Interaction between -VS Heterozygosity and ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer's Disease.

-VS heterozygosity (-VS) promotes longevity and protects against cognitive decline in aging. To determine whether -VS mitigates Alzheimer's disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures in AD patients stratified by carrier status. We aggregated data on 665 participants (208 -VS/, 307 -VS/, 66 -VS/, and 84 -VS/) from two prospective cohorts, the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. All participants were initially diagnosed with mild cognitive impairment, later developed AD dementia during the study, and had at least three subsequent visits. -VS conferred slower cognitive decline in non-carriers (+0.287 MMSE points/year, = 0.001; -0.104 CDR-SB points/year, = 0.026; -0.042 ADCOMS points/year, < 0.001) but not in carriers who generally had faster rates of decline than non-carriers. Stratified analyses showed that the protective effect of -VS was particularly prominent in male participants, those who were older than the median baseline age of 76 years, or those who had an education level of at least 16 years. For the first time, our study provides evidence that -VS status has a protective effect on AD progression and interacts with the allele.