MOLECULAR-BIOLOGY OF APO-E ALLELES IN ALZHEIMERS AND NON-ALZHEIMERS DEMENTIAS

Current research into the aetiology of the dementias is focused upon g enetic factors which give rise to the disease process. Recently the Ap olipoprotein E gene (APO E) and in particular the epsilon 4 allele has been shown to be a risk factor for late onset Alzheimer's disease (AD ) where there is an increased frequency of the epsilon 4 allele. The e psilon 4 allele has also been shown to reduce the age at onset of deme ntia in AD in a dose dependant manner, with the epsilon 2 allele havin g an opposing effect. We have genotyped a large series of clinically a nd neuropathologically confirmed cases of AD and found the expected in crease in the Apolipoprotein epsilon 4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LED) an inc reased epsilon 4 frequency is also found though a normal epsilon 2 fre quency exists, unlike in AD where the epsilon 2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Par kinson's disease with or without dementia, or in Down's syndrome. No a ssociation was found between any of the APO E alleles and the histopat hological indices of AD, cortical senile plaques and neurofibrillary t angles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E gen otype. Whilst their appears to be a strong association between the APO E allele and AD and also in LED, other related neurodegenerative diso rders associated with dementia do not show such a linkage. Changes in the epsilon 2 allele frequency may indicate a genetic difference betwe en AD and LED. The epsilon 4 allele does not appear to influence the b urden of AD type pathology and this is particularly relevant given the relative lack of NFT in LED indicating that factors other than SP or NFT may govern the onset of dementia.