APOE GENOTYPE IS A RISK FACTOR IN NONPRESENILIN EARLY-ONSET ALZHEIMERS-DISEASE FAMILIES

The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD), We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD g roups: families with a mutation in the presenilin-1 gene (PS-1) on chr omosome 14, and families without a mutation detectable in the PS-1, pr esenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-P S early-onset familial AD), The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP ge ne, The effects of a double dose of ApoE4 on age of onset were not ass essed in the PS-1 AD families due to the lack of any affected ApoE4 ho mozygotes in the sample set; this insufficiency will need to be assess ed in further studies, There was no association between the ApoE4 alle le and AD in the PS-1 families, Non-PS early-onset AD families were sh own to have a significantly higher frequency of ApoE4 compared to cont rols and the PS-1 AD group, These observations are important and sugge st that 1) other genetic and environmental factors modify the AD pheno type in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family mem bers. (C) 1998 Wiley-Liss, Inc.