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Alzheimers Dement ; 19(6): 2560-2574, 2023 06.
Article in English | MEDLINE | ID: mdl-36547260

ABSTRACT

INTRODUCTION: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS: We examined post-mortem brain tissue from people in mid-life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer's brain homogenate. RESULTS: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid-life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline. DISCUSSION: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.


Subject(s)
Alzheimer Disease , Cognitive Aging , Healthy Aging , Synapses , Cognition , Synapses/metabolism , Synapses/pathology , Brain/metabolism , Brain/pathology , Sequence Analysis, RNA , Neural Stem Cells/metabolism , Neural Stem Cells/pathology , Neurons/metabolism , Neurons/pathology , Synaptic Transmission , Postmortem Changes , Healthy Aging/metabolism , Healthy Aging/pathology , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Humans , Male , Female , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Gliosis/pathology
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