Synaptic resilience is associated with maintained cognition during ageing

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 from people in mid-life (n=15), healthy ageing with either maintained cognition (n=8) or lifetime cognitive decline (n=7), 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 signalling 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 signalling genes compared to people with cognitive decline. DISCUSSION Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing. ### Competing Interest Statement TSJ received collaborative grant funding from an anonymous industry partner for this work. TSJ is on the scientific advisory board of Cognition Therapeutics, receives honoraria for talks from academic and industry, and is a trustee of the Guarantors of Brain and the British Neuroscience Association. ### Funding Statement LBC1936 is supported by the Biotechnology and Biological Sciences Research Council, and the Economic and Social Research Council \[BB/W008793/1\] (which supports SEH), Age UK (Disconnected Mind project), the Medical Research Council (MR/M01311/1), and the University of Edinburgh. KH is funded by the Wellome Trust (628TRN R46470). SRC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). JAO is supported by an Economic and Social Research Council new investigator grant (ES/S015604/1); TSJ is supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 681181) and the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. Funding for this study was received from an anonymous industry partner who had no influence over the publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Brain tissue and blood donations have been reviewed and approved for use by the Edinburgh Brain Bank ethics committee and the Academic and Clinical Central Office for Research and Development, a joint office of the University of Edinburgh and NHS Lothian (approval 15-HV-016). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All software macros, R scripts, and analyzed data spreadsheets containing anonymized data are freely available on Edinburgh DataShare and GitHub.