Repository logo
 

Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Rahman, Md Shafiqur  ORCID logo  https://orcid.org/0000-0003-4068-6775
Harrison, Emma 
Biggs, Heather 
Seikus, Chloe 

Abstract

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible. Here, to address this gap, we cognitively profiled 21,051 people aged 17-85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility. Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline. Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

Description

Keywords

4203 Health Services and Systems, 42 Health Sciences, Genetics, Aging, Prevention, Dementia, Basic Behavioral and Social Science, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Behavioral and Social Science, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Clinical Research, 2.1 Biological and endogenous factors, 2 Aetiology, Mental health, Neurological, 3 Good Health and Well Being

Journal Title

Nat Med

Conference Name

Journal ISSN

1078-8956
1546-170X

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (Unknown)
Alzheimer's Society (482 (AS-PG-18b-022))
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (226653/Z/22/Z)
Wellcome Trust (212219/Z/18/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Wellcome Trust (via Imperial College London) (224486/Z/21/Z)