Authors
Francesca Mancinetti, Virginia Boccardi, Marta Valenza, Martina Alunno, Michela Scamosci, Roberta Facchinetti, Veronica Tecchio, Anna Giulia Guazzarini, Martina Procaccini, Luigi Cari, Giuseppe Nocentini, Carmelinda Ruggiero, Caterina Scuderi, Luca Steardo, Patrizia Mecocci
Published in
Nutrients. Volume 18. Issue 18. Sep 09, 2026. Epub Sep 09, 2026.
Abstract
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 signaling, oxidative and nitrosative stress, and amyloid-β-induced cellular injury while supporting neurotrophic signaling and neuronal survival. Preliminary clinical findings have suggested possible benefits in stroke rehabilitation, frontotemporal dementia, and other neuroinflammatory conditions. However, human evidence specifically addressing mild cognitive impairment and Alzheimer's disease remains limited, heterogeneous, and largely derived from preclinical and small or non-randomized studies. PEA-Lut therefore represents a biologically plausible investigational nutraceutical approach, although available clinical safety data are limited to relatively small and heterogeneous populations and short observation periods. 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.
PMID:
42796932
Bibliographic data and abstract were imported from PubMed on 14 Nov 2026.
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