Abstract
IMPORTANCE: It is unclear whether the duration of amyloid-β (Aβ) pathology is associated with neurodegeneration and whether this depends on the presence of tau. OBJECTIVE: To examine the association of longitudinal atrophy with Aβ positron emission tomography (PET)-positivity (Aβ+) and the estimated duration of Aβ+ (Aβ+ duration), controlling for tau-positivity. DESIGN, SETTING, AND PARTICIPANTS: Data for this longitudinal cohort study were drawn from the Wisconsin Registry for Alzheimer Prevention and the Wisconsin Alzheimer Disease Research Center Clinical Core Study. Participants who had 2 or more magnetic resonance imaging (MRI) visits, 1 Pittsburgh compound B (PiB) PET visit, and 1 MK-6240 PET visit with other covariates available were included. A replication analysis was conducted using data from the OASIS-3 dataset. All data were collected between June 1, 2009, and January 22, 2025. Follow-up times ranged from 1.0 to 13.0 years (median [IQR], 8.8 [5.9-10.6] years). EXPOSURES: Sampled iterative local approximation (SILA)-estimated PiB PET uptake at baseline MRI was used to estimate Aβ+ and its duration at baseline MRI. MK-6240 PET uptake in the entorhinal cortex was used to create tau-positive and tau-negative groups using a threshold of 1.27 standardized uptake value ratio. MAIN OUTCOMES AND MEASURES: SILA-based modeling of PiB PET data was used to obtain estimated Aβ+ duration at baseline MRI age. Linear mixed-effects models tested differences in atrophy between Aβ+ vs Aβ- individuals and with Aβ+ duration, controlling for individuals who were tau-positive (measured via MK-6240 tau PET) at their most recent PET scan within their MRI visits. Z-scored volumes in temporo-parietal regions of interest associated with AD dementia were assessed via a robust normative approach. RESULTS: A total of 95 Aβ+ (median [IQR] age, 66.4 [61.1-70.4] years; 59 female [62.11%]) and 275 Aβ- (median [IQR] age, 60.2 [55.7-64.6] years; 183 [66.55%] female) individuals were included. Aβ+ (partial η2, 0.015-0.043) and tau-positivity (partial η2, 0.018-0.100) were independently associated with neurodegeneration, with generally small effect sizes. Aβ+ duration was associated with atrophy in a greater number of regions of interest than Aβ+ status alone with somewhat larger effect sizes (partial η2, 0.013-0.056). Results were mostly similar in the OASIS-3 dataset. CONCLUSIONS AND RELEVANCE: In this longitudinal cohort study, subtle neurodegeneration was observed soon after the onset of Aβ pathology. These results may be consistent with Aβ pathology as a pathological state.