Modeling grey matter atrophy as a function of time, aging or cognitive decline show different anatomical patterns in Alzheimer's disease

Abstract

BACKGROUND: Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy. METHODS: We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3-5] scans per individual over 2 [1.6-4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology. RESULTS: < 0.05). Associations with time, aging and MMSE remained when accounting for these effects in the other models, suggesting that all measures explain part of the variance in GM atrophy. Repeating analyses in amyloid normal individuals, effects for time and aging showed similar widespread anatomical patterns, while associations with MMSE were largely reduced. CONCLUSION: Effects of time, aging and MMSE all explained variance in GM atrophy slopes within individuals. Associations with MMSE were weaker than those for time or age, but specific for amyloid pathology. This suggests that at least some of the atrophy observed in time or age models may not be specific to AD.