Preprints.org · Jul 29, 2026

Palmitoylethanolamide and Luteolin in Brain Aging and Cognitive Decline: Biological Rationale and Current Evidence

By Mancinetti F, Boccardi V, Valenza M et al.

Cognitive decline is closely associated with biological aging and with interconnected processes, including chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and cellular senescence. Nutraceutical strategies capable of modulating several of these pathways may represent a complementary approach to supporting cognitive health. This narrative review examines the biological rationale and available evidence regarding palmitoylethanolamide (PEA), luteolin, and their co-ultramicronized formulation (PEA-Lut) in cognitive impairment and dementia. Evidence from mechanistic studies, animal models, observational studies, and clinical trials was considered. PEA is an endogenous N-acylethanolamine with anti-inflammatory and neuroprotective properties, whereas luteolin exerts complementary antioxidant and anti-inflammatory effects. Co-ultramicronization may improve their physicochemical properties and biological activity. Preclinical studies suggest that PEA-Lut may attenuate glial activation, pro-inflammatory signalling, oxidative and nitrosative stress, and amyloid-β-induced cellular injury while supporting neurotrophic signalling and neuronal survival. Preliminary clinical findings have suggested possible benefits in postoperative delirium, stroke rehabilitation, frontotemporal dementia, and other neuroinflammatory conditions. However, human evidence specifically addressing mild cognitive impairment and Alzheimer’s Disease (AD) remains limited, heterogeneous, and largely derived from small or non-randomized studies. PEA-Lut therefore represents a biologically plausible and potentially well-tolerated nutraceutical approach. Adequately powered randomized controlled trials are needed to determine its clinical efficacy, optimal timing and dosage, and long-term safety in individuals at risk of dementia or in the early stages of AD.

doi.org/10.20944/preprints202607.2125.v1Open accessInterventions