We aimed to delineate the clinicopathological Alzheimer’s disease (AD) phenotype of carriers with a premature termination codon (PTC) in the ATP-Binding Cassette Subfamily A Member 7 (ABCA7) gene, leading to loss of ABCA7 expression. ABCA7 was initially identified as a risk gene in GWAS of large AD patient cohorts. 

Using targeted resequencing of the coding region of ABCA7 in an extended Belgian AD patient cohort (n=1480), we identified 16 different PTC mutations in 72 carriers in ABCA7 with onset ages varying from early- to late-onset AD.

Reviewing of available demographic, clinical, imaging and neuropathological data. 

The 72 carriers had a mean onset age of 69.8±9.2 years, with an age range of 48-90 (n=42) years, independent of APOE genotype. Mean disease duration was 8.1±4.1 years (range 1-17). A positive familial history was noted in 78.6% of carriers (33/42). Most carriers displayed an amnestic phenotype (72.5%, 59/70), without clear distinctive features in clinical examination or structural and functional neuroimaging. Cerebrospinal fluid (CSF) biomarkers were available for 28 carriers, showing an AD profile in 82.1% of patients. Additional, (re)analysis of CSF biomarkers is ongoing for 35 carriers, including Aβ_1-42/Aβ_1-40 ratio as ancillary biomarker. Brain autopsy was performed in 10 carriers and revealed AD pathology as well as cerebral amyloid angiopathy (CAA) in all carriers. High levels of CAA were present in both meningeal and capillary blood vessels, and moderate to high levels of CAA in the parenchymal blood vessels. CAA did not correlate with the levels of AD pathology or APOE genotype. 

Carriers of ABCA7 PTC mutations present with a classical AD phenotype, but with wide onset-age ranges, even for carriers of the same mutation. Additional to AD hallmarks in pathology, extensive levels of CAA were present in all 10 autopsied brains. These findings have important implications for future research and clinical practice.