INTRODUCTION:Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS:Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS:Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION:In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

AIM:Distressing dreams were previously reported to predict future all-cause dementia among predominantly white US participants aged 79-89 years, particularly in men. We investigated whether disturbing dreams (nightmares and bad dreams) were associated with all-cause and Alzheimer dementia (AD) among individuals aged 60-89 years from diverse international regions. METHODS:Data were from six longitudinal cohort studies across Brazil, China, France, Italy, South Korea, and Taiwan (n = 10,238, 42.5% men). Cox regressions with a random effect for study investigated associations between disturbing dreams and incident dementia, with all participants and stratified separately by sex and baseline age. Analyses examined (i) any disturbing dreams and (ii) disturbing dreams at least once a week. Fully adjusted analyses included three studies with covariates for sleep problems, medications, mental and physical health, cognition, and APOE ε4 status. RESULTS:Disturbing dreams were reported by 24.2% overall and all-cause dementia, and AD incidence was 10.8 and 5.3 per 1000 person-years, respectively. In fully adjusted analyses, having any disturbing dreams was associated with increased incidence of all-cause dementia among 60-69-year-olds (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.32-11.67). There were no significant effects for older individuals. In fully adjusted sex-stratified analyses, having disturbing dreams at least once a week was associated with AD only among men (HR 3.59, 95% CI 1.44-8.96). CONCLUSIONS:We found some evidence for disturbing dreams being associated with incident all-cause dementia among individuals aged 60-69 years and with AD among men. The mechanisms potentially underlying these associations remain to be clarified.

BACKGROUND:Individuals living in socioeconomically disadvantaged areas are disproportionately affected by dementia. However, the pathway leading from neighbourhood deprivation to cognitive symptoms is not well understood. To test our hypothesis that this relationship is associated with cerebral small vessel disease (SVD), we examined (1) whether neighbourhood deprivation related to midlife SVD burden and cognition, and (2) whether these links can be explained by modifiable lifestyle risk factors. METHOD:In this multi-centre cross-sectional study, 514 cognitively healthy midlife participants aged 40-59 years (median 52 years, 64.6% female) underwent clinical assessment and 3T MRI. Postcode data were used to obtain national indices of neighbourhood deprivation. To quantify SVD, we assessed white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, and lacunes. Cognition was assessed using the Computerized Assessment of Information Processing (COGNITO) battery. Lifestyle risk factors were evaluated based on clinical data. Using multivariate statistics like structural equation modelling (SEM) and canonical correlation analysis (CCA), we examined associations between these constructs both globally and at the item-level (i.e., distinction between domains of cognition/deprivation), to shed light on specific domains that could inform targeted prevention strategies. RESULT:Neighbourhood deprivation related to greater prevalence of lifestyle risk factors (r = 0.36, p < .001), greater SVD burden (b=0.18, p = .01; Figure 1), and greater cognitive impairment (r = 0.36, p < .001), independent of educational attainment, sex, and age. These links with neighbourhood deprivation were largely driven by lifestyle factors relating to vascular health (sleep, physical activity, obesity, hypertension) (Figure 2), and cognitive deficits consistent with SVD (processing speed, visuospatial) (Figure 3). Residents of deprived neighbourhoods displayed greater prevalence of lifestyle risk factors, except alcohol consumption. Lower cognitive scores were most closely associated with deprivation domains of Crime and Living Environment (Figure 3). The DEPRIVATION→SVD path was mediated by lifestyle risk factors (z=2.57, p = .010), and the DEPRIVATION→COGNITION path was mediated by SVD (z=-2.14, p = .032) (global SVD & hypertensive subtype, but not CAA-SVD). CONCLUSION:The pathway linking neighbourhood disadvantage to cognitive impairment at midlife is influenced by vascular risk factors and cerebrovascular burden. Tailored strategies could promote resilience against dementia by promoting health behaviours aligned with the community's unique needs.

High-income countries (HICs) are over-represented in current global dementia incidence rates, skewing estimates. Variance in diagnostic methods between HICs and low- and middle-income countries (LMICs) is speculated to contribute to the regional differences in rates. Cohort Studies of Memory in an International Consortium (COSMIC) offers a unique opportunity to address these research inequalities by harmonising data from international studies, including representation from LMICs. This study aimed to identify dementia incidence rates by age and sex in various regions worldwide, where data for dementia diagnosis were available. Data were obtained from 36 members of COSMIC, representing 28 countries across 6 continents (HICs: Australia, Canada, Faroe Islands, France, Germany, Greece, Italy, Japan, Netherlands, South Korea, Spain, Sweden, & USA; LMICs: Brazil, China, Cuba, Dominican Republic, Ecuador, Indonesia, Malaysia, Mexico, Nigeria, Peru, Philippines, Republic of Congo, & Tanzania). For each member study, we calculated incidence rates for all-cause dementia. Findings from 14 studies, with a consensus diagnosis are presented in the results. Using an Item Response Theory approach, we are currently calculating a comparable incidence rate for those studies without a consensus diagnosis. Consistent with previous trends, incidence rates (per 100 person-years) increased with age, from 65-70 years-old to 85-90 years-old, for both males (i.e., Republic of Congo, 4.41 to 19.57; France, 0.46 to 3.89; USA, 0.17 to 3.22; Spain, 0.31 to 4.22; 65-70 & 85-90 cohorts respectively) and females (i.e., Republic of Congo, 3.57 to 15.31; France, 0.45 to 3.72; USA, 0.22 to 4.25; Spain, 0.36 to 4.96; 65-70 & 85-90 cohorts respectively). There were no sex differences in incidence rates in younger age groups (60-65). Among older age groups, however, women tended to have higher incidence rates than men, in some countries (Faroe Islands, Germany, Sweden, and USA). Geographical differences in dementia incidence rates likely represent inherent variation among countries, beyond methodological considerations. We are working to expand the range of studies and regions for which we calculate dementia incidence rates. This involves the development of approaches to classify and harmonise incident dementia in studies lacking consensus diagnoses. Doing so will bolster LMIC representation.

Distressing dreams were reported to predict future dementia among predominantly white US participants aged 79-89 years, particularly in men (Otaiku AI. eClinicalMedicine 2022;52:101640). We extended this research by investigating whether disturbing dreams (nightmares and bad dreams) predicted Alzheimer's disease (AD) additionally to all-cause dementia among individuals aged more broadly (60-89 years) and from diverse international regions. Six longitudinal cohort studies from Brazil, China, France, Italy, South Korea, and Taiwan had complete data for 8339 participants (56.4% women) without baseline dementia or Parkinson's disease. Four studies had dementia/AD diagnoses, and 2 studies classified dementia using screening tests (Table). Disturbing dream data were harmonized as yes/no across all studies and weekly frequency (none, <1, ≥1) in 4 studies (3 with AD data, Table). All studies had a 21-covariate set including sleep problems and medications, depression, and APOE*4 . The maximum follow-up across studies was 5.7-16.6 years. Cox regressions with a random effect for study were used with all participants and stratified separately by sex and baseline age (60-69, 70-79, 80-89 years). Analyses were repeated in study subsets with additional covariates, including anxiety (Table). Disturbing dreams were reported by 24.3% overall. Dementia and AD incidence was 9.52 and 6.12 per 1000 person-years, respectively. When including all age groups, disturbing dreams did not predict incident dementia, overall or in either sex. Similarly, disturbing dreams did not predict AD overall or in women, but any and ≥1/week disturbing dreams predicted AD among men in 2 fully-adjusted studies (OR=2.03, p  = .047; OR=4.00, p  = .004). Age-stratified analyses found effects only for 60-69-year-olds. Among these, disturbing dreams predicted dementia across all studies (OR=1.89, p  = .009) and 3 fully-adjusted studies (OR=3.93, p  = .014), and tended to predict AD in 2 fully-adjusted studies (OR=4.96, p  = .054). Additionally, disturbing dreams <1/week predicted dementia across 4 studies (OR=6.41, p  < .001) and 3 fully-adjusted studies (OR=4.65, p  = .007), as well as AD in 3 studies (OR=4.94, p  = .039) and 2 fully-adjusted studies (OR=6.22, p  = .031). Disturbing dreams predicted incident dementia and AD among individuals aged 60-69 years, and incident AD among men aged 60-89 years. Disturbing dreams may be a pre-clinical indicator and possible prodrome of dementia and AD.

Large-scale trials of multidomain interventions indicate that modifying lifestyle and psychological risk factors can slow cognitive decline. This study evaluated whether a lower-intensity, personally tailored secondary dementia prevention programme, informed by behaviour change theory, could reduce cognitive decline over two years in adults with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We conducted a multi-site, single-blind randomised controlled trial (ISRCTN17325135) in England, recruiting 747 older adults with SCD or MCI between 05/10/2020 and 31/12/2022. Participants were randomised 1:1 to the 12-month APPLE-Tree intervention or control (usual care plus brief written dementia prevention information). The intervention focused on promoting healthy lifestyles, enhancing social connections and enjoyable activities, and improving self-management of long-term conditions. Shifting online due to COVID-19, it comprised ten 1-hour group video sessions over six months, delivered by two non-clinical facilitators, supervised by a clinical psychologist. Sessions were supplemented with alternating video-call “tea breaks” for informal interaction and biweekly individual goal-setting calls. From months 6–12, participants continued with monthly “tea breaks”. The primary outcome was cognition, measured by NTB composite score at 24 months. An intention-to-treat analysis was conducted using a three-level mixed effects model including treatment arm, time, treatment-by-time interaction, baseline Neuropsychological Test Battery (NTB) score, and site as fixed effects. Random effects accounted for intervention arm group clustering and repeated measures at 12 and 24 months. The trial recruited above target, with high intervention adherence (305/374 [82%] attending ≥5 main sessions). In the primary analysis that included 635/746 (85%) of participants randomised, the mean adjusted NTB scores increased over time in both arms (Table 1 and Figure 1), but the increment was higher in the intervention compared with the control arm (adjusted mean difference at 24 months: 0.06 [95% Confidence Interval -0.00–0.13], p =0.055). APPLE-Tree provides an accessible, scalable model for secondary dementia prevention. The small effect size is comparable with previous successful, more intensive dementia prevention interventions with similar participant groups. Leveraging remote delivery and non-clinical facilitators could enable wide-scale implementation to support older adults with memory concerns. Secondary outcomes (e.g., quality of life, intervention-targeted factors) available May 2025.

Smartphone-based assessments are a promising tool for early detection of cognitive decline in midlife. Previous research has shown such cognitive markers can be sensitive to a range of potentially modifiable dementia risk factors even in healthy adults. However, their sensitivity to genetic risk factors like APOE-ε4 is likely to differ by cognitive domain, with evidence of strong negative effects on wayfinding tasks but mixed for other domains. We investigated the associations between a set of previously validated smartphone-based cognitive markers and APOE-ε4. N = 87 cognitively unimpaired, APOE-genotyped participants (aged 44-67, 57.5% female) of the PREVENT study completed a self-administered module in the smartphone application Neureka, including gamified cognitive tasks and memory self-evaluation (completion rates: 81%–99%). Controlling for age, gender, education, and parental history of dementia, we compared APOE-ε4 carriers ( n = 35) with non-carriers in their performance on five cognitive measures: model-based planning, visual working memory, processing speed (∼Trails A), cognitive flexibility (∼Trails B), and subjective memory problems. We conducted receiver operating characteristic (ROC) analysis to assess if APOE-ε4 status can be predicted from norm-adjusted cognitive scores, i.e., the difference between observed cognitive performance and what we would predict for given demographics based on an additional benchmark sample ( N = 3,376, aged 18-84, 65% female). In univariate analyses, APOE-ε4 carriers did not significantly differ from non-carriers in their demographic characteristics or cognitive scores except for visual working memory, which was better in carriers ( t (63.226) = 2.245; p = .028). After controlling for covariates, APOE-ε4 status was not significantly linked to, which was better in APOE-ε4 carriers ( β [bootstrapped 95% CI] = -0.29[-0.53,-0.06]; t = -2.30; p = .025). In ROC-analysis, norm-adjusted visual working memory scores modestly differentiated between carriers and non-carriers (AUC(SE) = .648(0.067); bootstrapped 95% CIs = 0.515–0.774). The non-significant associations between APOE-ε4 and most cognitive markers suggest limited sensitivity to genetic risk. Interestingly, APOE-ε4 carriers outperformed non-carriers in visual working memory, which could be due to antagonistic pleiotropy effects, but needs to be replicated in larger samples. The current study shows limited evidence for the clinical utility of our cognitive markers as indicators of genetic risk in middle-aged cognitively unimpaired adults.

INTRODUCTION:Neighborhood deprivation increases dementia risk, although mechanisms remain unclear. We tested a framework in which modifiable risk factors and cerebral small vessel disease (SVD) mediate the link between neighborhood deprivation and cognition. METHODS:In 585 cognitively healthy midlife adults (ages 40-59), neighborhood deprivation was derived from postcodes, cognition was assessed using the COGNITO, lifestyle risk factors were measured using clinical assessments, and SVD (white matter hyperintensities, lacunes, microbleeds, perivascular spaces) was assessed on 3T magnetic resonance imaging. Multivariate analyses examined association pathways among these variables. RESULTS:Neighborhood deprivation was associated with poorer cognition (r = 0.36, p < 0.001), greater prevalence of modifiable risk factors (r = 0.36, p < 0.001), and greater SVD burden (β = 0.18, p = 0.008). Serial mediation showed that the effects of deprivation on cognition were indirect, possibly operating via lifestyle risk and SVD, explaining 20% of the total effect, whereas SVD alone explained 28%. DISCUSSION:Neighborhood disadvantage relates to poorer cognition, possibly mediated through vascular risk factors and cerebrovascular disease. HIGHLIGHTS:Neighborhood deprivation linked to poorer cognition in healthy midlife adults Deprivation linked to small vessel disease (SVD) and modifiable risk factors (chiefly cardiovascular risk) Association between deprivation and cognition mediated by modifiable risk and SVD Mediation was exclusive to hypertensive SVD, but not cerebral amyloid angiopathy (CAA)-related SVD.

Female sex is associated with higher incidence and risk of dementia. Estrogen may represent one important mechanism contributing to the increase in incidence rates. In this review, we synthesize narratively the evidence for associations between estrogen-across the life course from menarche to menopause, estrogen-containing hormonal contraception and hormone replacement therapies, and pregnancy-with potential modifiable risk factors for dementia. These include education, hearing loss, traumatic brain injury, hypertension, alcohol use, obesity, smoking, depression, physical inactivity, diabetes, low-density lipoprotein (LDL) cholesterol, social isolation, air pollution, and untreated visual loss, as well as apolipoprotein E ε4. In addition, evidence is summarized for associations with sleep, diet, and stress. Evidence suggests that estrogen is associated with some of these modifiable risk factors for dementia, particularly LDL cholesterol, smoking, and depression. Research needs to further define these associations and understand whether interventions targeting estrogen levels at key life stages could offer intervention opportunities to reduce future risk of dementia in women. HIGHLIGHTS: Higher dementia risk in women may be associated with estrogen. Estrogen is associated with some of the modifiable risk factors for dementia. However, significant gaps exist in the literature for most risk factors.

BACKGROUND:Approximately 30% of women experience intimate partner violence (IPV) in their lifetime, often with traumatic brain injury (TBI) exposure. Nevertheless, there has been limited research exploring lifelong brain health outcomes following IPV with TBI. To address this, we investigated the relationship between IPV, TBI and midlife mental health outcomes within an observational cohort study. METHODS:PREVENT Dementia is a cohort study with participants recruited aged 40-59 years for longitudinal measures of brain health. Participants reporting histories of IPV-related physical abuse (IPV-PA) at study recruitment were identified and compared with control participants with no IPV-PA exposure regarding histories of TBI and prevalence of lifetime and ongoing mental health outcomes using standardised assessments. RESULTS:Among 632 participants, 90 (14%) reported IPV-PA history. Compared with unexposed participants, history of IPV-PA was associated with higher TBI exposure, together with higher lifetime and ongoing diagnoses of depression, anxiety and sleep disorders, and post-traumatic stress disorder (PTSD) symptomology. Notably, the risk of ongoing and concurrent midlife mental health disorders remained despite IPV-PA exposure having ceased on average 27 years before assessment. History of TBI in individuals with IPV was associated with increased risk of ongoing PTSD symptomology and concurrent mental health outcomes. CONCLUSIONS:Our data confirm high TBI exposure among individuals with a history of IPV-PA, while also demonstrating that this population shows higher rates of ongoing adverse mental health outcomes in midlife, often decades after abuse. This work underlines the prevalence of IPV-PA and the necessity to consider TBI exposure and long-term brain health outcomes among this population.

Background This concurrent, exploratory, mixed-methods process evaluation, embedded within a randomised controlled trial, investigates how the ‘active prevention in people at risk of dementia through lifestyle behaviour change and technology to build resilience’ (APPLE-Tree) secondary dementia prevention intervention might support behavioural and lifestyle goal attainment, through determining the contexts influencing engagement and testing intervention theoretical assumptions. Aims We aimed to investigate (a) intervention reach, dose and fidelity, (b) contexts influencing engagement and (c) alignment of findings with theoretical assumptions about how the intervention might have supported participants to meet personalised behavioural and lifestyle goals. Method We measured intervention reach and dose. We selected interviewees for setting, gender and ethnic diversity from the 374 APPLE-Tree trial participants randomised to the intervention arm. We interviewed 25 intervention participants, 12 facilitators and 3 study partners. Additionally, we analysed 11 interviews previously conducted during or after intervention delivery for an ethnography, and 233 facilitator-completed participant goal records. We thematically analysed data, combining inductive/deductive approaches informed by the ‘capability, opportunity and motivation-behaviour’ (COM-B) behaviour change model. We video-recorded a randomly selected tenth of sessions and rated fidelity. Results A total of 346 of 374 (92.5%) intervention arm participants received some intervention (reach), and 305 of 374 (81.6%) attended ≥5 main sessions (predefined as adhering: dose). According to facilitator records, participants met a mean of 5.1 of 7.5 (68.3%) goals set. We generated three themes around (a) building capability and motivation, (b) connecting with other participants and facilitators and (c) flexibility and a tailored approach. Conclusions The intervention supported behaviour change, through increasing knowledge and providing space to plan, implement and evaluate new strategies and make social connections. Feedback indicated that the intervention was flexible and inclusive of diverse preferences and needs.

OBJECTIVES:Altered insight into cognitive symptoms and diagnosis is a common feature of neurodegeneration, and can adversely impact on quality of life and ability to access medical care. Affected individuals can lose awareness of their symptoms and therefore decline to engage with medical assessment and treatment. Assessing insight is difficult, and there is a lack of short, easily administered clinical assessment tools. The aim of this study was to develop and evaluate the feasibility of a novel insight assessment questionnaire (The Clinical Insight Questionnaire, CLIQ) which can be independently completed by adults with a range of cognitive abilities. METHODS:A discrepancy score approach was used to evaluate insight. A novel questionnaire targeting the domains of memory, personality and social behaviour, executive function, language, and activities of daily living was devised using the Delphi approach and public feedback. Participant and informant mirror versions of each item were written. The discrepancy between participant and informant scores provides an overall insight score. 12 UK based experts in cognitive disorder diagnosis and assessment were invited to review potential questionnaire items, as was a PPI group. A feasibility study was conducted where people with mild memory or thinking symptoms and an informant completed the questionnaire and the Montreal Cognitive Assessment. RESULTS:Following an iterative process using the expert Delphi group and public feedback, 20 final questionnaire items were selected from an initial pool of 30 items. 21 people with mild cognitive symptoms but no formally diagnosed cognitive disorder (median MoCA score 24.5) participated in feasibility testing. The mean discrepancy score was 1.14, close to the ideal score of zero. No participants found the assessment upsetting or too long, and 81% rated the questions as easy to understand. CONCLUSIONS:The Clinical Insight Questionnaire (CLIQ) is a novel clinical tool for the assessment of insight in people with mild to moderate neurodegeneration. In feasibility testing it was quick and easy for people with mild cognitive symptoms and informants to self-complete. Initial feasibility testing showed very promising findings for usability and acceptability, and a full validation study is now in progress.

To estimate the additive associations of cardiometabolic multimorbidity (CMM) and depression on long-term cognitive trajectory in multi-regional cohorts and validate the generalizability of the findings in varying clinical settings. Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed to assess generalizability. Cross-sectional and longitudinal analyses were conducted. CMM was defined as: 1) CMM5: ≥ 2 among hypertension, hyperlipidemia, diabetes mellitus, stroke, and heart disease and 2) CMM3 (aligned with previous studies): ≥ 2 among diabetes mellitus, stroke, and heart disease. Depression was identified using the Geriatric Depression Scale, Center for Epidemiological Studies-Depression scale, or medical history. A one-step individual participant data meta-analysis was utilized to investigate associations between the co-occurrence of CMM and depression and cognitive outcomes in the COSMIC studies. Stratified analyses were conducted based on baseline dementia status, demographics, and APOE genotype. Repeated analyses were performed in external validation studies for generalization. Of the 32,450 older adults in the 14 COSMIC cohorts, we included 31,243 participants with complete data on CMM, depression, and cognitive assessment for cross-sectional analyses. Among them, 23,242 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. From the three external studies we included 1964 participants, representing 3 multi-ethnic Asian elderly cohorts (community cohort, memory clinic cohort, and stroke cohort). In the COSMIC studies analysis, the co-occurrence of CMM and depression was associated with both cross-sectional cognitive performance (β = -0.20, 95%CI = (-0.25,-0.16) for CMM5 and depression, β = -0.17, (95%CI = -0.044,-0.031) for CMM3 and depression), and rate of cognitive decline (β = -0.038, 95%CI = (-0.25,-0.16) for CMM5 and depression, β = -0.023, (95%CI = -0.036, -0.009) for CMM3 and depression). This combined effect remained consistent across different subgroups particularly among participants without dementia. These findings were reproduced in the three external validation studies. Our study demonstrated an additive effect between CMM and depression on cognitive decline. Targeting both cardiometabolic and psychological conditions could lead to greater effectiveness in delaying or preventing cognitive decline.

Individuals living in socioeconomically disadvantaged areas are disproportionately affected by dementia. However, the pathway leading from neighbourhood deprivation to cognitive symptoms is not well understood. To test our hypothesis that this relationship is associated with cerebral small vessel disease (SVD), we examined (1) whether neighbourhood deprivation related to midlife SVD burden and cognition, and (2) whether these links can be explained by modifiable lifestyle risk factors. In this multi-centre cross-sectional study, 514 cognitively healthy midlife participants aged 40-59 years (median 52 years, 64.6% female) underwent clinical assessment and 3T MRI. Postcode data were used to obtain national indices of neighbourhood deprivation. To quantify SVD, we assessed white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, and lacunes. Cognition was assessed using the Computerized Assessment of Information Processing (COGNITO) battery. Lifestyle risk factors were evaluated based on clinical data. Using multivariate statistics like structural equation modelling (SEM) and canonical correlation analysis (CCA), we examined associations between these constructs both globally and at the item-level (i.e., distinction between domains of cognition/deprivation), to shed light on specific domains that could inform targeted prevention strategies. Neighbourhood deprivation related to greater prevalence of lifestyle risk factors ( r  = 0.36, p  < .001), greater SVD burden (b=0.18, p  = .01; Figure 1), and greater cognitive impairment ( r  = 0.36, p  < .001), independent of educational attainment, sex, and age. These links with neighbourhood deprivation were largely driven by lifestyle factors relating to vascular health (sleep, physical activity, obesity, hypertension) (Figure 2), and cognitive deficits consistent with SVD (processing speed, visuospatial) (Figure 3). Residents of deprived neighbourhoods displayed greater prevalence of lifestyle risk factors, except alcohol consumption. Lower cognitive scores were most closely associated with deprivation domains of Crime and Living Environment (Figure 3). The DEPRIVATION→SVD path was mediated by lifestyle risk factors (z=2.57, p  = .010), and the DEPRIVATION→COGNITION path was mediated by SVD (z=-2.14, p  = .032) (global SVD & hypertensive subtype, but not CAA-SVD). The pathway linking neighbourhood disadvantage to cognitive impairment at midlife is influenced by vascular risk factors and cerebrovascular burden. Tailored strategies could promote resilience against dementia by promoting health behaviours aligned with the community's unique needs.

IntroductionAge 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.MethodsEmax 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.ResultsIn 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.DiscussionEmax modeling could be used to design more efficient trials which has implications for randomized control trials targeting the earlier stages of AD.

Females have a higher age-adjusted incidence of Alzheimer’s Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building cognitive reserve, particularly through stimulating avocational activities and occupational attainment presents a crucial, underexplored, dementia prevention approach for mid-life. It is currently unknown, however, whether modifiable lifestyle factors can protect against AD processes, from mid-life, differentially for females and males who carry inherited risk for late-life dementia. To address this gap, this study investigated the impact of biological sex and APOE4 carrier status on the relationship between stimulating activities, occupational attainment, and cognition in mid-life. We leveraged the PREVENT–Dementia program, the world’s largest study investigating the origins and early diagnosis of dementia in mid-life at-risk individuals (N = 700; 40–59 years). Cognitive performance was measured using the Cognito Battery and the Visual Short Term Memory Binding task. Mid-life specific reserve contributors were assessed via the Lifetime of Experiences Questionnaire. Females had significantly better episodic and relational memory (p < 0.001), and lower occupational attainment than males (p < 0.001). Engagement in stimulating activities was positively associated with episodic and relational memory, regardless of sex and APOE4 status (β = 0.05, CI 0.03–0.07, p < 0.001). APOE4 carriers showed significant sex differences in the association between occupational attainment and episodic and relational memory (β = 0.38, CI 0.12–0.63, p = 0.003). APOE4 carrier females with higher occupational attainment showed better cognition (β = 0.16, CI -0.002–0.32, p = 0.053), whereas APOE4 carrier males showed the opposite effect (β = -0.20, CI -0.40 – -0.001, p = 0.049). Our findings suggest that occupational attainment in mid-life contributes to cognitive reserve against inherited risk of dementia in females, but not males. They highlight the need for high precision approaches that consider biological sex and APOE4 carrier status to inform Alzheimer’s disease prevention strategies and clinical trials.

Background Cardiometabolic multimorbidity (CMM) and depression are often co-occurring in older adults and associated with neurodegenerative outcomes. The present study aimed to estimate the independent and joint associations of CMM and depression on cognitive function in multi-regional cohorts, and to validate the generalizability of the findings in additional settings, including clinical. Methods Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed for generalization. Participants were eligible for inclusion if they had data for CMM and were free of dementia at baseline. Baseline CMM was definedfined as: 1) CMM 5, >= 2 among hypertension, hyperlipidemia, diabetes, stroke, and heart disease and 2) CMM 3 (aligned with previous studies), >= 2 among diabetes, stroke, and heart disease. Baseline depression was primarily characterized by binary classification fi cation of depressive symptom measurements, employing the Geriatric Depression Scale and the Center for Epidemiological Studies-Depression scale. Global cognition was standardized as z-scores through harmonizing multiple cognitive measures. Longitudinal cognition was calculated as changes in global cognitive z-scores. A pooled individual participant data (IPD) analysis was utilized to estimate the independent and joint associations of CMM and depression on cognitive outcomes in COSMIC studies, both cross-sectionally and longitudinally. Repeated analyses were performed in three external validation studies. Findings Of the 32,931 older adults in the 14 COSMIC cohorts, we included 30,382 participants with complete data on baseline CMM, depression, and cognitive assessments for cross-sectional analyses. Among them, 22,599 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. The three external studies for validation had 1964 participants from 3 multi-ethnic Asian older adult cohorts in different settings (community-based, memory clinic, and post-stroke study). In COSMIC studies, each of CMM and depression was independently associated with cross-sectional and longitudinal cognitive function, without significant fi cant interactions between them (Ps P s > 0.05). Participants with both CMM and depression had lower cross-sectional cognitive performance (e.g. (3 = - 0.207, 95% CI = (-0.2 - 0.2 55, - 0.159) for CMM5 (+)/depression (+)) and a faster rate of cognitive decline (e.g. (3 = - 0.040, 95% CI = (-0.04 - 0.04 7, - 0.034) for CMM5 (+)/depression (+)), compared with those without either condition. These associations remained consistent after additional adjustment for APOE genotype and were robust in two-step random-effects IPD analyses. The findings regarding the joint association of CMM and depression on cognitive function were reproduced in the three external validation studies. Interpretation Our findings highlighted the importance of investigating age-related co-morbidities in a multidimensional perspective. Targeting both cardiometabolic and psychological conditions to prevent cognitive decline could enhance effectiveness. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction The mechanistic associations between small vessel disease (SVD) and dementia are still poorly understood. The APOE ε4 allele, recognised as the strongest genetic risk factor for Alzheimer's disease, has been previously implicated in SVD, although it remains unclear whether this association is gene-dose dependent. An emerging neuroimaging biomarker of SVD is Peak Width of Skeletonised Mean Diffusivity (PSMD), obtained from histogram analyses of diffusion weighted imaging (DWI) datasets. Here, we investigated the relationship between APOE ε4 gene dose and PSMD, as a surrogate marker of SVD, in a group of cognitively normal middle-aged adults. Methods The study included data from 1954 asymptomatic middle-aged adults from the ALFA (ALzheimer and FAmilies) and PREVENT-Dementia cohorts (See Table 1 for sample characteristics). PSMD was calculated from the DWI datasets using a publicly available script, and harmonised using COMBAT to account for site-related differences. Using non-parametric permutation models, our primary analyses focused on the (a) comparison of group differences (APOE ε4 heterozygotes vs homozygotes vs non-carriers) in PSMD, adjusting for age, sex, years of formal education, and sites; and (b) potential interactions between APOE ε4 gene dose and age on PSMD values. Marginal predictions were used to estimate the earliest age at which differences might emerge between the APOE ε4 groups and non-carriers. Results There were no significant differences in PSMD values across the non-carriers (n=1,197), heterozygous carriers (n=659), and homozygous APOE ε4 carriers (n=98) (p = 0.6; Figure 1). However, there was a statistically significant interaction between APOE ε4 gene dose and age on PSMD. Specifically, homozygous APOE ε4 carriers exhibited a steeper increase in PSMD with age compared to non-carriers and heterozygous carriers (T = 4.7, p<0.01; Figure 2). Marginal effect analyses revealed higher PSMD values in homozygous APOE ε4 carriers at the estimated age of 57 relative to non-carriers and heterozygous carriers. Discussion Homozygosity for APOE ε4 could hasten dementia onset by accelerating age-dependent increases in PSMD. Future studies with a longitudinal design are warranted to clarify the molecular mechanisms through which the APOE ε4 allele influences PSMD and if this contributes to the contributes to the development of dementia.

Background Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD. Methods Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen. Results At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory. Conclusion Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score’s potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk.

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. 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. 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. Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.