Nutritional strategies targeting glucose metabolism to slow cognitive aging: a scoping review of human trials

Cerebral glucose hypometabolism is a hallmark of cognitive aging and Alzheimer’s disease (AD), underscoring the need for nutritional strategies that support brain energy metabolism. This scoping review synthesized evidence from human interventions evaluating alternative energy substrates and nutrients that support cerebral energy metabolism and their effects on cognition in older adults. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. MEDLINE, EMBASE, and Scopus were searched for studies published during 2014 to 2024, involving adults aged ≥60 y, with mild cognitive impairment (MCI), AD, subjective cognitive decline, or normal cognition. Thirty-two studies were included, investigating medium chain triglycerides (MCTs), ketogenic diets, omega [ꞷ-3 (n–3)] fatty acids, amino acids, histidine-containing dipeptides, serotonin precursors, and dietary fat modification. Cognitive outcomes were global and domain-specific measures including memory, executive function, and attention, whereas other outcomes included functional capacity, neuroimaging markers, inflammation, mood, and quality of life. ꞷ-3 Supplementation showed mixed evidence with cognitive benefits reported particularly in MCI populations receiving higher docosahexaenoic acid doses and longer intervention durations (≥1 g/d, ≥6 mo). Ketogenic and MCT-based strategies improved cognitive function in MCI and early AD, with effects tied to plasma ketone concentrations; however, benefits were not consistently observed. Limited evidence suggested that anserine and carnosine supplementation may improve verbal memory and executive function, particularly in adults aged ≥70 y and apolipoprotein E genotype carriers. L-arginine improved global cognition in frail hypertensive older adults, whereas tryptophan and amino acid interventions demonstrated domain-specific or age-dependent effects, rather than consistent improvements. Findings were heterogeneous across interventions and populations. Cognitive benefits were most evident in early disease stages, with sufficient dosing and adherence. Several studies reported favorable biomarker, inflammatory, metabolic, or quality-of-life outcomes despite limited cognitive effects. Overall, nutritional strategies targeting brain energy metabolism show promise for supporting cognitive health. However, substantial heterogeneity, small sample sizes, short intervention durations, and inconsistent cognitive outcomes limit the strength of the evidence. Future research should prioritize biomarker-based, longer-term, and multimodal approaches to clarify efficacy and clinical applicability.