Molecular biology of APO E alleles in Alzheimer’s and non-Alzheimer’s dementias

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Abstract
Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the ε4 allele has been shown to be a risk factor for late onset Alzheimer’s disease (AD) where there is an increased frequency of the ε4 allele. The ε4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependant manner, with the ε2 allele having an opposing effect. We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein ε4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased ε4 frequency is also found though a normal ε2 frequency exists, unlike in AD where the ε2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinson’s disease with or without dementia, or in Down’s syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype. Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the ε2 allele frequency may indicate a genetic difference between AD and LBD. The ε4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.