Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Abstract

AbstractBackgroundThe current shift towards (early) secondary intervention AD trial designs warrants the need for detection of subtle changes of both amyloid‐β (Aβ) burden and cognitive functioning. This study investigated the longitudinal trajectory of global and regional Aβ measurements and their value in predicting cognition in initially cognitively unimpaired (CU) subjects.MethodWe included 133 CU subjects with available longitudinal cognition (MMSE: 2‐13 assessments, 7.9±2.5 years; neuropsychological memory tasks: 2‐5 assessments, 4.0±1.9 years) and [11C]PiB PET imaging (2‐5 scans, 4.4±1.9 years) from the OASIS‐3 cohort. Baseline and annualized Aβ measures (DVR) were computed for a global composite and 4 clusters of regions, reflecting different stages of the amyloid accumulation process. Linear mixed effect models were used to examine the predictive value of Aβ measurements (i.e. Aβbaseline, Aβslope, and Aβbaseline*slope) on global cognition (MMSE) and several aspects of memory performance. All analyses were controlled for age, sex, years of education, and time between baseline PET and first cognitive assessment.ResultGlobal baseline amyloid burden and slope were non‐linearly related (). This was also apparent in stages 1, 2, and 3 clusters, but less in stage 4 (). MMSE performance over time could only be predicted by Aβ burden and accumulation in cluster 2 (precuneus, lateral orbitofrontal (LOFC), and insula; β baseline=‐0.37, p<.001; β interaction=14.16, p<.05). Focusing on the precuneus ROI by itself significantly improved the model (βbaseline =‐0.29, p<.001; βslope =‐9.71, p<.05; βinteraction =8.71, p<.01), where fast‐decliners were those at the plateau phase of accumulation (). Similarly, precuneal slope and the interaction term were both predictive of changes in immediate (βslope =‐60.95, p<.05; βinteraction =53.39, p<.05) and delayed episodic memory (βslope =‐65.45, p<.05; βinteraction =53.14, p<.05). In the Aβ‐ at baseline group (N=93), LOFC slope and the interaction term predicted changes in working (βslope =‐172.0, p<.05; βinteraction =‐147.2, p<.05) and semantic memory performance (βslope =‐439,4, p<.01; βinteraction =393.1, p<.01).ConclusionQuantifying longitudinal and regional changes in Aβ can improve the prediction of future cognitive functioning in initially CU individuals. For individuals with established amyloid pathology, longitudinal Aβ measures help to identify those subjects most likely to show cognitive decline within the short timelines of clinical trials.