Alzheimer’s disease (AD) is the most frequent cause of dementia worldwide and represents one of the leading factors for severe disability in older persons. Although its etiology is not fully known yet, AD may develop due to multiple factors, including inflammation and oxidative stress, conditions where microRNAs (miRNAs) seem to play a pivotal role as a molecular switch. All these aspects may be modulated by nutritional factors. Among them, vitamin E has been widely studied in AD, given the plausibility of its various biological functions in influencing neurodegeneration. From a cohort of old-aged people, we measured eight vitamin E forms (tocopherols and tocotrienols), thirty cytokines/chemokines, and thirteen exosome-extracted miRNAs in plasma of subjects suffering from subjects affected by AD and age-matched healthy controls (HC). The sample population included 80 subjects (40 AD and 40 HC) with a mean age of 77.6 ± 3.8 years, mostly women (45; 56.2%). Of the vitamin E forms, only α-tocopherol differed between groups, with significantly lower levels in AD. Regarding the examined inflammatory molecules, G-CSF, GM-CSF, INF-α2, IL-3, and IL-8 were significantly higher and IL-17 lower in AD than HC. Among all miRNAs examined, AD showed downregulation of miR-9, miR-21, miR29-b, miR-122, and miR-132 compared to controls. MiR-122 positively and significantly correlated with some inflammatory molecules (GM-CSF, INF-α2, IL-1α, IL-8, and MIP-1β) as well as with α-tocopherol even after correction for age and gender. A final binary logistic regression analysis showed that α-tocopherol serum levels were associated with a higher AD probability and partially mediated by miR-122. Our results suggest an interplay between α-tocopherol, inflammatory molecules, and microRNAs in AD, where miR-122 may be a good candidate as modulating factor.

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.

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.