Abstract
Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management.
Key points
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Brain health is a worldwide priority, and dementia is the biggest threat to healthy brain ageing.
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The brain requires a supportive environment maintained by healthy organ systems to function optimally and to confer resilience to neurodegenerative diseases such as Alzheimer disease and Parkinson disease.
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Increasing evidence links subclinical dysfunction of the cardiovascular, pulmonary, renal, gastrointestinal, hepatic and endocrine systems with age-related cognitive decline and dementia.
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Cardiovascular, renal and hepatic dysfunction as well as changes in the gut microbiome have been associated with the presence of Alzheimer disease biomarkers in human research.
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Pathways that might lead from organ dysfunction to brain dysfunction include systemic endothelial dysfunction, reduced peripheral clearance of wastes (including amyloid-β and tau), systemic inflammation and alterations in the microbiome.
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Future research needs to explore mechanisms that link peripheral organ dysfunction to risk of age-related neurodegenerative and cerebrovascular diseases and to elucidate whether improving organ function reduces this risk.
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E.E.S. reports unpaid consulting for Alnylam Pharmaceuticals, Eisai and Eli Lilly. G.J.B. consults for Nestlé Health Science. All financial compensation for these services is transferred to his employer, University Medical Center Utrecht. A.L. reports consulting for Roche and Sanofi, and research funding from CSL Behring. N.S.P. is now employed by Alnylam Pharmaceuticals; his contribution to this work occurred while employed at Weill Cornell Medicine and does not reflect the views of his current employer. C.I. serves on the scientific advisory board of Broadview Ventures. V.G. and R.F.G. declare no competing interests.
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Smith, E.E., Biessels, G.J., Gao, V. et al. Systemic determinants of brain health in ageing. Nat Rev Neurol 20, 647–659 (2024). https://doi.org/10.1038/s41582-024-01016-z
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DOI: https://doi.org/10.1038/s41582-024-01016-z
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