Insulin resistance (IR)-related miRNAs have been associated with the development and progression of Alzheimer’s disease (AD). The dietary modulation of these miRNAs could become a potential strategy to manage AD. The aim of this study was to evaluate the effect of a high-fat diet (HFD), which aggravates AD-related pathogenic processes, on serum, cortex and hippocampus IR-related miRNA expression. C57BL/6J WT and APP_Swe/PS1dE9 mice were fed either an HFD or a conventional diet till 6 months of age. The mice fed with the HFD showed a significant increase in body weight and worsening glucose and insulin metabolism. miR-19a-3p was found to be up-regulated in the cortex, hippocampus and serum of APP/PS1 mice and in the serum and hippocampus of WT mice fed with the HFD. miR-34a-5p and miR-146a-5p were up-regulated in the serum of both groups of mice after consuming the HFD. Serum miR-29c-3p was overexpressed after consuming the HFD, along with hippocampal miR-338-3p and miR-125b-5p, only in WT mice. The HFD modulated the expression of peripheral and brain miRNAs related to glucose and insulin metabolism, suggesting the potential role of these miRNAs not only as therapeutic targets of AD but also as peripheral biomarkers for monitoring AD.

Lipidomics offers potential for the early detection of Alzheimer’s disease (AD) and for elucidating the molecular mechanisms driving the progression from mild cognitive impairment (MCI) to AD. In this study, we investigated and validated the association between 139 cerebrospinal fluid (CSF) lipids and MCI-to-AD conversion. We included 400 MCI participants from the Ace Alzheimer Center Barcelona (ACE) cohort, all free of type 2 diabetes, comprising both ATN+ and ATN− individuals. After a median follow-up of 2.1 years, 142 participants progressed to AD dementia. We identified a multi-lipid signature of 11 lipids (including phosphatidylcholines, lysophosphatidylcholines, triglycerides, phosphatidylethanolamines, lysophosphatidylethanolamines and phosphatidylinositols) in CSF, which was associated with increased AD progression (HR = 1.85, 95% CI: 1.53–2.27). This signature was validated in paired plasma samples, a less invasive biofluid (HR = 1.26, 95% CI: 1.04–1.52) and in plasma samples from an external cohort of 189 participants (149 with subjective cognitive decline, 40 with MCI; β = 0.261, 95% CI: 0.022–0.500), demonstrating moderate-to-high predictive accuracy for MCI-to-AD progression. Counterfactual-based mediation analysis revealed that plasma phosphorylated tau-181 mediated up to 47% of the association between the lipid signature and AD dementia, highlighting glycerophospholipid metabolism as a key pathway. Exploratory Mendelian randomisation analyses suggested a potential causal association of lipid signature and AD, with two instrumental single-nucleotide polymorphisms mapped to loci implicated in neurodevelopmental and metabolic regulation (RBFOX1 and CDKAL1). In conclusion, our findings support the growing evidence of lipid metabolism dysregulation as an early marker of AD and identify plasma lipids reflecting CSF profiles that may be promising prognostic markers for AD dementia.

Background: Dementia risk is influenced by metabolic and lifestyle factors, including hyperinsulinemia, chronic inflammation, and type 2 diabetes. Glycemic index (GI) and glycemic load (GL) reflect the quality and quantity of dietary carbohydrates and their impact on glucose metabolism and systemic health. However, their associations with the risk of dementia subtypes remain unclear. This study examined the associations between dietary GI and GL and the risk of all-cause and different dementia subtypes, such as Alzheimer’s disease (AD), vascular dementia (VD), and frontotemporal dementia. Methods: A prospective analysis was conducted by using data from 202 302 dementia-free participants in the UK Biobank cohort. Dietary GI and GL were estimated by using the Oxford WebQ 24-hour web-based dietary questionnaire. Cox proportional hazards regressions with restricted cubic splines were used to evaluate nonlinear relationships. Two-piece Cox models were used to identify inflection points, which served as reference values to estimate hazard ratios (HRs). Results: Dementia incidence was 0.89 per 1000 person-years. GI (mean±SD: 48.71 ± 7.68) showed an inverse J-shaped association with dementia risk, while GL (121.49 ± 39.00) showed a J-shaped pattern, with inflection points at 49.30 and 111.01, respectively. After adjusting for potential confounders, GI values of 111.01 were associated with higher dementia risk (HR, 1.145; 95% CI, 1.048–1.251). Similar findings were observed for AD and VD. Conclusion: Low-GI diets may offer protective effects against all-cause dementia, AD, and VD, whereas high-GL diets may increase the risk. These findings underscore the importance of considering both carbohydrate quality and quantity in dementia prevention and management strategies.

Background/Objectives: Low semen quality and male infertility are critical global health issues. Emerging research highlights that nutritional factors could play a significant role in determining reproductive outcomes. Understanding and optimizing these dietary influences, including the role of polyphenols, is crucial for developing targeted strategies to improve male fertility. We aimed to explore the relationship between the intake of different classes of polyphenols and semen quality indicators in a cohort of healthy young males. Methods: This is a secondary analysis involving 106 male individuals, aged 18–35 years, from the FERTINUTS trial. Dietary intake was assessed using 3-day dietary records, and semen quality parameters were analyzed. Multivariable linear regression analysis was employed to evaluate the associations between dietary polyphenol consumption and semen quality indicators. Results: Our findings revealed both positive and negative associations between polyphenol consumption and sperm morphology parameters. A higher intake of total polyphenols was associated with a lower percentage of abnormalities in sperm heads but a higher rate of abnormalities in the principal piece. Similar results were observed for lignan and flavonoid intake. Additionally, a higher intake of flavonoids was also associated with a greater percentage of normal sperm forms. In contrast, a higher dietary intake of stilbenes was associated with a higher percentage of combined abnormalities. Conclusions: Higher intake of polyphenols, particularly flavonoids and lignans, was associated with improved sperm head morphology but also with increased tail abnormalities, although no associations with motility or vitality were observed. These results suggest that specific polyphenol classes may have both beneficial and adverse effects on sperm structure, warranting consideration of compound type and dosage in dietary recommendations. Further studies are needed to determine whether these morphological changes impact fertilization outcomes and reproductive potential.

Background/Objectives: Low semen quality and male infertility are critical global health issues. Emerging research highlights that nutritional factors could play a sig-nificant role in determining reproductive outcomes. Understanding and optimizing these dietary influences, including the role of polyphenols, is crucial for developing targeted strategies to improve male fertility. We aimed to explore the relationship between the intake of different classes of polyphenols and semen quality indicators in a cohort of healthy young males. Methods: This is a secondary analysis involving 106 male individuals, aged 18–35 years from the FERTINUTS trial. Dietary intake was as-sessed using 3-day dietary records, and semen quality parameters were analysed. Multivariable linear regression analysis was employed to evaluate the associations between dietary polyphenol consumption and semen quality indicators. Results: Our findings revealed both positive and negative associations between polyphenol con-sumption and sperm morphology parameters. A higher intake of total polyphenols was associated with a lower percentage of abnormalities in sperm heads but a higher rate of abnormalities in the principal piece. Similar results were observed for lignan and fla-vonoid intake. Additionally, a higher intake of flavonoids was also associated with a greater percentage of normal sperm forms. In contrast, a higher dietary intake of stil-benes was associated with a higher percentage of combined abnormalities. Conclu-sions: While these results suggest that higher intake of polyphenols, particularly fla-vonoids and lignans may protect sperm head integrity by supporting DNA and acro-some function, we also observed an increase in tail abnormalities, without significant effects on motility or vitality. As fertility relies on multiple factors, such morphological changes could influence reproductive success. These findings highlight the need to consider both type and dosage of polyphenols to better understand its implications for reproductive health.

In mice, a nut-enriched diet preserved memory, reduced neuroinflammation and maintained dendritic spine density. Changes in circulating and brain miRNAs linked to insulin signalling suggest a molecular basis for nut-driven neuroprotection.