Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.

Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.

The Mediterranean diet is not associated with neuroimaging or cognition in middle-aged adults: a cross-sectional analysis of the PREVENT dementia programme.

BACKGROUND AND PURPOSE: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. METHODS: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. RESULTS: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. CONCLUSIONS: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

Lifestyle and incident dementia: A COSMIC individual participant data meta­analysis.

INTRODUCTION: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. METHODS: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. RESULTS: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. DISCUSSION: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. HIGHLIGHTS: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study.

A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.

Toward the right treatment at the right time: Modeling the trajectory of cognitive decline to identify the earliest age of change in people with Alzheimer's disease.

Introduction: Age is the greatest risk factor for Alzheimer's disease (AD). A limitation of randomized control trials in AD is a lack of specificity in the age ranges of participants who are enrolled in studies of disease-modifying therapies. We aimed to apply Emax (i.e., maximum effect) modeling as a novel approach to identity ideal treatment windows. Methods: Emax curves were fitted to longitudinal cognitive data of 101 participants with AD and 1392 healthy controls. We included the Mini-Mental State Examination (MMSE) and tests of verbal fluency and executive functioning. Results: In people with AD, the earliest decline in the MMSE could be detected in the 67-71 age band while verbal fluency declined from the 41-45 age band. In healthy controls, changes in cognition showed a later trajectory of decline. Discussion: Emax modeling could be used to design more efficient trials which has implications for randomized control trials targeting the earlier stages of AD.

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure.

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis.

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Insulin resistance, age and depression's impact on cognition in middle-aged adults from the PREVENT cohort.

BACKGROUND: Alzheimer's disease (AD), type 2 diabetes mellitus (characterised by insulin resistance) and depression are significant challenges facing public health. Research has demonstrated common comorbidities among these three conditions, typically focusing on two of them at a time. OBJECTIVE: The goal of this study, however, was to assess the inter-relationships between the three conditions, focusing on mid-life (defined as age 40-59) risk before the emergence of dementia caused by AD. METHODS: In the current study, we used cross-sectional data from 665 participants from the cohort study, PREVENT. FINDINGS: Using structural equation modelling, we showed that (1) insulin resistance predicts executive dysfunction in older but not younger adults in mid-life, that (2) insulin resistance predicts self-reported depression in both older and younger middle-aged adults and that (3) depression predicts deficits in visuospatial memory in older but not younger adults in mid-life. CONCLUSIONS: Together, we demonstrate the inter-relations between three common non-communicable diseases in middle-aged adults. CLINICAL IMPLICATIONS: We emphasise the need for combined interventions and the use of resources to help adults in mid-life to modify risk factors for cognitive impairment, such as depression and diabetes.

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife.

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.

Childhood adverse events and BDNF promoter methylation in later-life.

Studies have shown that the effects of early-life stress and trauma can be enduring, with long-term negative effects on health. Epigenetics, including DNA methylation, have been implicated as a potential mechanism for these effects. Brain-derived neurotropic factor (BDNF) is a neurotransmitter involved in learning and memory, and altered BDNF promoter methylation measured in peripheral tissue has been found with early-life stress. However, whether such methylation differences remain stable into later life, is unknown. This study aimed to investigate the association between childhood adversity and BDNF promoter methylation in adults aged 65 years and over. Data came from a large study of older community-dwelling individuals in France (ESPRIT). Information on three major childhood adverse events, namely abuse/maltreatment, war/natural disaster, and financial difficulties/poverty, was obtained by retrospective reporting from participants of ESPRIT study. BDNF promoter I and IV methylation was assessed in blood and buccal tissue. Linear regression analysis was performed, adjusting for age, sex, education, depression, and morbidity. Among 927 participants, there was no strong evidence that childhood abuse/maltreatment or financial difficulties/poverty were associated with BDNF methylation in older individuals. For war/natural disaster, differential methylation at four of twenty-nine CpG sites was observed, however, these would not have remained significant after correction for multiple testing. Together, these findings do not support a long-term association between adverse childhood events and BDNF methylation in older age, but further large prospective studies are needed, which do not target specific genes, but consider DNA methylation across the genome.

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium.

INTRODUCTION: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups. METHODS: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models. RESULTS: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs. DISCUSSION: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.

Path integration selectively predicts midlife risk of Alzheimer's disease.

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

Brain-derived neurotrophic factor (BDNF) variants and promoter I methylation are associated with prolonged nocturnal awakenings in older adults.

Brain-derived neurotrophic factor (BDNF) is important for sleep physiology. This study investigates whether BDNF variants and promoter I methylation may be implicated in sleep disturbances in older adults. Genotyping was performed for seven BDNF single nucleotide polymorphisms (SNPs) in 355 community-dwelling older adults (aged ≥65 years) and BDNF exon 1 promoter methylation was measured in blood samples at baseline (n = 153). Self-reported daytime sleepiness and insomnia, ambulatory polysomnography measures of sleep continuity and architecture, and psychotropic drug intake were assayed during follow-up. Logistic regression adjusted for age, sex, comorbidities, body mass index, and psychotropic drug intake. Associations were found specifically between wake time after sleep onset (WASO) and four SNPs in the participants not taking psychotropic drugs, whereas in those taking drugs, the associations were either not significant (rs6265 and rs7103411) or in the reverse direction (rs11030101 and rs28722151). Higher BDNF methylation levels were found at most CpG units in those with long WASO and this varied according to psychotropic drug use. The reference group with short WASO not taking drugs showed the lowest methylation levels and the group with long WASO taking treatment, the highest levels. Some SNPs also modified the associations, the participants carrying the low-risk genotype having the lower methylation levels. This genetic and epigenetic study demonstrated blood BDNF promoter methylation to be a potential biomarker of prolonged nocturnal awakenings in older people. Our results suggest the modifying effect of psychotropic drugs and BDNF genetic variants in the associations between methylation and WASO.

Modifiable Lifestyle Activities Affect Cognition in Cognitively Healthy Middle-Aged Individuals at Risk for Late-Life Alzheimer's Disease.

BACKGROUND: It is now acknowledged that Alzheimer's disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. OBJECTIVE: We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40-59 years) completed cognitive and clinical assessments at baseline (N = 206) and two years follow-up (N = 174). METHODS: Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for sporadic late-onset AD (Apolipoprotein E ɛ4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. RESULTS: More frequent engagement in physically, socially, and intellectually stimulating activities was associated with better cognition (verbal, spatial, and relational memory), at baseline and follow-up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. CONCLUSION: These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of AD.

COGNITO (Computerized assessment of adult information processing): Normative scores for a rural Indian population from the SANSCOG study.

INTRODUCTION: Neuropsychological assessments are inexpensive and efficient methods to understand the cognitive abilities of individuals in research studies and clinical settings. Normative scores for such measures are crucial in serving as a reference standard for identifying cognitively healthy and impaired individuals belonging to similar sociodemographic characteristics. METHODS: Study subjects in rural India recruited into the Srinivaspura Aging, Neuro Senescence and Cognition (SANSCOG) study were administered the COGNITO battery of tests, which traverse cognitive domains of attention, memory, language, and visuospatial abilities. Percentile norms based on age and education stratification were derived for the above cohort. RESULTS: Percentile norms are commensurate with literacy levels in this population. The percentile scores for the cognitive tests show a decline for the individuals aged 75 years and above indicating lower cognitive functioning in this age group. DISCUSSION: This is the first-ever study reporting norms for diverse cognitive domains for illiterate, literate, low-literate individuals enrolled in a large-scale community-based cohort study in rural India.

The relationship between alcohol use and dementia in adults aged more than 60 years: a combined analysis of prospective, individual-participant data from 15 international studies.

AIM: To synthesize international findings on the alcohol-dementia relationship, including representation from low- and middle-income countries. METHODS: Individual participant data meta-analysis of 15 prospective epidemiological cohort studies from countries situated in six continents. Cox regression investigated the dementia risk associated with alcohol use in older adults aged over 60 years. Additional analyses assessed the alcohol-dementia relationship in the sample stratified by sex and by continent. Participants included 24 478 community dwelling individuals without a history of dementia at baseline and at least one follow-up dementia assessment. The main outcome measure was all-cause dementia as determined by clinical interview. RESULTS: At baseline, the mean age across studies was 71.8 (standard deviation = 7.5, range = 60-102 years), 14 260 (58.3%) were female and 13 269 (54.2%) were current drinkers. During 151 636 person-years of follow-up, there were 2124 incident cases of dementia (14.0 per 1000 person-years). When compared with abstainers, the risk for dementia was lower in occasional [hazard ratio (HR) = 0.78; 95% confidence interval (CI) = 0.68-0.89], light-moderate (HR = 0.78; 95% CI = 0.70-0.87) and moderate-heavy drinkers (HR = 0.62; 95% CI = 0.51-0.77). There was no evidence of differences between life-time abstainers and former drinkers in terms of dementia risk (HR = 0.98; 95% CI = 0.81-1.18). In dose-response analyses, moderate drinking up to 40 g/day was associated with a lower risk of dementia when compared with lif-time abstaining. Among current drinkers, there was no consistent evidence for differences in terms of dementia risk. Results were similar when the sample was stratified by sex. When analysed at the continent level, there was considerable heterogeneity in the alcohol-dementia relationship. CONCLUSIONS: Abstinence from alcohol appears to be associated with an increased risk for all-cause dementia. Among current drinkers, there appears to be no consistent evidence to suggest that the amount of alcohol consumed in later life is associated with dementia risk.

Mediterranean diet score is associated with greater allocentric processing in the EPAD LCS cohort: A comparative analysis by biogeographical region.

Background: Adherence to the Mediterranean diet (MedDiet), a primarily plant-based eating pattern, has been associated with lower dementia incidence. Much of the research has focused on Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), with less research looking at the preclinical symptomatically silent stages that pre-empt MCI and AD dementia. Although there is evidence from studies conducted globally, no studies have compared the effects of the MedDiet within and outside of the Mediterranean region in one cohort. Methods: Our study explored cross-sectional and longitudinal associations between MedDiet and cognition in the pan-European EPAD LCS, comparing those living within and outside of the Mediterranean region (as classified by European Union biogeographical definitions). After deriving MEDAS scores to quantify adherence to the MedDiet, we used linear regression and linear mixed effects models to test for associations between the MEDAS score and cognitive function measured by the Four Mountains Test (FMT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We additionally calculated MEDAS continuous and PYRAMID scores to provide alternative measures of MedDiet adherence. Results: We included 1826 participants, mean age 65.69 (±7.42) years, majority female (56.2%) with family history (65.8%) and minority APOEε4 carriers (38.9%). Higher MEDAS scores were associated with better performance on the FMT both cross-sectionally (n = 1,144, ß: -0.11, SE: 0.04, p = 0.007) and longitudinally (slope: 0.10, 95% CI: 0.04-0.17, p: 0.002). The effect was marginally greater in the Mediterranean region in the cross-sectional analysis, with a stronger effect emerging longitudinally. In exploratory analyses, the association between MEDAS and FMT scores was only seen in female participants. A sensitivity analysis excluding Toulouse and Perugia, as cities near, but not within, the biogeographical region, found significant associations between higher MEDAS and MEDAS continuous scores, and a number of RBANS total and index scores. Conclusion: MedDiet adherence is associated with better FMT scores, with effects seen most strongly in the Mediterranean region from longitudinal data. Our sensitivity analysis suggested a more global cognitive benefit of MedDiet adherence. This study highlights the need to further explore for whom and for what brain health outcomes the MedDiet confers benefit. This evidence would identify a window of opportunity in the life-course to maximise the benefit and better inform public health campaigns and patient-level interventions.

Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study.

BACKGROUND: Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD. METHODS: Cognitively healthy middle-aged adults (aged 40-59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction. RESULTS: In SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (ß = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (ß = - 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results. CONCLUSIONS: Established modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major 'silent' contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.