Systemic determinants of brain health in ageing

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.

Fig. 1 ∣. Spectrum of organ dysfunction and its association with neurodegeneration and cognitive decline.

Frank organ failure (far right) has long been recognized as a cause of acute encephalopathy mediated by various derangements, including hypoxia, ischaemia and metabolic abnormalities. More recent evidence shows that a spectrum of organ dysfunction, from asymptomatic alterations in functional tests to clinically recognized mild diseases, can increase the risk of later-life cognitive decline. Each of the abnormalities shown has been linked with future risk of cognitive decline in population-based cohort studies^,,,,,,,,,,,. In turn, brain dysfunction can induce organ dysfunction through neurohumoral mechanisms and poor self-care. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; GFR, glomerular filtration rate; HbA_1c, haemoglobin A_1c; NAFLD, nonalcoholic fatty liver disease.

Fig. 2 ∣. Mechanisms linking peripheral organ dysfunction to brain health.

Endothelial dysfunction, reduced peripheral clearance of toxins, altered microbiome composition and systemic inflammation have been linked to neurovascular unit dysfunction in experimental studies. CSF, cerebrospinal fluid.