The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

Associations of Later-Life Education, the BDNF Val66Met Polymorphism and Cognitive Change in Older Adults.

In 358 participants of the Tasmanian Healthy Brain Project, we quantified the cognitive consequences of engaging in varying loads of university-level education in later life, and investigated whether or not BDNF Val66Met affected outcomes. Assessment of neuropsychological, health, and psychosocial function was undertaken at baseline, 12-month, and 24-month follow-up. Education load was positively associated with change in language processing performance, but this effect did not reach statistical significance (P = 0.064). The BDNF Val66Met polymorphism significantly moderated the extent to which education load was associated with improved language processing (P = 0.026), with education load having a significant positive relationship with cognitive change in BDNF Met carriers but not in BDNF Val homozygotes. In older adults who carry BDNF Met, engaging in university-level education improves language processing performance in a load-dependent manner.

Frequent attendance and the concordance between PHQ screening and GP assessment in the detection of common mental disorders.

OBJECTIVE: Frequent Attenders (FAs) have high rates of both common mental disorders (CMD) and physical disorders, partly justifying this service use behaviour. This study examines both case and non-case concordance between CMDs as estimated by a self-report screening questionnaire and as rated by the general practitioner (GP), in FAs compared to Other Attenders (OAs). METHODS: 2275 patients of an overlapping sample of 55 GPs from 2 surveys performed 10 years apart, completed in the waiting room the Patient Health Questionnaire (PHQ) and Client Service Receipt Inventory on 6-month service use. For each patient, the GP rated mental health on a 0-4 scale, with a clear indication that scores of 2 and above referred to caseness. PHQ-CMDs included major and other depressive, anxiety, panic, and somatoform disorders, identified using the original PHQ DSM-IV criteria-based algorithms. FA was defined as the top 10% of attenders in age, sex and survey-year stratified subgroups. RESULTS: FAs had higher rates of PHQ-CMDs (42% versus 23% for OAs, p < .0001). They reported more personal and social problems, disability and had higher GP-rated physical illness. Survey-day antidepressant/anxiolytic medication prescription was higher for FAs (p < .0001), with (p = .02) but also without a CMD (p < .0001). Both GP/PHQ case and non-case concordance differed between FAs and OAs, with a non-case concordance odds ratio of 0.5 (95% CI: 0.3-0.7, p = .001) for FAs compared to OAs. CONCLUSION: Despite a greater likelihood of GPs detecting CMDs in FAs, our findings suggest a potential risk of 'over-detection' of patients not reaching CMD threshold criteria among FAs.

Predicting pharmacy naloxone stocking and dispensing following a statewide standing order, Indiana 2016.

BACKGROUND: While naloxone, the overdose reversal medication, has been available for decades, factors associated with its availability through pharmacies remain unclear. Studies suggest that policy and pharmacist beliefs may impact availability. Indiana passed a standing order law for naloxone in 2015 to increase access to naloxone. OBJECTIVE: To identify factors associated with community pharmacy naloxone stocking and dispensing following the enactment of a statewide naloxone standing order. METHODS: A 2016 cross-sectional census of Indiana community pharmacists was conducted following a naloxone standing order. Community, pharmacy, and pharmacist characteristics, and pharmacist attitudes about naloxone dispensing, access, and perceptions of the standing order were measured. Modified Poisson and binary logistic regression models attempted to predict naloxone stocking and dispensing, respectively. RESULTS: Over half (58.1%) of pharmacies stocked naloxone, yet 23.6% of pharmacists dispensed it. Most (72.5%) pharmacists believed the standing order would increase naloxone stocking, and 66.5% believed it would increase dispensing. Chain pharmacies were 3.2 times as likely to stock naloxone. Naloxone stocking was 1.6 times as likely in pharmacies with more than one full-time pharmacist. Pharmacies where pharmacists received naloxone continuing education in the past two years were 1.3 times as likely to stock naloxone. The attempted dispensing model yielded no improvement over the constant-only model. CONCLUSIONS: Pharmacies with larger capacity took advantage of the naloxone standing order. Predictors of pharmacist naloxone dispensing should continue to be explored to maximize naloxone access.

Association between lifetime headache and history of suicide attempts in the elderly.

BACKGROUND: Pain-related conditions have been reported to play a key role among risk factors for suicide. Headache in particular has been repeatedly associated with suicidal thoughts and behaviors. The aims of this study were: 1) to assess the association between lifetime headache (both non-migrainous headache and migraine) and lifetime suicide attempts (SA); 2) to differentiate, within subjects with lifetime SA, patients with and without lifetime headache in terms of socio-demographic and clinical features. METHODS: We studied 1965 subjects from a cohort of community-dwelling persons aged 65 years and over without dementia (the ESPRIT study), divided in two groups: those with (n=75), and those without a lifetime SA (n=1890). Logistic regression analyses were used to compare these groups according to lifetime headache status. RESULTS: After adjusting for gender, living alone, tobacco and alcohol consumption, and depressive, manic/hypomanic and anxiety disorders, lifetime headache frequency was significantly higher in subjects with a lifetime SA compared with controls (OR=1.92 [1.17-3.15]). Additionally, different factors were identified as being associated with lifetime SA in participants with lifetime headache (female gender, a lower level of high-density lipoprotein cholesterol, insomnia, lifetime major depression) versus participants without headache (glycemia and lifetime major depression). CONCLUSIONS: Lifetime headache was associated with lifetime SA. Subjects who are women and report the co-occurrence of headache and insomnia as well as lifetime major depression require higher attention and a careful screening for suicidal thoughts and behaviors.

Chronic and remitting trajectories of depressive symptoms in the elderly. Characterisation and risk factors.

BACKGROUND: In elderly general population sub-syndromal clinically significant levels of depressive symptoms are highly prevalent and associated with high co-morbidity and increased mortality risk. However changes in depressive symptoms over time and etiologic factors have been difficult to characterise notably due to methodological shortcomings. Our objective was to differentiate trajectories of depressive symptoms over 10 years in community-dwelling elderly men and women using statistical modelling methods which take into account intra-subject correlation and individual differences as well as to examine current and life-time risk factors associated with different trajectories. METHODS: Participants aged 65 and over were administered standardised questionnaires and underwent clinical examinations at baseline and after 2, 4, 7 and 10 years. Trajectories over time of the Center for Epidemiologic Studies Depression scores were modelled in 517 men and 736 women separately with latent class mixed models which include both a linear mixed model to describe latent classes of trajectories and a multinomial logistic model to characterise the latent trajectories according to baseline covariates (socio-demographic, lifestyle, clinical, genetic characteristics and stressful life events). RESULTS: In both genders two different profiles of symptom changes were observed over the 10-year follow-up. For 9.1% of men and 25% of women a high depressive symptom trajectory was found with a trend toward worsening in men. The majority of the remaining men and women showed decreasing symptomatology over time, falling from clinically significant to very low levels of depressive symptoms. In large multivariate class membership models, mobility limitations [odds ratio (OR) = 4.5, 95% confidence interval (CI) 1.6-12.9 and OR = 4.9, 95% CI 2.3-10.7, in men and women respectively], ischemic pathologies (OR = 2.9, 95% CI 1.0-8.3 and OR = 3.1, 95% CI 1.0-9.9), and recent stressful events (OR = 4.5, 95% CI 1.1-18.5, OR = 3.2, 95% CI 1.6-6.2) were associated with a poor symptom course in both gender as well as diabetes in men (OR = 3.5, 95% CI 1.1-10.9) and childhood traumatic experiences in women (OR = 3.1, 95% CI 1.6-5.8). CONCLUSIONS: This prospective study was able to differentiate patterns of chronic and remitting depressive symptoms in elderly people with distinct symptom courses and risk factors for men and women. These findings may inform prevention programmes designed to reduce the chronic course of depressive symptomatology.

Biological and psychological predictors of posttraumatic stress disorder onset and chronicity. A one-year prospective study.

BACKGROUND: Few studies have prospectively examined risk factors for posttraumatic stress disorder (PTSD) in the aftermath of a traumatic exposure. The aim of this study is to identify the concurrent influence of psychological and biological diatheses on PTSD onset and maintenance, taking into account socio-demographic factors and psychiatric antecedents. METHODS: A total of 123 civilians (61.8% of women) recruited in emergency units, were assessed using validated instruments during the first week and then at 1, 4, and 12 months post-trauma. Baseline assessment included evaluation of the psychological diathesis (i.e. psychiatric history and peritraumatic distress and dissociation), and the biological diathesis [i.e. cortisol, norepinephrine, epinephrine, c-reactive protein, total cholesterol, HDL cholesterol, glycosylated haemoglobin, waist-to-hip ratio (WHR), body mass index, diastolic and systolic blood pressure (SBP), and heart rate]. RESULTS: Multivariate logistic regression analyses demonstrated both psychological and biological diatheses to be independent risk factors for PTSD. Peritraumatic distress and dissociation predicted onset (1-month) and mid-term PTSD (4-months), respectively. PTSD risk was associated positively with SBP and negatively with WHR, throughout the follow-up. In addition, a higher level of 12 h-overnight urinary norepinephrine independently predicted mid-term PTSD (4-months). CONCLUSIONS: This prospective study shows that peritraumatic psychological and biological markers are independent predictors of PTSD onset with specificities according to the stage of PTSD development; the psychological diathesis, i.e. peritraumatic distress and dissociation, being a better predictor of short-term dysfunction whereas biological diathesis was also predictive of development and maintenance of PTSD.

Are migraine and non-migrainous headache risk factors for stroke in the elderly? Findings from a 12-year cohort follow-up.

BACKGROUND AND PURPOSE: There is evidence that migraine is a risk factor for stroke but little is known about this association in elderly people. Furthermore, non-migrainous headache (NMH) has received little attention despite being the most frequently reported type of headache. Late-life migraine and NMH were examined as candidate risk factors for stroke in a community-dwelling elderly sample over a 12-year follow-up. METHODS: One thousand nine hundred and nineteen non-institutionalized subjects aged 65+, without dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, DSM-IV criteria) and with no stroke history at baseline, were drawn from the Three-City Montpellier cohort (recruitment 1999-2001) for longitudinal analysis. Ischaemic and haemorrhagic stroke was reported at baseline and at each of the five follow-ups, with cases validated by a panel of experts, according to ICD-10 criteria (International Classification of Diseases, 10th revision). Migraine and NMH were determined at baseline during a neurological interview and examination using 1988 International Headache Society criteria. RESULTS: A total of 110 (5.4%) cases of migraine and 179 (8.9%) cases of NMH were identified at baseline. During the median 8.8-year follow-up, incident stroke was observed in 1.9% of baseline migrainers, 6.2% of NMH and 3.6% of those with no lifetime history of headache. Cox proportional hazard models indicated that migraine was not a risk factor for stroke; however, NMH sufferers were twice as likely to have a stroke (hazard ratio 2.00, 95% confidence interval 1.00-3.93, P = 0.049). CONCLUSIONS: This study is one of the first to suggest that late-life NMH rather than migraine could be an independent risk factor for stroke and a warning sign. The incidence of stroke in elderly migrainers, seldom reported, is particularly low.

The impact of septoplasty on health-related quality of life in paediatric patients.

OBJECTIVES: To assess the impact that septoplasty had on health-related quality of life (HRQoL) in paediatric patients and to determine whether there were patient characteristics that predicted better outcomes. DESIGN: Retrospective cohort study. SETTING: Academic paediatric otolaryngology practice. PARTICIPANTS: All paediatric patients who underwent septoplasty during the study period. MAIN OUTCOME MEASURES: The current HRQoL was assessed using the Paediatric Quality of Life Inventory (PedsQL). The Glasgow Children's Benefit Inventory (GCBI) was used to evaluate the perceived change in HRQoL following septoplasty. RESULTS: A total of 29 patients (16 boys, mean age 13 years) and their caregivers responded (response rate of 72.5%). There was a statistically significant improvement in HRQoL following septoplasty, as demonstrated by the positive mean GCBI subscores and the total GCBI score (35.1, sd = 28.4). The total mean PedsQL score for child self-report was 95.2 (sd = 6.9) and for parent-proxy report was 91.8 (sd = 8.6), which indicated good current HRQoL. The enhancement in HRQoL post-septoplasty was moderately correlated with self-reported degree of nasal obstruction pre-septoplasty (r = 0.621 for total GCBI). Also, there were differences in GCBI scores between the groups of children who wanted to have the surgery versus those who did not want to have the surgery. CONCLUSIONS: There was a significant positive change in HRQoL following paediatric septoplasty in our study population. Children who reported more severe nasal obstruction and those who wanted to have the surgery were more likely to experience enhancement of HRQoL following their surgery.

Operational Definition of Active and Healthy Ageing (AHA): A Conceptual Framework.

Health is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached.

BDNF promoter methylation and genetic variation in late-life depression.

The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age ⩾ 65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean = 0.4%, P = 0.0002; promoter IV, Δ mean = 5.4%, P = 0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression.

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function.

The concept of cognitive reserve (CR) has been proposed to account for observed discrepancies between pathology and its clinical manifestation due to underlying differences in brain structure and function. In 433 healthy older adults participating in the Tasmanian Healthy Brain Project, we investigated whether common polymorphic variations in apolipoprotein E (APOE) or brain-derived neurotrophic factor (BDNF) influenced the association between CR contributors and cognitive function in older adults. We show that BDNF Val66Met moderates the association between CR and executive function. CR accounted for 8.5% of the variance in executive function in BDNF Val homozygotes, but CR was a nonsignificant predictor in BDNF Met carriers. APOE polymorphisms were not linked to the influence of CR on cognitive function. This result implicates BDNF in having an important role in capacity for building or accessing CR.

Induction of Larval Settlement in the Reef Coral Porites astreoides by a Cultivated Marine Roseobacter Strain.

Successful larval settlement and recruitment by corals is critical for the survival of coral reef ecosystems. Several closely related strains of γ-proteobacteria have been identified as cues for coral larval settlement, but the inductive properties of other bacterial taxa naturally occurring in reef ecosystems have not yet been explored. In this study, we assayed bacterial strains representing taxonomic groups consistently detected in corals for their ability to influence larval settlement in the coral Porites astreoides. We identified one α-proteobacterial strain, Roseivivax sp. 46E8, which significantly increased larval settlement in P. astreoides. Logarithmic growth phase (log phase) cell cultures of Roseivivax sp. 46E8 and filtrates (0.22µm) from log phase Roseivivax sp. 46E8 cultures significantly increased settlement, suggesting that an extracellular settlement factor is produced during active growth phase. Filtrates from log phase cultures of two other bacterial isolates, Marinobacter sp. 46E3, and Cytophaga sp. 46B6, also significantly increased settlement, but the cell cultures themselves did not. Monospecific biofilms of the three strains did not result in significant increases in larval settlement. Organic and aqueous/methanol extracts of Roseivivax sp. 46E8 cultures did not affect larval settlement. Examination of filtrates from cell cultures showed that Roseivivax sp. 46E8 spontaneously generated virus-like particles in log and stationary phase growth. Though the mechanism of settlement enhancement by Roseivivax sp. 46E8 is not yet elucidated, our findings point to a new aspect of coral-Roseobacter interactions that should be further investigated, especially in naturally occurring, complex microbial biofilms on reef surfaces.

Risk factors for late-onset generalized anxiety disorder: results from a 12-year prospective cohort (the ESPRIT study).

Generalized anxiety disorder (GAD) is a chronic and highly prevalent disorder associated with increased disability and mortality in the elderly. Treatment is difficult with low rate of full remission, thus highlighting the need to identify early predictors for prevention in elderly people. The aim of this study is to identify and characterize incident GAD predictors in elderly people. A total of 1711 individuals aged 65 years and above and free of GAD at baseline were randomly recruited from electoral rolls between 1999 and 2001 (the prospective ESPRIT study). The participants were examined at baseline and five times over 12 years. GAD and psychiatric comorbidity were diagnosed with a standardized psychiatric examination, the Mini-International Neuropsychiatry Interview on the basis of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria and validated by a clinical panel. During the follow-up, 8.4% (95% confidence interval=7.1-9.7%) of the participants experienced incident GAD, 80% being first episodes; the incident rate being 10 per 1000 person-years. The principal predictors of late-onset incident GAD over 12 years derived from a multivariate Cox model were being female, recent adverse life events, having chronic physical (respiratory disorders, arrhythmia and heart failure, dyslipidemia, cognitive impairment) and mental (depression, phobia and past GAD) health disorders. Poverty, parental loss or separation and low affective support during childhood, as well as history of mental problems in parents were also significantly and independently associated with incident GAD. GAD appears as a multifactorial stress-related affective disorder resulting from both proximal and distal risk factors, some of them being potentially modifiable by health care intervention.

C-reactive protein gene variants: independent association with late-life depression and circulating protein levels.

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation that is commonly elevated in depressed patients. Variants in the CRP gene that influence protein levels could thus be associated with depression but this has seldom been examined, especially in the elderly. Depression was assessed in 990 people aged at least 65 years as part of the ESPRIT study. A clinical level of depression (DEP) was defined as having a score of ⩾16 on The Center for Epidemiologic Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Five single-nucleotide polymorphisms spanning the CRP gene were genotyped, and circulating levels of high-sensitivity CRP were determined. Multivariable analyses adjusted for socio-demographic characteristics, smoking, ischemic pathologies, cognitive impairment and inflammation-related chronic pathologies. The minor alleles of rs1130864 and rs1417938 were associated with a decreased risk of depression in women at Bonferroni-corrected significance levels (P=0.002). CRP gene variants were associated with serum levels in a gender-specific manner, but only rs1205 was found to be nominally associated with both an increased risk of DEP and lower circulating CRP levels in women. Variants of the CRP gene thus influence circulating CRP levels and appear as independent susceptibility factors for late-life depression.

Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Impact of a premature menopause on cognitive function in later life.

OBJECTIVE: To determine whether premature menopause (≤40 years) can have long-lasting effects on later-life cognition and investigate whether this association varies depending on the type of menopause and use of hormone treatment (HT). DESIGN: Population-based cohort study. SETTING: The French Three-City Study. POPULATION: Four thousand eight hundred and sixty-eight women aged at least 65 years. METHODS: Multivariable-adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later-life cognitive function. MAIN OUTCOME MEASURES: Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis. RESULTS: Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non-surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12-1.87, P=0.004) and visual memory (OR 1.39, 95%CI 1.09-1.77, P=0.007) in later life. HT at the time of premature menopause appeared beneficial for later-life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years. CONCLUSION: Both premature surgical menopause and premature ovarian failure were associated with long-term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long-term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women.