ( Fig 5B). Pathway analysis revealed that the transcriptomic changes associated with Csf1r heterozygosity are consistent with activation of the RhoGDI signaling and LXR/RXR pathways ( Fig.…”

Minimotifs dysfunction is pervasive in neurodegenerative disorders

“…Late‐onset AD accounts for more than 95% of all AD cases and is caused by a complex underlying genetic architecture. To date, over 40 GWASs and meta‐analyses have identified a few hundred genes and single nucleotide polymorphisms; these include variants in apolipoprotein E ( APOE ) among other notable gene candidates [228]. In contrast to late‐onset AD, early onset AD is caused by highly penetrant variants located primarily in three genes with minimotif functions, APP (located at 21q21.2), presenilin 1 ( PSEN1 , located at 14q24.3), and presenilin 2 ( PSEN2 , located at 1q42.13) [226].…”

Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases

“…In contrast, sequencing studies have been successful at identifying more moderately to highly penetrant contributions to disease by examining rare variation. Successes in Alzheimer’s disease (AD) include ABCA7 , SORL1 , and TREM2 (reviewed in 7 ). Similar successes for the amyotrophic lateral sclerosis (ALS)-FTD spectrum include TBK1 8 , MFSD8 9 , DPP6 , UNC13A , and HLA-DQA2 10 .…”