Rare ABCA7 mutations in Alzheimer’s disease and cerebral amyloid angiopathy pathology

Rare mutations in the ATP binding cassette subfamily A member 7 (ABCA7) gene are known risk factors for Alzheimer's disease (AD). Genetic sequencing in 1372 Belgian patients previously revealed rare ABCA7 mutations in 102 carriers, 58 with a premature termination codon mutation (PTC) and 44 with a missense mutation. Among carriers, 14 received post-mortem examination. Here, we reviewed and report the demographics, clinicopathological phenotypes, and diagnoses of identified ABCA7 mutation carriers. Carriers mostly developed late-onset AD (71 ± 9 years) and had a high familial load (67 % with positive family history). Patients presented with classic amnestic AD based on neuropsychological assessment, imaging and CSF biomarkers. However, vascular involvement was observed in a considerable part of patients, leading to diagnosis of vascular dementia (9 %) and cerebral amyloid angiopathy (CAA) (6 %). In line with this, neuropathology of the 14 examined carriers uncovered extensive levels of CAA and AD hallmarks. Carriers of an ABCA7 missense mutations displayed a less aggressive phenotype, with comparable onset but longer disease duration compared to carriers of a PTC mutation. Furthermore, non-amnestic features including language, dysexecutive and behavioural symptoms, were more frequently seen in PTC patients (18 % vs 9 %), as was the case for concomitant vascular disease (22 % vs 10 %). Taken together, the clinical phenotype of rare ABCA7 mutation carriers spans the AD-CAA spectrum. Patients present with a classical AD phenotype although clinical heterogeneity is observed among carriers. The presence of a cerebrovascular component (CAA) may, in part, explain this heterogeneity.