Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline.

INTRODUCTION: Evaluating whether genetic susceptibility modifies the impact of lifestyle-related factors on dementia is critical for prevention. METHODS: We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non-carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION: Lifestyle-based prevention may be effective whatever the genetic susceptibility to dementia.

Mapping Cognitive Trajectories and Detecting Early Dementia Using the Mini-Mental State Examination Cognitive Charts: Application to the French Three-City Cohort.

The Cognitive Quotient (QuoCo) classification algorithm monitoring decline on age- and education-adjusted Mini-Mental State Examination (MMSE)-derived cognitive charts has proved superior to the conventionally-used cut-off for identifying incident dementia; however, it remains to be tested in different settings. Data were drawn from the Three-City Cohort to 1) assess the screening accuracy of the QuoCo, and 2) compare its performance to that of serial MMSE tests applying different cut-offs. For the QuoCo, sensitivity was 74.2 (95% CI: 71.4-76.8) and specificity 84.1 (83.6-84.7) and for the MMSE < 24, 64.1 (61.1-67.0) and 94.8 (94.4-95.1), respectively; whereas overall accuracy and sensitivity was highest for MMSE cut-offs <25 and <26. User-friendly charts for mapping cognitive trajectories over visits with an alert for potentially 'abnormal' decline can be of practical use and encourage regular monitoring in primary care where the <24 cut-off is still widely used despite its poor sensitivity.

Habitual coffee consumption and risk of dementia in older persons: modulation by CYP1A2 polymorphism.

Higher coffee consumption has been associated with reduced dementia risk, yet with inconsistencies across studies. CYP1A2 polymorphisms, which affects caffeine metabolism, may modulate the association between coffee and the risk of dementia and Alzheimer's disease (AD). We included 5964 participants of the Three-City Study (mean age 74 years-old), free of dementia at baseline when they reported their daily coffee consumption, with available genome-wide genotyping and followed for dementia over a median of 9.0 (range 0.8-18.7) years. In Cox proportional-hazards models, the relationship between coffee consumption and dementia risk was modified by CYP1A2 polymorphism at rs762551 (p for interaction = 0.034). In multivariable-adjusted models, coffee intake was linearly associated with a decreased risk of dementia among carriers of the C allele only ("slower caffeine metabolizers"; HR for 1-cup increased [95% CI] 0.90 [0.83-0.97]), while in non-carriers ("faster caffeine metabolizers"), there was no significant association but a J-shaped trend toward a decrease in dementia risk up to 3 cups/day and increased risk beyond. Thus, compared to null intake, drinking ≥ 4 cups of coffee daily was associated with a reduced dementia risk in slower but not faster metabolizers (HR [95% CI] for ≥ 4 vs. 0 cup/day = 0.45 [0.25-0.80] and 1.32 [0.89-1.96], respectively). Results were similar when studying AD and another CYP1A2 candidate polymorphism (rs2472304), but no interaction was found with CYP1A2 rs2472297 or rs2470893. In this cohort, a linear association of coffee intake to lower dementia risk was apparent only among carriers of CYP1A2 polymorphisms predisposing to slower caffeine metabolism.

Ambient Air Pollution Exposure and Cerebral White Matter Hyperintensities in Older Adults: A Cross-Sectional Analysis in the Three-City Montpellier Study.

BACKGROUND: Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive health, and this could be related to the effect of air pollution on vascular health. OBJECTIVE: We aim to evaluate the association between air pollution exposure and a magnetic resonance imaging (MRI) marker of cerebral vascular burden, white matter hyperintensities (WMH). METHODS: This cross-sectional analysis used data from the French Three-City Montpellier study. Randomly selected participants 65-80 years of age underwent an MRI examination to estimate their total and regional cerebral WMH volumes. Exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) at the participants' residential address during the 5 years before the MRI examination was estimated with land use regression models. Multinomial and binomial logistic regression assessed the associations between exposure to each of the three pollutants and categories of total and lobar WMH volumes. RESULTS: Participants' (n=582) median age at MRI was 70.7 years [interquartile range (IQR): 6.1], and 52% (n=300) were women. Median exposure to air pollution over the 5 years before MRI acquisition was 24.3 (IQR: 1.7) µg/m3 for PM2.5, 48.9 (14.6) µg/m3 for NO2, and 2.66 (0.60) 10-5/m for BC. We found no significant association between exposure to the three air pollutants and total WMH volume. We found that PM2.5 exposure was significantly associated with higher risk of temporal lobe WMH burden [odds ratio (OR) for an IQR increase=1.82 (95% confidence interval: 1.41, 2.36) for the second volume tercile, 2.04 (1.59, 2.61) for the third volume tercile, reference: first volume tercile]. Associations for other regional WMH volumes were inconsistent. CONCLUSION: In this population-based study in older adults, PM2.5 exposure was associated with increased risk of high WMH volume in the temporal lobe, strengthening the evidence on PM2.5 adverse effect on the brain. Further studies looking at different markers of cerebrovascular damage are still needed to document the potential vascular effects of air pollution. https://doi.org/10.1289/EHP12231.

The role of cardiovascular health and vascular events in the relationship between excessive daytime sleepiness and dementia risk.

Many studies suggest a relationship between excessive daytime sleepiness (EDS) and dementia incidence, but the underlying mechanisms remain uncertain. The study aimed to investigate the role of cardiovascular burden in the relationship between EDS and dementia incidence over a 12-year follow-up in community-dwelling older adults. We performed analyses on 6171 subjects (aged ≥65 years) free of dementia and vascular disease at baseline. Participants self-reported EDS at baseline and an expert committee validated both prevalent and incident dementia. We defined cardiovascular burden by a low Cardiovascular Health score, constructed using the American Heart Association metrics, and incident vascular events. To explore the potential role of the cardiovascular burden in the relationship between EDS and dementia, we conducted mediation analyses with inverse odds ratio-weighted estimation, using multivariable-adjusted proportional hazard Cox and logistic regression models. Subjects with EDS had a higher risk of all-cause dementia (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.69) and dementia with vascular component (DVC) (HR 2.14, 95% CI 1.30-3.51), but not Alzheimer's disease (HR 1.18, 95% CI 0.93-1.51). Cardiovascular burden explained 5% (95% CI 4.1-5.2) and 11% (95% CI 9.7-11.3) of the relationship between EDS and all-cause dementia and DVC, respectively. These findings confirm that EDS may be implicated in the development of dementia and indicate a weaker than expected role of cardiovascular burden in the relationship between EDS and DVC.

Plasma carotenoids and risk of depressive symptomatology in a population-based cohort of older adults.

BACKGROUND: As part of a healthy diet, higher carotenoid intakes have been associated with a reduced risk of depression, mainly in adults, while prospective studies on plasma carotenoids in older adults are lacking. The aim of this study was to assess the prospective association between plasma carotenoids and the risk of Depressive Symptomatology (DS) in older adults. METHODS: The study sample was based on the Three-City cohort of adults aged 65y+ free from DS at enrollment in 1999. Plasma carotenoids were measured at baseline. DS was assessed every 2-3 years over 17 years and defined by a Center for Epidemiologic Studies-Depression Scale score ≥ 16 and/or by antidepressant use. The association between plasma carotenoids or carotenoid/lipids (cholesterol and triglycerides) ratio and the risk for DS was assessed through multiple random-effect logistic regression. RESULTS: The study sample was composed of 1010 participants (mean age 74 y (±4.9), 58 % of women) followed-up during a median time of 13.4 years. Plasma zeaxanthin and ratios of zeaxanthin/lipids, lutein+zeaxanthin/lipids and ß-carotene/lipids were independently associated with a significant reduced risk of DS over time (Odds ratio (OR) = 0.81, 95 % Confidence Interval (CI) [0.67;0.99], OR = 0.79 [0.67;0.98], OR = 0.79 [0.64;0.94] and OR = 0.80 [0.66;0.97] for +1 standard deviation of each exposure respectively). LIMITATIONS: Plasma carotenoids were only available at study baseline. CONCLUSION: Focusing on circulating carotenoids and considering lipids levels, the present results suggested an association between higher levels of plasma zeaxanthin, combined lutein+zeaxanthin and ß-carotene and a decreased risk of DS over time in older adults.

Association of long-term exposure to ambient air pollution with retinal neurodegeneration: the prospective Alienor study.

Chronic exposure to air pollution may have adverse effects on neurodegenerative diseases. Glaucoma, the second leading cause of blindness worldwide, is a neurodegenerative disease of the optic nerve, characterized by progressive thinning of the retinal nerve fiber layer (RNFL). We investigated the relationship of air pollution exposure with longitudinal changes of RNFL thickness in the Alienor study, a population-based cohort of residents of Bordeaux, France, aged 75 years or more. Peripapillary RNFL thickness was measured using optical coherence tomography imaging every 2 years from 2009 to 2020. Measurements were acquired and reviewed by specially trained technicians to control quality. Air pollution exposure (particulate matter ≤2.5 µm (PM2.5), black carbon (BC), nitrogen dioxide (NO2)) was estimated at the participants' geocoded residential address using land-use regression models. For each pollutant, the 10-year average of past exposure at first RNFL thickness measurement was estimated. Associations of air pollution exposure with RNFL thickness longitudinal changes were assessed using linear mixed models adjusted for potential confounders, allowing for intra-eye and intra-individual correlation (repeated measurements). The study included 683 participants with at least one RNFL thickness measurement (62% female, mean age 82 years). The average RNFL was 90 µm (SD:14.4) at baseline. Exposure to higher levels of PM2.5 and BC in the previous 10 years was significantly associated with a faster RNFL thinning during the 11-year follow-up (-0.28 µm/year (95% confidence interval (CI) [-0.44;-0.13]) and -0.26 µm/year (95% CI [-0.40;-0.12]) per interquartile range increment; p < 0.001 for both). The size of the effect was similar to one year of age in the fitted model (-0.36 µm/year). No statistically significant associations were found with NO2 in the main models. This study evidenced a strong association of chronic exposure to fine particulate matter with retinal neurodegeneration, at air pollution levels below the current recommended thresholds in Europe.

Comparison of ultrasensitive and mass spectrometry quantification of blood-based amyloid biomarkers for Alzheimer's disease diagnosis in a memory clinic cohort.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with ß-amyloid pathology as a key underlying process. The relevance of cerebrospinal fluid (CSF) and brain imaging biomarkers is validated in clinical practice for early diagnosis. Yet, their cost and perceived invasiveness are a limitation for large-scale implementation. Based on positive amyloid profiles, blood-based biomarkers should allow to detect people at risk for AD and to monitor patients under therapeutics strategies. Thanks to the recent development of innovative proteomic tools, the sensibility and specificity of blood biomarkers have been considerably improved. However, their diagnosis and prognosis relevance for daily clinical practice is still incomplete. METHODS: The Plasmaboost study included 184 participants from the Montpellier's hospital NeuroCognition Biobank with AD (n = 73), mild cognitive impairments (MCI) (n = 32), subjective cognitive impairments (SCI) (n = 12), other neurodegenerative diseases (NDD) (n = 31), and other neurological disorders (OND) (n = 36). Dosage of ß-amyloid biomarkers was performed on plasma samples using immunoprecipitation-mass spectrometry (IPMS) developed by Shimadzu (IPMS-Shim Aß42, Aß40, APP669-711) and Simoa Human Neurology 3-PLEX A assay (Aß42, Aß40, t-tau). Links between those biomarkers and demographical and clinical data and CSF AD biomarkers were investigated. Performances of the two technologies to discriminate clinically or biologically based (using the AT(N) framework) diagnosis of AD were compared using receiver operating characteristic (ROC) analyses. RESULTS: The amyloid IPMS-Shim composite biomarker (combining APP669-711/Aß42 and Aß40/Aß42 ratios) discriminated AD from SCI (AUC: 0.91), OND (0.89), and NDD (0.81). The IPMS-Shim Aß42/40 ratio also discriminated AD from MCI (0.78). IPMS-Shim biomarkers have similar relevance to discriminate between amyloid-positive and amyloid-negative individuals (0.73 and 0.76 respectively) and A-T-N-/A+T+N+ profiles (0.83 and 0.85). Performances of the Simoa 3-PLEX Aß42/40 ratio were more modest. Pilot longitudinal analysis on the progression of plasma biomarkers indicates that IPMS-Shim can detect the decrease in plasma Aß42 that is specific to AD patients. CONCLUSIONS: Our study confirms the potential usefulness of amyloid plasma biomarkers, especially the IPMS-Shim technology, as a screening tool for early AD patients.

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-ß precursor protein processing, amyloid-ß aggregation, lipid metabolism and microglial function in AD.

Ambient air pollution exposure and depressive symptoms: Findings from the French CONSTANCES cohort.

BACKGROUND AND AIM: Few studies have reported the association between air pollution exposure with different dimensions of depression. We aimed to explore this association across different dimensions of depressive symptoms in a large population. METHODS: Data from the enrollment phase of the French CONSTANCES cohort (2012-2020) were analyzed cross-sectionally. Annual concentrations of particulate matter with a diameter < 2.5 µm (PM2.5), black carbon (BC), and nitrogen dioxide (NO2) from the land-use regression models were assigned to the residential addresses of participants. Total depressive symptoms and its four dimensions (depressed affect, disturbed interpersonal relations, low positive affect, somatic complaints) were measured using Centre of Epidemiologic Studies Depression questionnaire (CES-D). We reported results of negative binomial regression models (reported as Incidence Rate Ratio (IRR) and 95 % confidence interval (CI) for an interquartile range (IQR) increase in exposure), for each pollutant separately. Stratified analyses were performed by sex, income, family status, education, and neighborhood deprivation. RESULTS: The study included 123,754 participants (mean age, 46.50 ± 13.61 years; 52.4 % women). The mean concentration of PM2.5, BC and NO2 were 17.14 µg/m3 (IQR = 4.89), 1.82 10-5/m (IQR = 0.88) and 26.58 µg/m3 (IQR = 17.41) respectively. Exposures to PM2.5, BC and NO2 were significantly associated with a higher CES-D total (IRR = 1.022; 95 % CI = 1.002: 1.042, IRR = 1.027; 95 % CI = 1.013: 1.040, and IRR = 1.029; 95 % CI = 1.015: 1.042 respectively), and with depressed affect, and somatic complaints. For all pollutants, a higher estimate was observed for depressed affect. We found stronger adverse associations for men, lower-income participants, low and middle education groups, those living in highly deprived areas, and single participants. CONCLUSION: Our finding could assist the exploration of the etiological pathway of air pollution on depression and also considering primary prevention strategies in the areas with air pollution.

Trajectories of sleep duration and timing before dementia: a 14-year follow-up study.

BACKGROUND: given the complex relationship between sleep and neurodegenerative processes, it is important to examine whether changes in sleep patterns occur prior or close to dementia onset. OBJECTIVE: to examine the relationship between sleep parameters and dementia incidence and, to characterize trajectories of sleep patterns before dementia diagnosis. DESIGN: a 14-year longitudinal study including a nested case-control study. SETTING: the French Three-City Study. SUBJECTS: overall, 1,749 cognitively healthy participants (≥65 years) for the longitudinal study and, 182 incident dementia cases and 719 controls matched by sex, age and educational level for the case-control study. METHODS: dementia cases were assessed at each visit and self-reported sleep parameters at baseline, 2, 8, 10, 12 and 14 years. Cox models were used to estimate the risk of dementia associated with baseline sleep parameters (sleep duration, time in bed (TIB), sleep timing, sleepiness and insomnia). Latent-process mixed models were performed to compare sleep trajectories according to the case-control status. RESULTS: long baseline nighttime and 24-h sleep durations (≥9 h) as well as being persistent or becoming long sleepers during follow-up were associated with dementia incidence. Trajectories of sleep durations and TIB showed faster increases in cases compared with controls up to 12 years before dementia. The mean differences [95%CI] for 24-h sleep duration between cases and controls were: 0.27 h [0.01;0.52], 0.34 [0.09;0.58] and 0.67 [0.44;0.90] at -12, -8 and -2 years, respectively. Bedtime trajectories showed an earlier bedtime in cases up to -8 years. CONCLUSION: long sleep duration and earlier bedtime may impact dementia incidence.

Dementia Associated with Anticholinergic Drugs Used for Overactive Bladder: A Nested Case-Control Study Using the French National Medical-Administrative Database.

PURPOSE: We analyzed the relationship between use of anticholinergic drugs to treat overactive bladder (OAB) and risk of incident dementia in older patients, overall and for each drug separately. MATERIALS AND METHODS: We conducted a nested case-control study using the French National Medical-Administrative Database. We identified incident dementia cases and controls from January 1, 2013 to December 31, 2018 in individuals aged ≥60 years. Controls were matched 5:1 to cases by date of case diagnosis (index date), age, sex, and income. We set a 5-year exposure period ending 2 years before the index date (lag-time period to avoid protopathic bias). We quantified cumulative exposure to flavoxate, oxybutynin, solifenacin, trospium, and fesoterodine using defined daily doses (DDDs). We performed conditional logistic regression analyses adjusted for factors known to be associated with OAB and/or dementia including obesity, diabetes, stroke, coronary heart disease, and psychotic disorders. RESULTS: We analyzed 4,810 cases and 24,050 matched controls with a median age of 82 years. OAB anticholinergic use was associated with an increased risk of dementia (adjusted OR [aOR]=1.23, 95% CI 1.10-1.37) with a cumulative dose-response: aOR=1.07 (95% CI 0.91-1.25) for 1-90 DDDs, aOR=1.29 (1.05-1.58) for 91-365 DDDs and aOR=1.48 (1.22-1.80) for >365 DDDs. Considering each OAB anticholinergic separately showed a particularly marked increased risk of dementia for oxybutynin and solifenacin, but no increased risk for trospium. CONCLUSIONS: When treating OAB in older patients, OAB anticholinergics should be used with caution, taking into account the patient's cognitive status, the anticholinergic load, and the different therapeutic options.

Outdoor air pollution exposure and cognitive performance: findings from the enrolment phase of the CONSTANCES cohort.

BACKGROUND: Air pollution exposure is one of the modifiable risk factors of cognitive decline. We aimed to test the association between exposure to several outdoor air pollutants and domain-specific cognitive performance. METHODS: In this cross-sectional study, we used data from the enrolment phase of the French CONSTANCES cohort. From the 220 000 people (aged 18-69 years) randomly recruited in the French CONSTANCES cohort, participants aged 45 years old or older (104 733 people) underwent a comprehensive cognitive assessment (verbal episodic memory, language skills, and executive functions). After exclusion of those who were not suitable for our analysis, 61 462 participants with available data were included in the analyses. We used annual mean concentrations at residential addresses, derived from land-use regression models, to assign exposure to particulate matter with aerodynamic diameters less than 2·5 µm (PM2·5), nitrogen dioxide (NO2), and black carbon. We used multiple linear regression models with different covariate adjustments to test the associations between each pollutant and cognitive outcomes. We did several sensitivity analyses, including multilevel modelling, meta-analysis by centre of recruitment, and exclusion of specific population groups. FINDINGS: We found significantly poorer cognitive function, especially on semantic fluency and domains of executive functions, with an increase in exposure to black carbon and NO2. Exposure to PM2·5 was mainly significant for the semantic fluency test. We found that decrease in cognitive performance with an increase of one interquartile range of exposure ranged from 1% to nearly 5%. The largest effect size (percentage decrease) for both PM2.5 and NO2 was found for the semantic fluency test (PM2.5 4·6%, 95% CI 2·1-6·9 and NO2 3·8%, 1·9-5·7), whereas for black carbon, the largest effect size was found for the digit symbol substitution test of the domains of executive functions (4·5%, 2·7-6·3). Monotonic and linear exposure-response associations were found between air pollution exposure and cognitive performance, starting from a low level of exposures. INTERPRETATION: Significantly poorer cognitive performance was associated with exposure to outdoor air pollution even at low levels of exposure. This highlights the importance of further efforts to reduce exposure to air pollution. FUNDING: The Caisse Nationale d'Assurance Maladie, and partly funded by Merck Sharp & Dohme and L'Oréal, the French National Research Agency, and Fondation de France. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Sulcal morphology as cognitive decline predictor in older adults with memory complaints.

To determine whether sulcal morphology can predict changes in cognition, we investigated the relationship between width of 20 cerebral sulci and cognitive decline. Sulcal width was measured in T1-weighted MRI images at baseline in 433 adults aged ≥70 years with memory complaints from the MRI-Multidomain Alzheimer Preventive Trial study. Cognition was evaluated at baseline, 6, 12, 24, and 36 months of follow-up with a composite Z score. The composite score variations over time relative to the baseline sulcal width were assessed using linear mixed regression models. We observed a positive association between a greater decline in cognitive composite score and the width of the superior and the anterior inferior temporal sulci, and the cingulate anterior sulcus of the left hemisphere. Sulcal widening in the lateral temporal and the cingulate anterior areas might predict cognitive decline in individuals with memory complaints.

Modeling exposure to airborne metals using moss biomonitoring in cemeteries in two urban areas around Paris and Lyon in France.

Exposure of the general population to airborne metals remains poorly estimated despite the potential health risks. Passive moss biomonitoring can proxy air quality at fine resolution over large areas, mainly in rural areas. We adapted the technique to urban areas to develop fine concentration maps for several metals for Constances cohort's participants. We sampled Grimmia pulvinata in 77 and 51 cemeteries within ∼50 km of Paris and Lyon city centers, respectively. We developed land-use regression models for 14 metals including cadmium, lead, and antimony; potential predictors included the amount of urban, agricultural, forest, and water around cemeteries, population density, altitude, and distance to major roads. We used both kriging with external drift and land use regression followed by residual kriging when necessary to derive concentration maps (500 × 500 m) for each metal and region. Both approaches led to similar results. The most frequent predictors were the amount of urban, agricultural, or forest areas. Depending on the metal, the models explained part of the spatial variability, from 6% for vanadium in Lyon to 84% for antimony in Paris, but mostly between 20% and 60%, with better results for metals emitted by human activities. Moss biomonitoring in cemeteries proves efficient for obtaining airborne metal exposures in urban areas for the most common metals.

Air quality improvement and incident dementia: Effects of observed and hypothetical reductions in air pollutant using parametric g-computation.

INTRODUCTION: No evidence exists about the impact of air pollution reduction on incidence of dementia. The aim of this study was to quantify how air quality improvement leads to dementia-incidence benefits. METHODS: In the French Three-City cohort (12 years of follow-up), we used parametric g-computation to quantify the expected number of prevented dementia cases under different hypothetical interventions with particulate matter measuring <2.5 µm (PM2.5 ) reductions. RESULTS: Among 7051 participants, 789 participants developed dementia. The median PM2.5 reduction between 1990 and 2000 was 12.2 (µg/m3 ). Such a reduction reduced the risk of all-cause dementia (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76 to 0.95). If all study participants were enjoying a hypothetical reduction of more than 13.10 µg/m3 (median reduction observed in the city of Montpellier), the rate difference was -0.37 (95% CI, -0.57 to -0.17) and the rate ratio was 0.67 (95% CI, 0.50 to 0.84). DISCUSSION: These findings highlight the possible substantial benefits of reducing air pollution in the prevention of dementia.

Exposure to ambient air pollution and cognitive decline: Results of the prospective Three-City cohort study.

BACKGROUND: Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive decline. However, there is still some heterogeneity in the findings, with inconsistent results depending on the pollutant and the cognitive domain considered. We wanted to determine whether air pollution was associated with global and domain-specific cognitive decline. METHODS: This analysis used data from the French Three-City prospective cohort (participants aged 65 and older at recruitment and followed for up to 12 years). A battery of cognitive tests was administered at baseline and every 2 years, to assess global cognition (Mini Mental State Examination, MMSE), visual memory (Benton Visual Retention Test), semantic fluency (Isaacs Set Test) and executive functions (Trail Making Tests A and B). Exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) at the participants' residential address during the 5 years before the baseline visit was estimated with land use regression models. Linear mixed models and latent process mixed models were used to assess the association of each pollutant with global and domain-specific cognitive decline. RESULTS: The participants' (n = 6380) median age was 73.4 years (IQR: 8.0), and 61.5% were women. At baseline, the median MMSE score was 28 (IQR: 3). Global cognition decline, assessed with the MMSE, was slightly accelerated among participants with higher PM2.5 exposure: one IQR increment in PM2.5 (1.5 µg/m3) was associated with accelerated decline (ß: -0.0060 [-0.0112; -0.0007] standard unit per year). Other associations were inconsistent in direction, and of small magnitude. CONCLUSION: In this large population-based cohort, higher PM2.5 exposure was associated with accelerated global cognition decline. We did not detect any significant association for the specific cognitive domains or the other pollutants. Evidence concerning PM2.5 effects on cognition is growing, but more research is needed on other ambient air pollutants.

Complaints of daytime sleepiness, insomnia, hypnotic use, and risk of dementia: a prospective cohort study in the elderly.

BACKGROUND: Sleep disturbances are common in elderly and occur frequently in dementia. The impact of excessive daytime sleepiness (EDS), insomnia complaints, sleep quality, and hypnotics on the risk of all-cause dementia, Alzheimer disease (AD), and dementia with vascular component (DVC) remains unclear, as does the association between sleep profile and plasma ß-amyloid levels. METHODS: Analyses were carried out on 6851 participants aged 65 years and over randomly recruited from three French cities and free of dementia at baseline. A structured interview and self-questionnaire assessed sleep complaints (EDS, insomnia complaints, sleep quality) and medications at baseline. Incident cases of dementia were diagnosed systematically over a 12-year period. Multivariate Cox models were used to estimate the risk of dementia associated with the sleep complaints considered individually and globally. Plasma ß-amyloid levels were measured by an xMAP-based assay technology in 984 subjects. RESULTS: After adjustment for socio-demographic characteristics, lifestyle, APOE-ε4, cardiovascular factors, and depressive status, EDS had a higher risk of all-cause dementia (HR = 1.21; 95%CI = [1.01-1.46]) and DVC (HR = 1.58; 95%CI = [1.07-2.32]) but not AD. Persistent use of hypnotics increased the risk for all-cause dementia, specifically AD (HR = 1.28; 95%CI = [1.04-1.58]), but not DVC. No association was found for insomnia complaints and sleep quality taken as individual factors or combined with EDS on the risk of dementia. No association was found between ß-amyloid, sleep complaints, and incident dementia. CONCLUSIONS: The results suggest a deleterious role of EDS and hypnotics on dementia. Further studies are required to elucidate the mechanisms involved in these associations and whether its management can prevent the risk of dementia.

Cognitive decline as an outcome and marker of progression toward dementia, in early preventive trials.

INTRODUCTION: Recent Food and Drug Administration guidance endorses cognitive assessment as a possible primary endpoint for early trials for Alzheimer's disease but emphasizes the need for certainty regarding the relationship with progression to dementia. METHODS: We compared the validity of the 2-year change (Y0-Y2) of 11 markers of neuropsychological and functional abilities for the prediction of incident dementia over the following 3 years (Y2-Y5), in 860 subjects aged 70 years or older, who consulted for memory loss and were included in the "GuidAge" prevention trial. RESULTS: The Free and Cued Selective Reminding Test-Free Recall (FCSRT-FR) score showed the most predictive 2-year change (area under the curve = 0.72 95% confidence interval = 0.64;0.81). Changes in other subscores of the FCSRT, verbal fluencies tasks, and composite cognitive score were also significantly predictive. Conversely, 2-year change of Mini-Mental State Examination, Trail Making test (TMT)-A, TMT-B, Clinical Dementia Rating Sum of Boxes, and Instrumental Activities of Daily Living scores did not significantly predict occurrence of dementia. CONCLUSION: The FCSRT, the Fluency Task, and the composite cognitive score appear to be good cognitive markers of progression toward dementia in early prevention trials.

Five-Year Dynamic Prediction of Dementia Using Repeated Measures of Cognitive Tests and a Dependency Scale.

The progression of dementia prevalence over the years and the lack of efficient treatments to stop or reverse the cognitive decline make dementia a major public health challenge in the developed world. Identifying people at high risk of developing dementia could improve the treatment of these patients and help select the target population for preventive clinical trials. We used joint modeling to build a dynamic prediction tool of dementia based on the change over time of 2 neurocognitive tests (the Mini-Mental State Examination and the Isaacs Set Tests) as well as an autonomy scale (the Instrumental Activities of Daily Living). The model was estimated with data from the French cohort Personnes Agées QUID (1988-2015) and validated both by cross-validation and externally with data from the French Three City cohort (1999-2018). We evaluated its predictive abilities through area under the receiver operating characteristics curve and Brier score, accounting for right censoring and competing risk of death, and obtained an average area under the curve value of 0.95 for the risk of dementia in the next 5 or 10 years. This tool is able to discriminate a high-risk group of people from the rest of the population. This could be of help in clinical practice and research.