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.

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.

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.

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.

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.

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.

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study.

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.

European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases.

BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

The Association of Weight Loss, Weight Status, and Abdominal Obesity with All-Cause Mortality in Older Adults.

OBJECTIVES: The objectives of this study were to examine whether weight loss, weight status (based on body mass index [BMI] categories), and abdominal obesity (based on waist circumference [WC]) were associated with a 17-year mortality risk in community-dwelling older adults. METHODS: Participants were 2,017 community-dwelling adults aged 65 years or above in the longitudinal Enquête de Santé Psychologique-Risques, Incidence et Traitement study. Self-reported weight loss was collected at baseline during face-to-face interviews. Bodyweight (kg), height (m), and WC (cm) were independently measured at the baseline. BMI was categorized as follows: underweight (BMI <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2). Abdominal obesity was defined by a WC of ≥102 cm in men and ≥88 cm in women. Adjusted Cox proportional hazards models were used to examine associations of weight loss, weight status, and abdominal obesity with all-cause mortality. RESULTS: Over 17 years of follow-up (median 15.5 years), 812 participants died. Abdominal obesity compared to nonabdominal obesity was associated with a 49% increased mortality risk (95% confidence interval (CI): 1.22-1.83). However, being overweight (but not obese) was associated with a 20% decreased risk (95% CI: 0.66-0.97) compared to a normal BMI. Gender did not affect these associations. In the whole cohort, self-reported weight loss at baseline was not associated with an increased mortality risk after adjusting for health and lifestyle factors. However, in men, a baseline self-reported recent weight loss of >3 kg was associated with a 52% increase in mortality risk (95% CI: 1.05-2.18) in a fully adjusted model. CONCLUSION: In community-dwelling adults aged ≥65 years, abdominal obesity was strongly associated with increased mortality risk. Being overweight appeared, however, to be protective against mortality. Modest self-reported weight loss was not associated with all-cause mortality in community-dwelling older adults after adjusting for health and lifestyle factors. However, men reporting recent weight loss of more than 3 kg may be at increased risk. The findings of this study support the use of WC, rather than BMI, as a predictor of mortality risk in older adults.

Alzheimer's disease research progress in the Mediterranean region: The Alzheimer's Association International Conference Satellite Symposium.

As research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.

Proximity to dementia onset and multi-modal neuroimaging changes: The prevent-dementia study.

BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.

Late-life cynical hostility is associated with white matter alterations and the risk of Alzheimer's disease.

BACKGROUND: Cynical hostility (CH), a specific dimension of hostility that consists of a mistrust of others, has been suggested as a high-risk trait for dementia. However, the influence of CH on the incidence of Alzheimer's disease (AD) remains poorly understood. This study investigated whether late-life CH is associated with AD risk and structural neuroimaging markers of AD. METHODS: In community-dwelling older adults from the French ESPRIT cohort (n = 1388), incident dementia rate according to CH level was monitored during an 8-year follow-up and analyzed using Cox proportional hazards regression models. Brain magnetic resonance imaging volumes were measured at baseline (n = 508). Using automated segmentation procedures (Freesurfer 6.0), the authors assessed brain grey and white volumes on all magnetic resonance imaging scans. They also measured white matter hyperintensities volumes using semi-automated procedures. Mean volumes according to the level of CH were compared using ANOVA. RESULTS: Eighty-four participants developed dementia (32 with AD). After controlling for potential confounders, high CH was predictive of AD (HR 2.74; 95% CI 1.10-6.85; p = 0.030) and all dementia types are taken together (HR 2.30; 95% CI 1.10-4.80; p = 0.027). High CH was associated with white matter alterations, particularly smaller anterior corpus callosum volume (p < 0.01) after False Discovery Rate correction, but not with grey matter volumes. CONCLUSIONS: High CH in late life is associated with cerebral white matter alterations, designated as early markers of dementia, and higher AD risk. Identifying lifestyle and biological determinants related to CH could provide clues on AD physiopathology and avenues for prevention strategies.

11ß-Hydroxylase (CYP11B1) gene variants and new-onset depression in later life.

Background: Cumulative exposure to high glucocorticoid levels is detrimental for the brain and may have particular implications in later life. A feature of late-life depression is increased cortisol secretion. Variants in the CYP11B1 gene, which codes for the enzyme responsible for cortisol synthesis, could influence risk of late-life depression, but this hypothesis has not been examined. We investigated the associations between variants in the CYP11B1 gene and late-life depression, taking into account history of depression and potential sex-specific effects. Methods: We assessed depression in 1007 community-dwellers aged 65 years or older (60% women) at baseline and over a 14-year follow-up. A clinical level of depression was defined as a score of ≥ 16 on the Centre for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). We examined incident and recurrent depression in participants without or with a history of major depression, respectively. We genotyped 5 single-nucleotide polymorphisms (SNPs) spanning CYP11B1. We used multivariable analyses to adjust for age, body mass index, cardiovascular ischemic pathologies, hypertension, cognitive impairment and anxiety. Results: In women, rs6471580 and rs7016924 were associated with a 50% lower rate of incident (new-onset) late-life depression, and rs11783855 was associated with a 2.4-fold higher rate of late-life depression. These associations remained after correction for multiple testing, but we found no associations for recurrent depression in women or men. Limitations: This study focused on the major gene involved in corticosteroid biosynthesis, but other genes may also be implicated in this pathway. Conclusion: Variants of the CYP11B1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner.

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.

BACKGROUND: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. MATERIALS AND METHODS: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2  = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. RESULTS: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001). DISCUSSION: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

Does parity matter in women's risk of dementia? A COSMIC collaboration cohort study.

BACKGROUND: Dementia shows sex difference in its epidemiology. Childbirth, a distinctive experience of women, is associated with the risk for various diseases. However, its association with the risk of dementia in women has rarely been studied. METHODS: We harmonized and pooled baseline data from 11 population-based cohorts from 11 countries over 3 continents, including 14,792 women aged 60 years or older. We investigated the association between parity and the risk of dementia using logistic regression models that adjusted for age, educational level, hypertension, diabetes mellitus, and cohort, with additional analyses by region and dementia subtype. RESULTS: Across all cohorts, grand multiparous (5 or more childbirths) women had a 47% greater risk of dementia than primiparous (1 childbirth) women (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.10-1.94), while nulliparous (no childbirth) women and women with 2 to 4 childbirths showed a comparable dementia risk to primiparous women. However, there were differences associated with region and dementia subtype. Compared to women with 1 to 4 childbirths, grand multiparous women showed a higher risk of dementia in Europe (OR = 2.99, 95% CI = 1.38-6.47) and Latin America (OR = 1.49, 95% CI = 1.04-2.12), while nulliparous women showed a higher dementia risk in Asia (OR = 2.15, 95% CI = 1.33-3.47). Grand multiparity was associated with 6.9-fold higher risk of vascular dementia in Europe (OR = 6.86, 95% CI = 1.81-26.08), whereas nulliparity was associated with a higher risk of Alzheimer disease (OR = 1.91, 95% CI 1.07-3.39) and non-Alzheimer non-vascular dementia (OR = 3.47, 95% CI = 1.44-8.35) in Asia. CONCLUSION: Parity is associated with women's risk of dementia, though this is not uniform across regions and dementia subtypes.

Trauma and depressive symptomatology in middle-aged persons at high risk of dementia: the PREVENT Dementia Study.

OBJECTIVE: Depression and trauma are associated with changes in brain regions implicated in Alzheimer's disease. The present study examined associations between childhood trauma, depression, adult cognitive functioning and risk of dementia. METHODS: Data from 378 participants in the PREVENT Dementia Study aged 40-59 years. Linear and logistic models were used to assess associations between childhood trauma, depression, dementia risk, cognitive test scores and hippocampal volume. RESULTS: Childhood trauma was associated with depression and reduced hippocampal volume but not current cognitive function or dementia risk. Poorer performance on a delayed face/name recall task was associated with depression. Childhood trauma was associated with lower hippocampal volume however poorer cognitive performance was mediated by depression rather than structural brain differences. CONCLUSION: Depressive symptomatology may be associated with dementia risk via multiple pathways, and future studies should consider subtypes of depressive symptomatology when examining its relationship to dementia.

Association between midlife dementia risk factors and longitudinal brain atrophy: the PREVENT-Dementia study.

BACKGROUND: Increased rates of brain atrophy on serial MRI are frequently used as a surrogate marker of disease progression in Alzheimer's disease and other dementias. However, the extent to which they are associated with future risk of dementia in asymptomatic subjects is not clear. In this study, we investigated the relationship between the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score and longitudinal atrophy in middle-aged subjects. MATERIALS AND METHODS: A sample of 167 subjects (aged 40-59 at baseline) from the PREVENT-Dementia programme underwent MRI scans on two separate occasions (mean interval 735 days; SD 44 days). We measured longitudinal rates of brain atrophy using the FSL Siena toolbox. RESULTS: Annual percentage rates of brain volume and ventricular volume change were greater in those with a high (>6) vs low CAIDE score-absolute brain volume percentage loss 0.17% (CI 0.07 to 0.27) and absolute ventricular enlargement 1.78% (CI 1.14 to 2.92) higher in the at risk group. Atrophy rates did not differ between subjects with and without a parental history of dementia, but were significantly correlated with age. Using linear regression, with covariates of age, sex and education, CAIDE score >6 was the only significant predictor of whole brain atrophy rates (p=0.025) while age (p=0.009), sex (p=0.002) and CAIDE>6 (p=0.017) all predicted ventricular expansion rate. CONCLUSION: Our results show that progressive brain atrophy is associated with increased risk of future dementia in asymptomatic middle-aged subjects, two decades before dementia onset.

Aromatase (CYP19A1) gene variants, sex steroid levels, and late-life depression.

BACKGROUND: Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. METHODS: This population-based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. RESULTS: Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p-values .01 to .0005). Three SNPs were associated with an increased risk of late-life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. CONCLUSIONS: Variants of the CYP19A1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.

APPLE-Tree (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline) programme: Protocol.

BACKGROUND: Observational studies indicate that approximately a third of dementia cases are attributable to modifiable cardiometabolic, physical and mental health, and social and lifestyle risk factors. There is evidence that intensive behaviour change interventions targeting these factors can reduce cognitive decline. [Figure: see text] METHODS AND ANALYSIS: We will design and test a low intensity, secondary dementia-prevention programme (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline, "APPLE-Tree") to slow cognitive decline in people with subjective cognitive decline with or without objective cognitive impairment. We will embed our work within social science research to understand how dementia prevention is currently delivered and structured. We will carry out systematic reviews and around 50 qualitative interviews with stakeholders, using findings to coproduce the APPLE-Tree intervention. We plan a 10-session group intervention, involving personalised goal-setting, with individual sessions for those unable or unwilling to attend groups, delivered by psychology assistants who will be trained and supervised by clinical psychologists. The coproduction group (including public and patient involvement [PPI], academic and clinical/third-sector professional representatives) will use the Behaviour Change Wheel theoretical framework to develop it. We will recruit and randomly allocate 704 participants, 1:1 to the intervention: informational control group. This sample size is sufficient to detect a between-group difference at 2 years of 0.15 on the primary outcome (cognition: modified neuropsychological test battery; 90% power, 5% significance, effect size 0.25, SD 0.6). DISSEMINATION: We will work with Public Health England and third-sector partners to produce an effective national implementation approach, so that if our intervention works, it is used in practice.

Refined carbohydrate-rich diet is associated with long-term risk of dementia and Alzheimer's disease in apolipoprotein E ε4 allele carriers.

INTRODUCTION: In animal models, refined carbohydrates (RF) worsen Alzheimer's disease (AD). However, the long-term effects of high RF intake on the risk of dementia and AD are poorly described in epidemiological studies. Moreover, the interaction between RF and the apolipoprotein E ε4 allele (APOE-ε4) is unknown. Our study investigated whether RF-rich diets are associated with the risk of dementia and AD. METHODS: The glycemic load (GL) was quantified in 2777 elderly participants from the French Three-City Study to estimate RF intake. Then, the associations between GL and risk of dementia and AD, and the interaction with APOE-ε4 over a 12-year period were assessed using proportional hazards models. RESULTS: After adjustment for potential confounders, high afternoon-snack GL was associated with increased dementia and AD risk in APOE-ε4 carriers (hazard ratio = 1.27 [1.03-1.56]). DISCUSSION: This study highlights that RF-rich diets are a risk factor for dementia and AD in APOE-ε4 carriers.