Rare ABCA7 mutations in Alzheimer’s disease and cerebral amyloid angiopathy pathology
(2026) Neurobiology of Aging — Vol. 160, p. 33-46 (2026)
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- 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, clini-copathological 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.
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Hendrickx Van De Craen, E., Bossaerts, L., Sieben, A., Van Den Bossche, T., Bjerke, M., Hanseeuw, B., Bergmans, B., Vandenberghe, R., De Deyn, P., Cras, P., Sleegers, K., Engelborghs, S., Van Broeckhoven, C., & Van Der Zee, J. (2026). Rare ABCA7 mutations in Alzheimer’s disease and cerebral amyloid angiopathy pathology. Neurobiology of Aging, 160, 33-46. https://doi.org/10.1016/j.neurobiolaging.2025.12.010 (Original work published 2026)