Introduction: Current models posit a sequence of amyloid β (Aβ), tau, atrophy, and cognitive change leading to Alzheimer's disease, but ambiguities remain. We examined these sequences via serial mediations.
Methods: We studied normal controls, early mild cognitive impairment, and late mild cognitive impairment individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database for the mediation of baseline cerebrospinal fluid Aβ effects on 2-year cognitive change via regional longitudinal atrophy rate (AR) alone or AR and tau.
Results: In normal controls, Aβ correlated directly with regional ARs and memory loss, with no mediations. In early mild cognitive impairment, tau and lateral temporal ARs serially mediated the influence of Aβ on memory while Aβ affected memory via hippocampal AR. Late mild cognitive impairment consistently showed serial mediations of tau followed by atrophy. However, Aβ effects on memory also continued to be specifically mediated by medial temporal ARs without intermediate tau.
Discussion: Biomarker sequences vary by region and disease state, suggesting the need to refine current cascade models.
Keywords: Alzheimer's disease; Amyloid β; Cognitive aging; Longitudinal atrophy; MCI; Tau.