Familial Alzheimer’s disease in Australia

Abstract

AbstractBackgroundFamilies with dementia occurring in multiple generations suggest the possibility of inheritance of a single gene disorder. Since the discovery of the Amyloid Precursor Protein gene (APP) Val717Ile London mutation (Goate et al., 1991) and of variants in the Presenilin‐1 and ‐2 (PSEN1 & PSEN2) genes in 1995 (Sherrington et al., 1995), many such families with Alzheimer’s disease (AD) have been able to obtain a genetic diagnosis for their condition. Here we report details of 28 families in Australia and New Zealand who have been found to carry a pathogenic variant in one of these three genes.MethodFamilies with young‐onset dementia seeking a genetic diagnosis in Australia were studied according to the following protocol. Family history and clinical characterisation: we enquired about the presence of dementia in siblings, parents and grandparents of the proband. Clinical features of the illness were recorded. We sought consent for DNA studies from living affected individuals: DNA was screened for variants in APP, PSEN1 and PSEN2. Neuropathology: we sought consent for post‐mortem examination of the brain of affected family members for neuropathological characterisation.ResultSince 1988, at least 28 families in Australia and New Zealand have been found to carry pathogenic AD variants. There were 6 families with variants in APP and 22 with variants in PSEN1. No families have yet been found to carry a pathogenic PSEN2 variant. 24 families have had AD confirmed neuropathologically. Only one proband with a pathogenic variant had no known family history of dementia. This individual carried a PSEN1 Arg278Thr variant and died at 41 of dementia and spastic paraparesis. Brain biopsy showed AD. One parent had died of cancer at 65; the other parent was unaffected on examination at 67 and did not carry the PSEN1 variant.ConclusionFamily history of young‐onset dementia in at least two generations suggests dominant inheritance and DNA studies may reveal a pathogenic variant. Such variants can occur in individuals without a family history, but we found this to be uncommon.