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From the Dementia Research Group (J.C. Janssen and Drs. Fox, Harvey, and Rossor) and Neurogenetics Section (H. Houlden), Department of Clinical Neurology, Institute of Neurology, and Department of Neurodegenerative Disease (J.A. Beck, T.A. Campbell, A. Dickinson, and J. Collinge), The National Hospital for Neurology and Neurosurgery; and Department of Neurology (Dr. Rossor), St. Mary’s Hospital, London, UK.
*These authors contributed equally to this work.
Address correspondence and reprint requests to Professor John Collinge, Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK; e-mail: pacollinge{at}prion.ucl.ac.uk
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.
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