The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease

Background: Dementia severity can be modeled as the construct delta, representing the "cognitive correlates of functional status." Objective: We recently validated a model for estimating delta in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of delta with neuropathology remains untested. Methods: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (delta). Results: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of epsilon 2 and epsilon 4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more epsilon 2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more epsilon 4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD. Conclusions: Using delta as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.