Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias

Abstract

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAAknock-in mouse model of Alzheimer’s disease

“…First, this Aβ-driven phenomenon coincides with the earliest detection of soluble Aβ 1-40/42 in brain and CSF and occurs months before plaques and other key AD features emerge in this transgenic mouse model [18]. Second, NiMA disruption does not impact overall mitochondrial metabolism, which is regulated by a plethora of inputs including a diverse source of nutrients [32], but specifically interferes with mitochondrial respiration triggered by amino acids and likely, insulin as well.…”

Diet, Pace of Biological Aging, and Risk of Dementia in the Framingham Heart Study

“…15 Nutrition is involved in the regulation of many of these processes. Previous research has shown the involvement of brain metabolism, 4,51 inflammation and oxidative processes, 24 and periodontitis 52 in the relationship of diet with cognitive aging. Our findings of the mediation role of DunedinPACE on the effect of healthy diet on the risk of dementia hence are consistent with these previous findings, but in a more comprehensive way by capturing multiple systems through DunedinPACE.…”

“…Epigenetic clock analysis tested the hypothesis that multi-system biological aging is a mechanism underlying diet-dementia associations. 4,24 We analyzed data on diet, biological aging, and incidence of dementia collected over 3 decades of follow-up in the Framingham Heart Study Offspring Cohort. We assessed long-term healthy diet by the Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet, specifically developed for the prevention of dementia by emphasizing foods and nutrients with the most robust evidence for brain health.…”

“…By far the greatest risk factor for dementia is aging. Biological processes linked with both healthy diet and reduced dementia risk include reversal of several so‐called hallmarks of aging, including metabolic regulation, reduced inflammation and oxidative stress, and vascular health, among others 4–6 . These observations, together with data from animal model and human observational studies relating healthy diet with health‐span and lifespan, 7 suggest the hypothesis that 1 mechanism through which healthy diet reduces dementia risk is by slowing processes of biological aging.…”

“…We also conducted analysis of PhenoAge and GrimAge for comparison purposes. Epigenetic clock analysis tested the hypothesis that multi‐system biological aging is a mechanism underlying diet‐dementia associations 4,24 …”