THE CYP2D6B ALLELE IS ASSOCIATED WITH A MILDER SYNAPTIC PATHOLOGY IN ALZHEIMERS-DISEASE

Both genetic and environmental factors affect the progression of Alzhe imer's disease (AD). The presence of cortical Lewy bodies in AD patien ts is associated with an altered presentation of AD pathology suggesti ve of an interaction between the pathogenesis of Lewy bodies and AD le sions. Since the CYP2D6B mutant allele is often present in patients wi th Lewy body diseases (Parkinson's disease and Lewy body variant of AD ), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele in a pure A D population without Lewy bodies. AD patients who possessed the CYP2D6 B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic markers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofib rillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Associati on of the CYP2D6B mutant allele with Lewy body formation in both Parki nson's disease and the Lewy body variant of AD and with the milder syn aptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this m utant allele may be involved with different aspects of neurodegenerati on.