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Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimers dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimers dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimers dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimers dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimers dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimers disease could have a major impact on the understanding, treatment and prevention of this terrible disease.

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