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.
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.
| Original language | English |
|---|---|
| Journal | Alzheimer's & Dementia: The Journal of the Alzheimer's Association |
| Early online date | 22 Dec 2022 |
| DOIs | |
| Publication status | E-pub ahead of print - 22 Dec 2022 |
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Data from paper: Synaptic resilience is associated with maintained cognition during ageing
Toombs, J. (Creator), King, D. (Creator), Holt, K. (Creator), Dando, O. (Creator) & Spires-Jones, T. (Creator), Edinburgh DataShare, 27 Oct 2022
DOI: 10.7488/ds/3777, https://www.medrxiv.org/content/10.1101/2022.05.04.22274679v1
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Images from paper: Synaptic resilience is associated with maintained cognition during ageing
King, D. (Creator) & Spires-Jones, T. (Owner), Edinburgh DataVault, 26 Oct 2022
DOI: 10.7488/b9dcf607-1339-4127-a3c0-263ce9f3d164
Dataset