Summary

A subpopulation of Alzheimer's disease (AD) patients with neocortical Lewy bodies (LB) and subtle extrapyramidal signs, a clinical-pathological phenotype that we have termed the Lewy body variant of AD (LBV), has an increased allele frequency of APO E e4 allele, similar to that observed in AD subjects without LB (pure AD), although individuals homozygous for the APO E e4 allele are overrepresented in pure AD as compared with age-matched controls, but not as markedly in subjects with LBV. Furthermore, we have found that the CYP2D6B mutant allele, a risk factor for Parkinson's disease (PD), is overrepresented in LBV, a finding that has been controversial. To further evaluate the involvement of the CYP2D6 locus in LBV, the Xbal restriction fragment length polymorphisms (RFLP) of CYP2D6, 44 kb, 15/9 kb, and 13 kb (D mutation), were examined for association with LBV. The 15/9-kb RFLP was found in pure AD or in non-AD individuals but was not found in LBV. On the other hand, the 44-kb Xbal RFLP in the presence of the concomitant CYP2D6B mutant allele was strongly associated with LBV. The tightest association with LBV was found in the combination of the 44-kb RFLP and CYP2D6B mutant allele in the absence of the 15/9-kb RFLP. A CYP2D6 deletion mutation D, detected as 13-kb RFLP, was not linked to LBV. Taken together, these findings suggest that the inactivation of CYP2D6 represented by the B or D mutation may not per se be the risk factor for LBV but that an independent mutation or allele linked to the CYP2D6B mutation and the 44-kb Xbal RFLP (such as NF-H or PDGfb genes) might be associated with LB formation in AD.