Reduced apolipoprotein ϵ4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals

Recent genetic studies show that the apolipoprotein E ϵ4 allele (ApoE- ϵ4) is a risk factor for Alzheimer's disease (AD). If ApoE- ϵ4 individuals develop AD as they get older, we would expect a decrease in ApoE- ϵ4 allele frequency with increasing age. We found a marked decline in ApoE- ϵ4 allele frequency with advancing age in both AD and cognitively normal controls (p < 0.003), although in all age groups the ApoE- ϵ4 allele was overrepresented (p < 0.0001). Nonetheless, a few cognitively normal nonagenarians were ApoE- ϵ4 positive. Thus, our data support two new conclusions: (1) the ApoE- ϵ4 associated risk for AD is age-dependent, probably due to censoring by the earlier development of AD in ApoE- ϵ4 individuals, and (2) despite the ApoE- ϵ4 associated risk for AD, it is possible to reach extreme old age with normal cognition.