Deakin University

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Early onset familial Alzheimer's disease: mutation frequency in 31 families

journal contribution
posted on 2003-01-28, 00:00 authored by J C Janssen, J A Beck, T A Campbell, A Dickinson, N C Fox, Richard HarveyRichard Harvey, H Houlden, M N Rossor, J Collinge
Background: Three causative genes have been identified for autosomal dominant AD. Objective: To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes. Methods: A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years. Results: The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001). Conclusions: Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.









235 - 239


Lippincott Williams & Wilkins


Philadelphia, Pa.





Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2003, American Academy of Neurology