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Contribution of rare variants in ABCA7 to the genetic etiology of Alzheimer’s disease

Boek - Dissertatie

Despite decades of research, no treatment is available to halt or slow down Alzheimer’s disease (AD), the leading cause of dementia. Unravelling the molecular mechanisms underlying the pathogenesis of AD is imperative to find novel therapeutic targets. Genome-wide association studies in large AD and control cohorts identified ABCA7 as a risk gene for AD. ABCA7, or the ATP-binding cassette subfamily A member 7 gene, encodes a transmembrane protein involved in lipid metabolism and phagocytosis, and was found to regulate the generation and clearance of amyloid β, an important neuropathological hallmark of AD. Post-GWAS studies identified an enrichment of rare heterozygous premature termination codon (PTC) mutations in AD patients versus healthy control individuals. In fact, our research group was one of the first to report this association in a Belgian cohort of 772 AD patients and 757 control individuals. The general aim of this PhD work was to explore the genetic contribution of rare ABCA7 variants to AD. To get more insights in the mutational spectrum and prevalence of PTC mutations, as well as to better understand the variability in onset age of PTC carriers, we first expanded the ABCA7 screening to a larger Belgian patient (n = 1376) and control (n = 976) cohort. This screening revealed 67 PTC mutations in the patient cohort and 18 in the control group. We also investigated the frequency and pathogenicity of missense, indel and splice variants in the Belgian AD and control cohort. We explored the effect of missense mutations, selected from the Belgian patient cohort, on the subcellular localization of ABCA7 in HeLa cells and show for the first time that these mutations can induce mislocalization and impaired trafficking to the plasma membrane, resulting in a loss-of-functional ABCA7. In addition, we describe co-segregation of a mislocalizing missense mutation with AD in a pedigree showing an autosomal dominant inheritance pattern. Neuropathological examination in ABCA7 PTC and missense mutation carriers revealed prominent levels of cerebral amyloid angiopathy (CAA) additional to AD pathological hallmarks. Therefore, we investigated the contribution of rare ABCA7 variants to CAA in a cohort of 83 Belgian CAA patients. This pilot study reveals a significant role for ABCA7 in the pathogenesis of CAA. In conclusion, this work contributes to the establishment of ABCA7 as a strong genetic risk factor for AD and CAA. In addition, we highlight new pathogenic mechanisms through which rare variants in ABCA7 contribute to AD and CAA.
Aantal pagina's: 141
Jaar van publicatie:2022
Trefwoorden:Doctoral thesis
Toegankelijkheid:Open