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Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease

Department of Psychiatry, Institute of Psychiatry, London

MICHAEL J. OWEN, PhD, JULIE WILLIAMS, PhD, FRANCES RICE, BA, STEPHANIE CARTY, BSc, SARA LILLYSTONE, BSc, PATRICK KEHOE, PhD and VARUNI RUDRASINGHAM, BSc

Department of Psychological Medicine, University of Wales College of Medicine, Cardiff

DAVID NEILL, MRCPsych

Institute for Health of the Elderly, Newcastle, UK

PAK SHAM, MRCPsych

Department of Psychological Medicine, Institute of Psychiatry, London, UK

Declaration of interest Funding received from the Medical Research Council (project grant G9530757N).

Correspondence: Dr N. Tunstall, Department of Psychiatry, Institute of Psychiatry, London SE5 8AF

Background Alzheimer's disease manifests considerable heterogeneity, the cause of which is unknown.

Aims To determine the familial (genotypic) influence on phenomenology (phenotype) in Alzheimer's disease.

Method Affected sibling pairs with Alzheimer's disease were assessed for a range of cognitive and non-cognitive symptoms. Resemblance for phenotypic characteristics was estimated using intraclass correlations for continuous traits and by pairwise concordance for dichotomous traits. The relationship between age of onset and APOEgenotype was examined using linear regression analysis.

Results Significant familial effects on age of onset (intraclass correlation 0.41) and mood state (intraclass correlation 0.26), and a relatively high pairwise concordance for agitation (excess concordance 0.1) were found. The APOE locus was found to account for 4% of the variance in age of onset.

Conclusions Substantial familial influence on age of onset, depression and agitation suggests that genotype does influence phenotype in Alzheimer's disease. Establishing the molecular basis for this phenotypic variation may prove relevant to other neuropsychiatric disorders.

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