Background: Deposition of the beta-amyloid peptide (Abeta) in neuritic plaques is a hallmark of Alzheimer disease (AD). Mutations in genes encoding amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) are associated with increased accumulation of Abeta in neuritic plaques or in the walls of cerebral vessels. Intracerebral hemorrhage occasionally affects patients with AD.
Methods: A Finnish family with dementia in four generations and with frequent co-occurrence of dementia and intracerebral hemorrhage was identified. Clinical features of 14 family members with a cognitive decline were evaluated. All exons in genes encoding APP, PSEN1, PSEN2, cystatin C, transthyretin, gelsolin, and ITM2B were sequenced, and an association study of APP was conducted by identification of single-nucleotide polymorphisms.
Results: Neuropathologic examination revealed Alzheimer-type changes with Abeta in neuritic plaques and vessel walls, but the cognitive profile of the patients differed from that in AD, as the visuoconstructive functions and verbal fluency were well preserved even in the moderate stage of the disease. In addition to cognitive decline, five patients had had lobar intracerebral hemorrhages and one was diagnosed with hemosiderin deposits in MRI, suggesting previous cerebral microbleeds. No causative mutations were identified in candidate genes associated with amyloid diseases, but linkage to APP region could not be entirely excluded.
Conclusions: The family presents an autosomal dominant form of beta-amyloidogenic disease that resembles the Italian, Flemish, and Iowa types of AD. No amyloidogenic mutations were identified, but the role of the APP region could not be entirely excluded.