Synaptic resilience is associated with maintained cognition during ageing

TY - JOUR

T1 - Synaptic resilience is associated with maintained cognition during ageing

AU - King, Declan

AU - Holt, Kris

AU - Toombs, Jamie

AU - He, Xin

AU - Dando, Owen

AU - Okely, Judith A.

AU - Tzioras, Makis

AU - Rose, Jamie

AU - Gunn, Ciaran

AU - Correia, Adele

AU - Montero, Carmen

AU - McAlister, Hannah

AU - Tulloch, Jane

AU - Lamont, Douglas

AU - Taylor, Adele M.

AU - Harris, Sarah E.

AU - Redmond, Paul

AU - Cox, Simon R.

AU - Henstridge, Christopher M.

AU - Deary, Ian J.

AU - Smith, Colin

AU - Spires-Jones, Tara L.

N1 - Funding Information: Biotechnology and Biological Sciences Research Council Grant Number: BB/W008793/1; Medical Research Council. Grant Number: MR/M01311/1; Wellome Trust. Grant Number: 628TRN R46470 the Wellcome Trust and the Royal Society. Grant Number: 221890/Z/20/Z; Economic and Social Research Council new investigator. Grant Number: ES/S015604/1; the European Union's Horizon 2020 research and innovation programme. Grant Number: 681181; UK Dementia Research Institute. Grant Number: DRI-Edin005 Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

KW - Alzheimer's

KW - ageing

KW - cognition

KW - synapse

UR - https://www.scopus.com/pages/publications/85145070538

U2 - 10.1002/alz.12894

DO - 10.1002/alz.12894

M3 - Article

C2 - 36547260

SN - 1552-5260

VL - 19

SP - 2560

EP - 2574

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 6

ER -