BACKGROUND:Alzheimer's disease (AD) shows considerable heterogeneity in cognitive decline. Executive function (EF), a core cognitive domain, may contribute to this heterogeneity and modulate AD progression. METHODS:We analyzed the trajectories of four EF-related tests in 649 incident cases of AD from the Three-City cohort, using multivariate latent class mixed modeling. We linked latent EF patterns with lifestyle at study entry, brain magnetic resonance imaging, clinical markers, and prognosis. RESULTS:The three identified EF patterns, Steep EF Decline, Low EF, and High EF, showed differences in lifestyle-related factors at baseline, white matter hyperintensity burden, hippocampal volume, and clinical progression. Steep EF Decline predicted worse outcomes and higher mortality. High EF indicated slower decline and better prognosis. DISCUSSION:EF trajectories diverge substantially before AD diagnosis, with implications for prognosis. Preserved EF appears protective, while early or steep EF decline correlates with worse evolution. Lifestyle and vascular factors contribute significantly, highlighting potential intervention targets for cognitive resilience in AD.

Background Chronic kidney disease (CKD) is a global health problem which is associated with poor outcomes, and its prevalence is expected to increase. Identifying novel risk factors for CKD may lead to improved outcomes. Circulating saturated fatty acids (SFAs) have been posited as contributors to CKD risk. Objectives We aimed to evaluate associations between circulating SFAs (measured in phospholipids in 7 cohorts, serum or plasma total in 5 cohorts, and cholesterol esters in 1 cohort) and incident CKD in 13 cohorts, and to pool results by meta-analysis across the studies. Methods SFAs were measured in 13 cohorts in the Fatty Acids Outcomes Research Consortium, including 18,193 participants with estimated glomerular filtration rate >60 mL/min/1.73 m2 across 9 countries. Associations between each SFA [palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)] and incident CKD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 and ≥25% decrease from baseline) were assessed by Cox or Poisson regressions. Results were pooled using inverse variance weighted meta-analysis. Results In total, 2554 participants developed CKD over a weighted median follow-up of 7.6 y. After adjustment, higher concentrations of 18:0 were associated with a lower risk of CKD with minimal heterogeneity (relative risk per interquintile range: 0.87; 95% confidence interval: 0.80, 0.95, P = 0.003, I2 = 14.7%). These associations remained consistent in secondary and sensitivity analyses. We did not observe significant associations of other SFAs with CKD. Conclusions In a meta-analysis of 18,193 participants across 9 countries, we observed no indication that SFA increased CKD risk, whereas higher 18:0 concentrations were associated with a lower risk of CKD. Future research is needed to assess mechanisms by which SFA 18:0 may exert kidney-protective effects, and how circulating SFA 18:0 concentrations may be altered.

Objective This systematic review synthesizes longitudinal evidence on associations between obesity and cognitive performance in early or middle adulthood aged 18 to 64. Methods A comprehensive search of PubMed, PsycINFO, and Web of Science identified prospective studies comparing adults with obesity to those of normal weight and assessing cognitive performance, using validated cognitive tests. Risk of bias was evaluated using ROBINS-E, and findings were synthesized narratively. Results Among a total of 4,871 studies, 4 met the inclusion criteria. Three studies evaluated global cognitive performance in middle-aged adults. Two studies reported poorer cognitive performance in individuals with midlife obesity and a more rapid decline in cognitive performance over 10 years in those who were metabolically unhealthy. One study found no association. Long-term obesity was also associated with lower overall cognitive performance in middle age. Executive performance appeared to be associated with obesity. Research on memory was mixed, as two studies found a negative association with obesity, while two found no association. Methodological weaknesses included imprecise exposure measurements and inadequate adjustment for confounding factors. Conclusions The available evidence is too sparse, heterogeneous, and methodologically uncertain to establish a clinically meaningful independent association between obesity and cognitive performance before age 65. Future prospective studies should include cognitive assessment at baseline and repeated follow-up, report standardized effect estimates, use domain-specific cognitive outcomes, address confounding a priori, and assess central adiposity and metabolic health alongside BMI, particularly in younger adults. PROSPERO registration: CRD42024573250 Keywords: Adults, Cognitive functions, Cohort studies, Executive functions, Obesity

Objective This systematic review synthesizes longitudinal evidence on the association between obesity and cognitive impairment in adults aged 18 to 64. Methods A comprehensive search of PubMed, PsycINFO, and Web of Science identified prospective studies comparing adults with obesity to those of normal weight, using validated cognitive tests. Results Among a total of 4,871 studies, 4 met the inclusion criteria. Three studies evaluated global cognitive function in middle-aged adults. Two studies reported impairments in individuals with midlife obesity and a more rapid decline in those who were metabolically unhealthy. One study found no association. Long-term obesity was also linked to poorer global cognition in midlife. Executive functions appeared to be impacted by obesity. Research on memory was mixed, as two studies found a negative association with obesity, while two found no association. Methodological weaknesses included imprecise exposure measurements and inadequate adjustment for confounding factors. Conclusions Despite evidence that obesity may increase the risk of cognitive impairment in midlife, evidence from a very limited number of studies is inconsistent, and an independent association remains unconfirmed. Future work should clarify which cognitive domains might be particularly vulnerable to obesity in younger adults, thereby guiding early and targeted interventions. PROSPERO registration: CRD42024573250 Keywords: Adults, Cognitive functions, Cohort studies, Executive functions, Obesity

Longitudinal cohort studies produce repeated data that enable the assessment of time-varying association patterns between exposures and health outcomes. Classical linear mixed-effects models (LMMs) can accommodate a large variety of association patterns while accounting for the irregularly spaced, partially observed measurement. But they require the analyst to pre-specify the functional form linking the exposure history to the outcome. We propose the Neural ODE-LMM, which embeds a Neural Ordinary Differential Equation (Neural ODE) within the linear mixed-effects framework: a learned vector field encodes covariate trajectories into a continuous-time latent state that drives both the fixed- and random-effect design, while preserving the standard LMM observation model. This retains classical likelihood-based inference while learning complex, potentially cumulative, covariate effects flexibly. All parameters are estimated by maximising a penalised marginal likelihood. To quantify covariate effects, we introduce contrasts of counterfactual predictions that compare the expected outcome under alternative covariate trajectories with variance estimated via the delta method. In simulations, the model recovers both instantaneous and cumulative-burden effects without prior specification of the functional form. Applied to the Trois-Cités (3C) cohort, a population-based study of 7,324 participants, the method reveals trajectory-dependent associations of BMI and fasting glucose with cognitive decline.

Sleep disorders and, to a lesser extent, anxiety disorders, have been studied independently for their association with weight status. However, these mental disorders are highly comorbid. We investigated the prospective associations of anxiety, insomnia, and anxiety-insomnia comorbidity with obesity risk in general-population adults. Enrollees in the ongoing NutriNet-Santé cohort were selected if they had anxiety (Spielberger's State-Trait Anxiety Inventory [STAI-T], 2013-16) and insomnia data (sleep questionnaire, 2014), were without obesity at baseline, and had body mass index (BMI) data during follow-up. Four baseline morbidity groups were modeled: neither insomnia nor anxiety (reference), high anxiety only (STAI-T ≥ 40), insomnia only, comorbid anxiety, and insomnia. The associations between each of these morbidity groups and incident obesity (BMI ≥30 kg/m2) were assessed using adjusted Cox proportional hazards models. Among 23 797 participants, anxiety, insomnia, and comorbid anxiety and insomnia were present in 21%, 6%, and 7% of men, respectively, and in 29%, 8%, and 14% of women, respectively. Mean follow-up was 6.2 ± 2.0 years. An adjusted significant association between anxiety-insomnia comorbidity and incident obesity was found in men (HR = 1.71, 95% CI: 1.06-2.76) but not in women (HR = 1.00, 95% CI: 0.77-1.30) or in the full sample (HR = 1.12, 95% CI: 0.89-1.42). No associations were observed between anxiety alone or insomnia alone and incident obesity. This large prospective study advances public health knowledge about multimorbidity by suggesting a prospective, sex-specific association between anxiety-insomnia comorbidity and increased risk of new-onset obesity. Upon replication, the findings could help inform obesity prevention programs.

Nutrition, as a modifiable exposure, seems relevant to prevent depression. Several nutrients have been associated with a lower risk of depression in older adults, but longitudinal studies examining nutrient combinations are lacking. Therefore, we investigated the association between a posteriori nutrient patterns and the odds of depressive symptomatology (DS) in older adults over time. The sample included participants from the French Three-City cohort, a prospective population-based study focusing on adults ≥ 65 years. Nutrient intakes were assessed using a 24-hour recall in 2001 and Principal Component Analysis based on 40 nutrients, was performed to identify nutrient patterns. DS was assessed at each visit (up to eight visits until 2018) and defined by a Center for Epidemiologic Studies-Depression score ≥ 16 and/or antidepressant medication. Random effect logistic regression was performed to examine the association between nutrient patterns and DS over time controlled for potential confounding variables. The study sample comprised 1,063 individuals (mean age 75.6y +/- 4.8) and 39.3

Higher Mediterranean- DASH for Neurodegenerative Delay (MIND) diet scores have previously been associated with larger total brain volume (TBV) in the Framingham Offspring Study (FOS) community-based cohort. We investigated cross-sectional relationships between the MIND diet and structural brain imaging volumes and white matter hyperintensity volume (WMHV) across six community-based cohorts. We analyzed data from 3130 dementia-, stroke- and other neurological disease free adults (aged 65 to 74) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, FOS cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort. Individuals completed a brain magnetic resonance imaging (MRI) scan, and a validated food frequency questionnaire (FFQ) (ARIC, CHS, FOS, RS), 24h dietary recall (3C), or an extensive food list (SHIP). The MIND diet consists of ten healthy (e.g. green leafy vegetables, berries and fish) and five unhealthy (e.g. cheese, red meat and products and fast fried foods) components. Outcomes from brain MRI included TBV, total grey matter volume (TGMV), hippocampal volume (HPV), and WMHV. We used multivariable linear regression to relate MIND diet adherence to the outcomes. Results were combined in meta-analysis using fixed effects and random effects models. Higher MIND diet scores (score range: 0-15) were associated with larger HPV (beta = 0.015, 95% confidence interval = 0.004 to 0.026, cm³ per one unit MIND diet score increase) after adjustment for age, age squared, sex, time from clinical exam to brain MRI exam, total intracranial volume and energy intake, but not with TBV, TGMV and WMHV. Heterogeneity between studies was low (I 2 = 0% TBV, TGMV, HPV) to moderate (I 2 = 44% WMHV). In cross-sectional analyses, higher MIND diet scores were associated with larger HPV, but not with other brain volume measures. It might be that HPV was a more sensitive marker of brain health in the populations under study. Future studies are encouraged to examine the associations between the MIND diet and amyloid and tau positron emission tomography (PET) imaging to elucidate whether a relationship between the MIND diet and dementia pathologies exists.

BACKGROUND:Persistent Organic Pollutants (POP), including polychlorinated biphenyls (PCBs) and organochlorine pesticides, are established neurotoxicants in experimental models; yet it remains uncertain whether exposures in the general population increase the risk to develop brain aging pathologies. We assessed the prospective associations of plasma POP concentrations with three dementia-related outcomes in a population-based cohort of older adults. METHODS:Analyses included 515 participants from the Three-City Study, free of dementia at baseline at the time of blood measurements (1999-2000, mean age 72.5), who underwent up to 8 repeated assessments of cognitive function and dementia over 17 years and up to 3 neuroimaging examinations over 10 years. Plasma concentrations of 15 PCBs, 12 organochlorine pesticides and 1 brominated flame retardant were measured by gas chromatography coupled with tandem mass spectrometry (detection rate ≥5 %), and a POP score summarizing overall exposure was derived via factorial analysis. Associations with dementia risk, longitudinal changes in cognitive function (composite measure of four tests) and in brain volume (medial temporal lobe) were analyzed using Cox and linear mixed models, adjusted for baseline age, sex, education, apolipoprotein E (APOE) genotype, body mass index and total lipid concentrations. RESULTS:In multivariable-adjusted models, neither individual POPs nor the total POP score were significantly and consistently associated with dementia-related outcomes. Significant interactions were observed between APOE genotype and highly-chlorinated PCBs (congeners 180, 194, and 196-203) across all outcomes (p for interaction ≤0.05), whereby adverse associations were seen in carriers of the APOE-ɛ4 allele, whereas opposing trends were observed in non-carriers. CONCLUSION:Overall, this prospective study does not provide robust evidence to support an adverse association between exposure to POPs in the general population and the risk of all-cause dementia, cognitive decline, or brain atrophy in older adults.

Findings from observational studies which examined relationships between Mediterranean- DASH for Neurodegenerative Delay(MIND) diet scores and risk of dementia are promising. We investigated whether MIND diet scores are associated with incident all-cause dementia and being alive and dementia free at age 80 across six community-based cohorts. We analyzed data from 8714 dementia free adults (mean age range across cohorts: 67 to 73) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, Framingham Offspring Study (FOS) cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort. Individuals had incident all-cause dementia surveillance data available and completed a validated food frequency questionnaire (FFQ) (ARIC, CHS, FOS, RS, 3C), 24h dietary recall (3C), or an extensive food list (SHIP). The MIND diet score is derived from ten healthy and five unhealthy components. We used Cox regression and logistic regression. Results were combined in meta-analysis using fixed effects and random effects models. Higher MIND diet scores (score range: 0-15) and MIND diet scores ≥6 were associated with decreased risk for all-cause dementia (Hazard ratio(HR) = 0.96,95% confidence interval(CI)=0.93-0.99; 0.86,95%CI=0.78-0.94, respectively) after adjustment for age at dietary intake assessment visit, sex, and total energy intake. Further, higher MIND diet scores and MIND diet scores ≥6 related to higher odds of being alive and dementia free at age 80 (Odds ratio(OR) = 1.11,95%CI=1.07-1.15;OR=1.37,95%CI=1.22-1.54, respectively). Heterogeneity between studies ranged between 0-30%. Higher MIND diet scores associated with decreased all-cause dementia risk and being alive and dementia free at age 80. We encourage clinical trials to examine the MIND diet in relation to dementia related outcomes such as amyloid and tau to elucidate whether a causal relationship between the MIND diet and dementia pathologies exists.

We investigated macronutrient, caffeine and water intake by mental morbidity level, focusing on pure and comorbid anxiety, insomnia, and eating disorders (ED). This descriptive, cross-sectional study used 2013-2017 data from the NutriNet-Santé cohort. Diet was assessed with ≥3 24-hour records; mean daily intake of total energy and % contribution of carbohydrates, proteins, and lipids to total energy; total, simple, complex carbohydrates; total, animal, vegetable protein; total lipids, SFA, MUFA, PUFA; cholesterol; caffeine and water was analyzed. Data were weighted using the 2016 French Census, and ANOVA was performed (N = 23,965). Overall, men presenting all 3 mental disorders had the highest % carbohydrates and the lowest % proteins and lipids. The multimorbidity group had the highest obesity rates and caffeine intake across sex; water intake had no dose-response association with mental morbidity. The findings could help generate hypotheses regarding dietary exposures that might play a role in mental multimorbidity risk.

This critical overview aims to provide one of the most comprehensive synthesis of epidemiological and experimental evidence relating the chemical exposome to Alzheimer’s Disease (AD). We have focused on chemical pollutants that mostly result from anthropic activities and involved in toxicology pathways, including pesticides, organic solvents, metals, combustion air pollutants, dioxins, flame retardants, fluorosurfactants, plastic components and food/cosmetic additives. In total, we have reviewed over 120 epidemiological studies examining the link between chemical exposures and the risk of AD or cognitive impairment in older adults, along with more than 250 experimental studies assessing the impact of chemical exposures on neurodegeneration-related pathways. The predominant emphasis in epidemiological research has been on pesticides, metals, solvents and combustion air pollutants. The most consistently observed associations with AD/cognitive impairment involve occupational exposure to pesticides and exposure to fine particulate matter. Less is known about the impact of lower levels of pesticide exposure in the general population, with emerging evidence supported by a few studies. Conversely, in the general population, there is growing evidence of the role of air pollution, especially increased exposure to fine particulate matters, in AD. Regarding metals and solvents, associations with AD have been suggested in several case-control or cross-sectional studies but the overall weight of evidence remains low. In experimental studies, pesticides and metals have also been the most extensively investigated and predominantly implicated in the disruption of neurotransmission, oxidative stress and mitochondrial dysfunction; some pesticides might also specifically target amyloid-β aggregation. Finally, our comprehensive literature review highlights a gap in knowledge concerning the influence of many chemical exposures on AD, especially the most recent pesticide families as well as synthetic additive chemicals considered as ubiquitous. Yet, some of these chemicals have been incriminated in neurodevelopmental defects, and there exists suggestive, albeit still limited, evidence of their involvement in neurodegeneration-related pathways, such as neurotransmission disruption, supporting the need for further research efforts.

BACKGROUND:Findings from observational studies which examined relationships between Mediterranean- DASH for Neurodegenerative Delay(MIND) diet scores and risk of dementia are promising. We investigated whether MIND diet scores are associated with incident all-cause dementia and being alive and dementia free at age 80 across six community-based cohorts. METHOD:We analyzed data from 8714 dementia free adults (mean age range across cohorts: 67 to 73) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, Framingham Offspring Study (FOS) cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort. Individuals had incident all-cause dementia surveillance data available and completed a validated food frequency questionnaire (FFQ) (ARIC, CHS, FOS, RS, 3C), 24h dietary recall (3C), or an extensive food list (SHIP). The MIND diet score is derived from ten healthy and five unhealthy components. We used Cox regression and logistic regression. Results were combined in meta-analysis using fixed effects and random effects models. RESULT:Higher MIND diet scores (score range: 0-15) and MIND diet scores ≥6 were associated with decreased risk for all-cause dementia (Hazard ratio(HR) = 0.96,95% confidence interval(CI)=0.93-0.99; 0.86,95%CI=0.78-0.94, respectively) after adjustment for age at dietary intake assessment visit, sex, and total energy intake. Further, higher MIND diet scores and MIND diet scores ≥6 related to higher odds of being alive and dementia free at age 80 (Odds ratio(OR) = 1.11,95%CI=1.07-1.15;OR=1.37,95%CI=1.22-1.54, respectively). Heterogeneity between studies ranged between 0-30%. CONCLUSION:Higher MIND diet scores associated with decreased all-cause dementia risk and being alive and dementia free at age 80. We encourage clinical trials to examine the MIND diet in relation to dementia related outcomes such as amyloid and tau to elucidate whether a causal relationship between the MIND diet and dementia pathologies exists.

INTRODUCTION:An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high-risk individuals and improve risk prediction. METHODS:We developed an iPRS for dementia (iPRS-DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [APOE]). iPRS-DEM was evaluated across cohorts comprising older community-dwelling people (N = 3702), a multi-ancestry biobank (N = 130,797 Europeans; 105,404 non-Europeans), and dementia-free memory clinic participants (N = 2032). RESULTS:iPRS-DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR]per1SD = 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR-sHRper1SD = 1.28, 95% CI: 1.09 to 1.51]), East-Asians (EAS-sHRper1SD = 5.29, 95% CI: 1.43 to 34.36), and memory-clinic participants (sHRper1SD = 1.25, 95% CI: 1.11 to 1.42). Prediction was comparable to clinical risk factors in older community-dwelling people, with improved performance among memory-clinic patients. Risk stratification was enhanced by defining four genetic risk groups with iPRS-DEM and APOE ε4, reaching five-fold increased risk in APOE ε4+/iPRS-DEM+ memory-clinic participants. DISCUSSION:Alongside APOE ε4, iPRS-DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs. HIGHLIGHTS:iPRS-DEM reflects neurodegenerative and vascular contribution to dementia. We show iPRS-DEM captures additional dementia genetic risk beyond APOE and AD-PRS. iPRS-DEM, in combination with APOE ε4, shows promise for dementia risk stratification. Our results generalize across both population-based and memory-clinic settings. We show transportability of iPRS-DEM to East Asian ancestry.

Persistent Organic Pollutants (POP), including polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP), are established neurotoxicants, especially during developmental periods. Mechanisms of actions include disruption in neurotransmitter systems, calcium dyshomeostasis, oxidative stress and certain OCPs also promote amyloidogenesis in experimental models. Yet, it remains uncertain whether low‐grade environmental exposures in the general population increase the risk to develop brain aging pathologies. We assessed the prospective associations of plasma POP concentrations with three dementia‐related outcomes in a population‐based cohort of older adults. We included 515 participants from the French Three‐City Study, free of dementia at baseline at the time of blood measurements (1999‐2000, mean age 72.5; 19% APOE‐ɛ4 carriers), who underwent up to 8 repeated assessments of cognitive function and dementia over 17 years and 3 neuroimaging examinations over 10 years. Plasma concentrations of 12 OCPs and 15 PCBs were measured by GC/MS/MS, and a POP score summarizing overall exposure was derived via factorial analysis. Associations with dementia risk, and longitudinal changes in cognitive function (composite measure of four tests) and volume of the medial temporal lobe (MTL) were analyzed using Cox and linear mixed models, adjusted for baseline age, sex, education, APOE genotype, body mass index and total lipid concentrations. Median plasma concentrations were in accordance with expected values in the population age range. In multivariable‐adjusted models, neither individual POPs nor the POP factorial score were significantly associated with any dementia‐related outcome. Significant interactions were observed between APOE genotype and highly‐chlorinated PCBs (congeners 180, 194, and 196‐203) across all outcomes ( p for interaction ≤0.05): adverse associations were seen in carriers of the APOE‐ɛ4 allele (e.g. for each SD increase in PCB 194, HR [95% CI] for dementia = 1.51 [1.03‐2.21]; β coefficient [95% CI] for cognitive decline and MTL atrophy = ‐0.15 [‐0.34; 0.04] and ‐0.42 [‐0.74; ‐0.10] SD per decade, respectively), whereas opposing trends were observed in non‐carriers. Overall, this prospective study does not provide robust evidence to support an adverse association between low‐grade environmental exposure to POPs in the general population and the risk of all‐cause dementia, cognitive decline, or brain atrophy in older adults.

Some older adults succeed in maintaining excellent cognition despite high genetic risk for Alzheimer’s disease (AD), reflecting cognitive resistance (CR) to potential neuropathologies. Although the etiological factors for CR are still unknown, some literature suggests that environmental/lifestyle risk factors may contribute to offset, or at least reduce, the effect of AD-related genes on cognitive decline and dementia risk. Yet, how modifiable lifestyle and health related risk factors may promote CR in genetically at-risk individuals remains to be elucidated. We selected 6,774 dementia-free participants from the Three-City study cohort (≥65 years), who underwent ApoE and genome-wide genotyping, at least 2 neuropsychological evaluations over time, and had information for the LIfestyle for BRAin health (LIBRA) score at baseline. LIBRA is a validated weighted score of 12 modifiable risk factors, including unhealthy lifestyle, poor cardiometabolic health, depression and renal dysfunction, with higher scores denoting increased lifestyle-related dementia risk. We defined high genetic risk through ApoE-ε4 status alone or combined with high AD-specific genetic risk scores (GRS) beyond ApoE. We operationalized the concept of CR to genetic risk based on the individual slopes of global cognition estimated using latent process mixed models adjusted for demographics and genetic risk. CR status was assigned to genetically at-risk participants with an adjusted cognitive slope in the slowest 25% of the overall population. Finally, focusing on genetically at-risk individuals, we examined the associations between the LIBRA score, its individual components, and CR status using separate logistic regression models adjusted for sex, age, education, and study center. Among genetically at-risk participants (n = 1,336 ε4-carriers; n = 2,065 ε4-carriers/GRS-high), 237 (18%) ε4-carriers and 470 (23%) ε4-carriers/GRS-high were cognitively resistant to susceptibility genes. Each unit increment in the LIBRA risk score at baseline was strongly associated with lower odds of CR in ε4-carriers (odds ratio [OR] = 0.915; 95% confidence interval [CI] = 0.865-0.967; P = .002; Figure ) and ε4-carriers/GRS-high (OR = 0.883; 95%CI = 0.847-0.920; P <.0001). When examining LIBRA components, cognitive activities and history of coronary heart diseases showed the strongest independent associations with CR (all P<0.01; Figure ). Genetically at-risk older adults can develop cognitive resistance, which may be substantially promoted by prevention programs targeting lifestyle modifications and health management.

BACKGROUND AND OBJECTIVES:Dementia and stroke are major global causes of disability, with modifiable lifestyle factors playing a significant role in their development. The updated LIfestyle for BRAin health (LIBRA2) score integrates 15 modifiable risk and protective factors to quantify lifestyle-based dementia risk, but its relationship with stroke and dementia subtypes remains unexplored. We investigated LIBRA2's association with stroke and dementia subtypes while also assessing potential interactions with genetic susceptibility. METHODS:Prospective data were used from the French multicenter Three-City (3C) Study, with participants aged 65 years and older followed for up to 17 years. Weighted LIBRA2 scores at baseline were constructed based on the presence of 15 modifiable risk and protective factors, with higher scores representing higher lifestyle-based dementia risk. Cox proportional hazards models were used to study the association of LIBRA2 with incident dementia (and subtypes) and stroke, adjudicated by expert neurologist panels. Genetic susceptibility to dementia and stroke was assessed using APOE ε4 carriership and disease-specific genetic risk scores. RESULTS:Analyses included 4,731 participants for stroke (mean age 73.8 years, 60.1% female) and 4,737 participants for dementia (mean age 73.8 years, 59.9% female). One-point increases in LIBRA2 scores (theoretical range -6.1 to +25.7) were associated with increased dementia risk (hazard ratio [HR] 1.08; 1.06-1.11), with a stronger association for vascular and mixed dementia (HR 1.13; 1.08-1.18) compared with Alzheimer disease (AD) dementia (HR 1.06; 1.03-1.09). LIBRA2 was not significantly associated with incident stroke risk (HR 1.03; 0.99-1.07). No significant interaction was found between LIBRA2 and APOE ε4 carriership or disease-specific genetic risk scores in relation to dementia subtypes or stroke. DISCUSSION:LIBRA2 serves as a valuable tool for assessing lifestyle-related dementia risk and its subtypes but showed no association with stroke, highlighting the potential for a stroke-specific risk reduction model. These associations were independent of genetic disease susceptibility, reinforcing the universal benefits of lifestyle modifications on dementia risk reduction. The stronger association between LIBRA2 (and some individual components) and vascular or mixed dementia, compared with AD dementia, highlights the pivotal role of vascular mechanisms in the relationship between lifestyle and brain health.

Chemicals are ubiquitous in modern life. More than 100,000 chemicals are currently used worldwide, and the production continues to increase. Measuring with accuracy all the components of the chemical exposome represents a tremendous challenge which has been only very partly met so far, and gaps in science remain multiple. For example, there is a need for a comprehensive understanding of the chemical exposome’s impact on the brain, emphasizing the integration of various exposure routes and an expanded list of emerging concern chemicals. Biomonitoring, a relatively recent approach, has begun linking internal exposure to neurological impacts, shedding light on the potential neurotoxicity of non-persistent pesticides like neonicotinoids and pyrethroids. Research should explore overlooked ubiquitous chemicals, such as flame retardants, fluorosurfactants, plasticizers, and food additives, and overlooked pathways such as neurovascular dysfunction or the impact on non-neuronal cells. Furthermore, analytical challenges posed by exposomic studies are specifically important, since the chemical space is highly variable, dynamic and diverse in concentration levels (with ultra-trace substances). Chemical exposures are multiple and potential additive or synergistic effects of chemicals, within mixtures, likely underlie the impact of the chemical exposome on the brain. Capturing the depth and breadth of that chemical exposome necessitates cutting-edge molecular markers. The development of high throughput omics-based molecular approaches has allowed simultaneous analysis of thousands of individual biological entities at a large scale – a technological revolution which has enabled the development of exposomics. High-resolution mass spectrometry (HRMS)-based methods applied to various matrices, allows to uncover unknown elements of the internal chemical exposome associated with neurodegenerative diseases. This presentation will discuss all the promises that new technologies combined with omics-based methodologies could provide to uncover unknown chemical signatures associated to neurodegenerative diseases.

In Alzheimer’s disease, microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of Alzheimer’s disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis, and microglial responses. We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer’s disease pathology. The objective of this study is to investigate the effects of Alzheimer’s disease serum on microglial phagocytosis. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer’s disease ( n = 30) and age-matched controls ( n = 30) (PRODEM study) on microglial phagocytosis. Exposure to Alzheimer’s disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB ( TFEB ) and of ATPase H + transporting lysosomal V1 subunit B2 ( ATP6V1B2 ), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to the serum of future Alzheimer’s disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls, depending on the presence of the apolipoprotein E ε4 allele in the Alzheimer’s disease patients. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid. We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with Alzheimer’s disease blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2 , possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels, suggesting an important role for dietary eicosapentaenoic acid in microglial function.

We are writing with regard to the letter by Mengqin Zhang, published in reference to our study: "Mental multimorbidity among general-population adults: sex-specific sociodemographic profiles of anxiety, insomnia, and eating disorders" [1]. We thank the author for the interest in our work which pertains to a descriptive analysis of the prevalence and sociodemographic profiles of mental multimorbidity. As we had noted in the text, and as observed by M. Zhang, a limitation common to epidemiological research is the reliance on self-reported data provided by volunteers. In addition, we had acknowledged the inability of the SCOFF questionnaire to distinguish among eating disorder (ED) types [2]. We agree with M. Zhang that this limitation precludes a granular understanding the comorbidity of different EDs with anxiety and insomnia. Nonetheless, we wish to point out that in our sample, EDs were the least prevalent of the three mental health conditions, especially among men. Splitting EDs into different types (i.e., restrictive/anorexic, bulimic, etc.) would have jeopardized the study due to the very small number of individuals in the various pure and comorbid ED categories. Thus, despite its limitations, the SCOFF allowed us to carry out our analyses with sufficient statistical power. We concur with M. Zheng that future studies, using more sensitive ED tools and possibly subtype-specific scales, could help characterize ED types and their distinct comorbidity patterns. Next, we assessed trait anxiety by modelling STAI-T in sex-specific quartiles, fully understanding that such an approach was sub-optimal as the instrument was initially conceptualized on a continuous scale [3]. While our approach aligns with epidemiological practices [4], we recognize the potential for measurement bias and suggest conducting sensitivity analyses in subsequent research. Whereas shedding light on the chronology of the three mental health conditions was beyond the scope of our study, we had acknowledged the inability to infer causality and had pointed out the availability of evidence of complex bidirectional and possibly mediated associations among anxiety, insomnia, and ED [5,6]. Furthermore, M. Zhang has rightfully observed that the temporal ordering of mental disorders could impact treatment outcomes and prognosis. Thus, we fully agree that prospective research in this domain (possibly integrating objective mental health assessments and biomarker data) is warranted, as are moderation and mediation analyses whose findings could help guide targeted public health interventions. Finally, we appreciate M. Zheng's observation that our study makes a notable contribution to the understanding of mental health multimorbidity. The results could serve as impetus for further epidemiological and mechanistic research aimed at elucidating the underlying mechanisms of the complex relationships among mental disorders.We declare no competing interests.