The role of ABCA7 in Alzheimer\u2019s disease: evidence from genomics, transcriptomics and methylomics

Arne De Roeck,Christine Van Broeckhoven,Kristel Sleegers

doi:10.1007/s00401-019-01994-1

Arne De Roeck, Christine Van Broeckhoven + Show 1 more

Open Access

https://doi.org/10.1007/s00401-019-01994-1

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Abstract

Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer’s disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting ABCA7 as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on ABCA7, with a focus on AD-related human -omics studies (e.g. genomics, transcriptomics, and methylomics). In European and African American populations, indirect ABCA7 GWAS associations are explained by expansion of an ABCA7 variable number tandem repeat (VNTR), and a common premature termination codon (PTC) variant, respectively. Rare ABCA7 PTC variants are strongly enriched in AD patients, and some of these have displayed inheritance patterns resembling autosomal dominant AD. In addition, rare missense variants are more frequent in AD patients than healthy controls, whereas a common ABCA7 missense variant may protect from disease. Methylation at several CpG sites in the ABCA7 locus is significantly associated with AD. Furthermore, ABCA7 contains many different isoforms and ABCA7 splicing has been shown to associate with AD. Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based –omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions on ABCA7 expression can serve as a valuable therapeutic target for AD.

Highlights

Dementia—and in particular Alzheimer’s disease (AD), which makes up 50–70% of dementia patients—is one of the major medical challenges of our time
While early tau pathology in the entorhinal and limbic system can manifest without any amyloid β (Aβ), severe neocortical AD-like tau pathology in the form of neurofibrillary tangles and neuritic plaques is not seen in absence of Aβ, indicating that Aβ is crucial for the development of clinically overt dementia [1]
While evidence is limited compared to neurodegenerative diseases, ABCA7 has been linked to cancer

Summary

Introduction

Dementia—and in particular Alzheimer’s disease (AD), which makes up 50–70% of dementia patients—is one of the major medical challenges of our time. Overview of studies reporting a significant association between AD endophenotypes and ABCA7 sentinel SNPs (rs-numbers) or CpG methylation markers (cg-numbers) CON cognitively healthy controls, MCI mild cognitive impairment, AD Alzheimer’s disease, PCA posterior cortical atrophy *21 individuals had other forms of dementia than AD **Unspecified how many of these were cognitively healthy or MCI

Results

Conclusion