Amyloid accumulation and functional connectivity in normal aging and preclinical Alzheimer’s Disease: a longitudinal analysis of the OASIS‐3 cohort

Abstract

AbstractBackgroundPathological changes in the brain begin accumulating decades before the appearance of cognitive symptoms in Alzheimer’s Disease (AD). The deposition of amyloid‐beta (Aβ) proteins and other neurotoxic changes occur, leading to disruption in functional connections between brain networks. Discrete characterization of the changes that take place in preclinical AD has the potential to help treatment development by targeting the neuropathological mechanisms to prevent cognitive decline and dementia from occurring entirely. Previous research has focused on cross sectional differences in the brains of patients with mild cognitive impairment (MCI) or AD and healthy controls or has concentrated on the stages immediately preceding cognitive symptoms. The present study emphasizes early preclinical phases of neurodegeneration.MethodWe use a longitudinal approach to examine the brain changes that take place during early stages of cognitive decline in the OASIS‐3 dataset. Among 1098 participants, 274 passed the inclusion criteria (i.e. had at least two repeated measures of cognitive status and amyloid levels). We use mixed‐effect linear models to examine rates of amyloid accumulation in those who showed cognitive decline compared to those who did not change in cognitive status.ResultOver 90% of participants were healthy at baseline. Over 8‐10 years, some participants progressed to very mild dementia (n = 48) while others stayed healthy (n = 226). Participants with cognitive decline have faster amyloid accumulation and greater increases in functional connectivity in similar brain regions, namely among lateral temporal, motor, and some lateral prefrontal cortex areas. These changes were linked to increases in functional connectivity of select default mode, frontoparietal and motor components.ConclusionOur findings advance the understanding of initial amyloid staging in preclinical Alzheimer’s, as well as contribute to the determination of the functional changes that occur among brain network components as the disease progresses.