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Background Whether a low-inflammatory diet relates to type 2 diabetes risk remains unclear. We examined the association between a low-inflammatory diet and risk of type 2 diabetes among normoglycemic and prediabetic participants. We also explored whether a low-inflammatory diet modifies genetic risk for type 2 diabetes. Methods Among 142,271 diabetes-free UK Biobank participants (aged 39–72 years), 126,203 were normoglycemic and 16,068 were prediabetic at baseline. Participants were followed for up to 15 years to detect incident type 2 diabetes. At baseline, dietary intake was assessed with a 24-h dietary record. An inflammatory diet index (IDI) was generated based on high-sensitivity C-reactive protein levels and was a weighted sum of 34 food groups (16 anti-inflammatory and 18 pro-inflammatory). Participants were grouped into tertiles corresponding to inflammatory level (low, moderate, and high) based on IDI scores. Prediabetes at baseline was defined as HbA1c 5.7–6.4% in diabetes-free participants. Incident type 2 diabetes and age of onset were ascertained according to the earliest recorded date of type 2 diabetes in the Primary Care and Hospital inpatient data. A diabetes-related genetic risk score (GRS) was calculated using 424 single-nucleotide polymorphisms. Data were analyzed using Cox regression and Laplace regression. Results During follow-up (median 8.40 years, interquartile range 6.89 to 11.02 years), 3348 (2.4%) participants in the normoglycemia group and 2496 (15.5%) in the prediabetes group developed type 2 diabetes. Type 2 diabetes risk was lower in normoglycemic (hazard ratio [HR] = 0.71, 95% confidence interval [CI] 0.65, 0.78) and prediabetic (HR = 0.81, 95% CI 0.73, 0.89) participants with low IDI scores compared to those with high IDI scores. A low-inflammatory diet may prolong type 2 diabetes onset by 2.20 (95% CI 1.67, 2.72) years among participants with normoglycemia and 1.11 (95% CI 0.59, 1.63) years among participants with prediabetes. In joint effect analyses, normoglycemic or prediabetes participants with low genetic predisposition to type 2 diabetes and low IDI scores had a significant 74% (HR = 0.26, 95% CI 0.21, 0.32) or 51% (HR = 0.49, 95% CI 0.40, 0.59) reduction in type 2 diabetes risk compared to those with high genetic risk plus high IDI scores. There were significant additive and multiplicative interactions between IDI and GRS in relation to type 2 diabetes risk in the normoglycemia group. Conclusions A low-inflammatory diet is associated with a decreased risk of type 2 diabetes and may delay type 2 diabetes onset among participants with normal blood glucose or prediabetes. A low-inflammatory diet might significantly mitigate the risk of genetic factors on type 2 diabetes development.

Identifying the mechanistic targets of crosstalk between sarcopenia (SA) and mild cognitive impairment (MCI) is critical for screening high‐risk populations and exploring effective prevention and treatment strategies. In a nationwide multicenter prospective cohort study combined with an RCT study, it is found that indexes of muscle health reveal a strong predictive relationship with cognitive performance assessed using the Montreal Cognitive Assessment (MoCA). Furthermore, Random Forest models suggest that lecithin can predict both diseases. Erythrocyte lipid analysis and RCT study indicate the protective function of lecithin and the potential involvement of irisin in that process. In rodent models, phosphocholine (PC) alleviates learning and memory impairments and muscle attenuation in SAMP8 mice, while FNDC5/irisin knockdown accelerates brain and muscle damage or eliminates the protective effects of PC. Transcriptome analysis shows that PGC1α (the regulator of FNDC5) is regulated by PC treatment, and the results of knocking out PGC1α and FNDC5/irisin are consistent. Here it is found that muscle‐secreted FNDC5/irisin is a key target of “muscle‐brain” crosstalk, and lecithin may postpone the progression of MCI and SA by stimulating PGC1α‐FNDC5/irisin‐mediated cross‐protection of cognition and skeletal muscle. This study opens a new avenue for safeguarding cognition and muscle health, averting disability in older age, and treating age‐related pathologies through lecithin supplementation. It serves as a promising nonpharmacological intervention for the crosstalk of muscle and cognition. The protective effects of lecithin demonstrate in the investigations of both humans and mice provide strong support for the development of PC interventions.

It remains unclear whether cognitive reserve can attenuate dementia risk among people with different genetic predispositions. We aimed to examine the association between cognitive reserve and dementia, and further to explore whether and to what extent cognitive reserve may modify the risk effect of genetic factors on dementia. Within the UK Biobank, 210 631 dementia-free participants aged ≥60 years were followed to detect incident dementia. Dementia was ascertained through medical and death records. A composite cognitive reserve indicator encompassing education, occupation and multiple cognitively loaded activities was created using latent class analysis, categorised as low, moderate and high level. Polygenic risk scores for Alzheimer's disease were constructed to evaluate genetic risk for dementia, categorised by tertiles (high, moderate and low). Data were analysed using Cox models and Laplace regression. In multi-adjusted Cox models, the hazard ratio (HR) of dementia was 0.66 (95% confidence interval (CI) 0.61-0.70) for high cognitive reserve compared with low cognitive reserve. In Laplace regression, participants with high cognitive reserve developed dementia 1.62 (95% CI 1.35-1.88) years later than those with low cognitive reserve. In stratified analysis by genetic risk, high cognitive reserve was related to more than 30% lower dementia risk compared with low cognitive reserve in each stratum. There was an additive interaction between low cognitive reserve and high genetic risk on dementia (attributable proportion 0.24, 95% CI 0.17-0.31). High cognitive reserve is associated with reduced risk of dementia and may delay dementia onset. Genetic risk for dementia may be mitigated by high cognitive reserve. Our findings underscore the importance of enhancing cognitive reserve in dementia prevention.

Metabolomics has been associated with cognitive decline and dementia, but the relationship between metabolites and brain aging remains unclear. We aimed to investigate the associations of metabolomics with brain age assessed by neuroimaging and to explore whether these relationships vary according to apolipoprotein E (APOE) ε4. This study included 17,770 chronic brain disorder‐free participants aged 40–69 years from UK Biobank who underwent neuroimaging scans an average of 9 years after baseline. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Brain age was estimated using LASSO regression and 1079 brain MRI phenotypes and brain age gap (BAG; i.e., brain age minus chronological age) was calculated. Data were analyzed using linear regression. We identified 64 and 77 metabolites associated with brain age and BAG, respectively, of which 55 overlapped. Lipids (including cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids) in S/M‐HDL, as well as phospholipids and triglycerides as a percentage of total lipids in different‐density lipoproteins, were associated with larger BAG. The percentages of cholesterol, cholesteryl esters, and free cholesterol to total lipids in VLDL, LDL, and HDL of different particle sizes were associated with smaller BAG. The associations of LA/FA, omega‐6/FA, SFA/FA, and phospholipids to total lipids in L‐HDL with brain age were consistent across APOE ε4 carriers and non‐carriers (all p for interaction > 0.05). Plasma metabolites show remarkably widespread associations with brain aging regardless of APOE ε4 genetic risk. Metabolic profiles could serve as an early indicator of accelerated brain aging. Plasma metabolites show remarkably widespread associations with brain aging regardless of APOE ε4 genetic risk. Metabolic profiles could serve as an early indicator of accelerated brain aging.

INTRODUCTION The associations of the Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet with brain structural changes are unclear. METHODS Among 26,466 UK Biobank participants, a 15‐point MIND score was calculated from 24‐hour diet recalls from 2009 to 2012. We assessed its associations with 17 magnetic‐resonance‐derived brain volumetric markers and their longitudinal changes and explored whether genetic factors modify the associations. RESULTS Higher MIND adherence was associated with larger volumes of thalamus, putamen, pallidum, hippocampus, and accumbens (beta per 3‐unit increment ranging from 0.024 to 0.033) and lower white matter hyperintensities (P‐trends < 0.05), regardless of genetic predispositions of Alzheimer's disease. MIND score was not associated with their longitudinal changes (P > 0.05) over a median of 2.2 years among participants with repeated imaging assessments (N = 2963), but was associated with slower atrophy in putamen (beta: 0.026, P‐trend = 0.044) and pallidum (beta: 0.030, P‐trend = 0.033) among APOE ε4 non‐carriers (N = 654). DISCUSSION The MIND diet showed beneficial associations with certain brain imaging markers, and its associations with long‐term brain structural changes warrants future investigation. Highlights Adherence to the Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet was significantly associated with higher volumes and larger gray matter volumes in certain brain regions in UK adults, and the associations were not modified by genetic factors. No significant associations were observed between MIND diet and longitudinal changes in the investigated brain structural markers over a median of 2.2 years. Higher MIND score was significantly associated with slower atrophy in the putamen and pallidum among APOE ε4 non‐carriers.

INTRODUCTION Apolipoprotein E4 (APOE4) carriers’ tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood‐brain barrier. METHODS Relationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment. RESULTS Levels of 24(S)‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), and 24‐OHC/27‐OHC ratio did not differ by APOE status (p’s > 0.05). Higher 24‐OHC and 27‐OHC were associated with higher total, low density lipoprotein (LDL), non‐high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p’s < 0.05). Higher 24‐OHC/27‐OHC was associated with greater dementia risk (hazard ratio = 1.51, 95% confidence interval:1.02‐2.22), which interaction analyses revealed as significant for APOE3 and APOE4+, but not APOE2+ carriers. DISCUSSION Less favorable lipid profiles were associated with higher oxysterol levels. A higher ratio of 24‐OHC/27‐OHC may contribute to dementia risk in APOE3 and APOE4+ carriers.

Connection Between Muscle and Brain Inspired by Auguste Rodin's sculpture The Thinker, the cover portrays a muscular and cerebral figure embodying the tension between physical strength and intellectual depth. Highlighting the profound connection between muscle and brain, red dots scattered across the sculpture represent lecithin. This creative artwork reflects the findings of Xianyun Wang et al., who reveal in article number 2405222 that lecithin can mitigate mild cognitive impairment and sarcopenia. The cover art was created by Coloring Guangzhou.

Background Pro‐inflammatory diets have been associated with cognitive decline and dementia, but their impact on overall brain aging is unclear. We aimed to investigate the relationship between a pro‐inflammatory diet and a machine learning‐based measure of brain age, taking into account age, genetic risk for Alzheimer’s disease (AD), and systemic inflammation. Method From the UK Biobank, 21,473 participants aged 40‐70 years and free of chronic brain diseases were included. Baseline Dietary Inflammatory Index (DII) scores were calculated from participants’ average intake of 31 nutrients, assessed up to five times between 2009‐2012 using the Oxford WebQ. Participants were categorized into DII tertiles (low [anti‐inflammatory], moderate, or high [pro‐inflammatory]). An AD polygenic risk score (PRSAD; tertiled as low, moderate, and high) and high‐sensitivity C‐reactive protein (hsCRP; a biomarker of systemic inflammation) were measured from baseline blood draw. We used least absolute shrinkage and selection operator (LASSO) regression to estimate brain age from 1,079 structural and functional magnetic resonance imaging (MRI) measures, obtained approximately 9 years after baseline. We calculated brain‐predicted age difference (BPAD; the difference between brain age and chronological age), where BPAD >0 indicates accelerated brain aging. Data were analyzed using linear regression and mediation analysis. Result Among all participants, DII scores ranged from ‐6.22 to 5.38 (low: ‐6.22 to ‐1.34; moderate: ‐1.35 to 0.49; high: 0.50 to 5.38). In multi‐adjusted linear regression, each unit increase in DII score was associated with older brain age by β = 0.07 (95% confidence interval: 0.02, 0.12) years and greater BPAD by 0.06 (0.02, 0.11) years. Compared to the low DII tertile, high DII was associated with older brain age by 0.35 (0.12, 0.58) years and greater BPAD by 0.34 (0.13, 0.55) years. These associations were pronounced in adults aged ≥60 years, attenuated in adults aged 40‐59 years, and did not differ by PRSAD. HsCRP levels mediated 10% of the DII‐brain age association and 14% of the DII‐BPAD association. Conclusion A pro‐inflammatory diet is associated with accelerated brain aging, especially in older adults and independently of genetic risk for AD. Systemic inflammation may partially mediate the association between a pro‐inflammatory diet and brain age.

Despite the well-established link between the ε4 allele of the apolipoprotein E (APOE) gene and AD, the underlying mechanisms that mediate the risk of developing AD remain elusive. Literature on the role of APOE in cholesterol metabolism suggests that blood cholesterol may be a key factor in the development of AD pathology. Current study aims to investigate whether total cholesterol differs by APOE status and whether this relationship is predictive of AD diagnosis and its biomarkers. Baseline total cholesterol, APOE status, AD diagnosis, global cognitive function, brain Aβ, plasma Aβ40 and Aβ42, and cerebrospinal fluid (CSF) Aβ, tau, and phosphorylated tau were collected between 2004 and 2019 from a sample of 3,099 older adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Higher total cholesterol was associated with AD incidence, higher Aβ in the brain, lower CSF Aβ, lower plasma Aβ40 and Aβ42, poorer cognitive function, and the APOE ε4 allele. Survival analysis showed that ε4 carriers had highest hazard rates of AD, but that cholesterol did not alter time to AD diagnosis. The findings suggest that total cholesterol in later life is predictive of AD and related biomarkers, but further research is needed to elucidate how blood cholesterol may relate to APOE risk for AD.

Human pregnancy-specific glycoproteins (PSGs) serve immunomodulatory and pro-angiogenic functions during pregnancy and are mainly expressed by syncytiotrophoblast cells. While PSG mRNA expression in extravillous trophoblasts (EVTs) was reported, the proteins were not previously detected. By immunohistochemistry and immunoblotting, we show that PSGs are expressed by invasive EVTs and co-localize with integrin α5. In addition, we determined that native and recombinant PSG1, the most highly expressed member of the family, binds to α5β1 and induces the formation of focal adhesion structures resulting in adhesion of primary EVTs and EVT-like cell lines under 21% oxygen and 1% oxygen conditions. Furthermore, we found that PSG1 can simultaneously bind to heparan sulfate in the extracellular matrix and to α5β1 on the cell membrane. Wound healing assays and single-cell movement tracking showed that immobilized PSG1 enhances EVT migration. Although PSG1 did not affect EVT invasion in the in vitro assays employed, we found that the serum PSG1 concentration is lower in African-American women diagnosed with early-onset and late-onset preeclampsia, a pregnancy pathology characterized by shallow trophoblast invasion, than in their respective healthy controls only when the fetus was a male; therefore, the reduced expression of this molecule should be considered in the context of preeclampsia as a potential therapy.