E.H. Corder, R. Huang, H.M. Cathcart, I.S. Lanham, G.R. Parker, D. Cheng, S.E. Poduslo

Neurodegeneration is a brickwall when considering extreme longevity. Alzheimer’s brain changes, i.e. the accumulation of neurofibrillary tangles and senile plaque, can begin in early adulthood and are almost universal by age 80. The continued loss of pyramidal neurons in early-affected brain areas, i.e. the hippocampus, and the sequential regional brain spreading of lesions predicts that eventually there will be compromised cognition. The wide variation in the rate of these changes is strongly influenced by inherited factors, APOE polymorphism and other less replicated genetic determinants. But, replication of exactly which variants are relevant is difficult, probably because common combinations vary in frequency by chance from sample to study sample. We identified high and low risk multilocus genotypes for APOE, APOCI, the LDL receptor, cystatin C and cathepsin D genes using a form of fuzzy latent classification called grade-of-membership analysis (8 loci; 180 patients, 120 controls), GoM. Five GoM groups were requested. There were three high-risk combinations. They varied widely in terms of age at onset. One of the two low-risk combinations represented long life without dementia. Membership in the high-risk groups predicted disease status: All 102 subjects having > 80% membership, and none of the 50 subjects having

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