17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

Poor nutritional status is associated with a higher risk of falling and fracture in elderly people living at home in France: the Three-City cohort study.

UNLABELLED: Falling and fractures are a public health problem in elderly people. The aim of our study was to investigate whether nutritional status is associated with the risk of falling or fracture in community-dwelling elderly. Poor nutritional status was significantly associated with a higher risk of both falling and fractures. INTRODUCTION: Nutrition could play a role to prevent falls and fractures. The purpose of this study is to investigate whether a poor nutritional status is associated with the risk of falling and of fracture in community dwelling elderly. METHODS: Baseline nutritional status of participants was assessed using the Mini Nutritional Assessment (MNA). After a follow-up of 12 years, 6040 individuals with available data for falls and 6839 for fracture were included. People who presented the outcomes at baseline were excluded. Cox models were used to evaluate the associations between nutritional status and the risks of fall or fracture. RESULTS: The frequency of poor nutritional status (MNA ≤ 23.5), at baseline, was respectively 12.0% in the "fall study sample" and 12.8% in the "fracture study sample." Incident fall and fracture over 12 years were reported in 55.8 and 18.5% of the respective samples, respectively. In multivariate models controlled for sociodemographic data and several baseline health indicators, poor nutritional status was significantly associated with a higher risk of falling (hazard ratio (HR) = 1.66, 95% confidence interval (95% CI) 1.35-2.04 in men and HR = 1.20, 95% CI 1.07-1.34 in women) and with a higher risk of fracture (HR = 1.28, 95% CI 1.09-1.49). CONCLUSION: Poor nutritional status was associated with a higher risk of both falling and fractures in French elderly community-dwellers. Early screening and management of the nutritional status may be useful to reduce the frequency of these events in older people.

Adherence to a Mediterranean diet and risk of fractures in French older persons.

UNLABELLED: Prevention of fractures is a considerable public health challenge. In a population-based cohort of French elderly people, a diet closer to a Mediterranean type had a borderline significant deleterious effect on the risk of fractures, in part linked to a low consumption of dairy products and a high consumption of fruits. INTRODUCTION: Higher adherence to the Mediterranean diet (MeDi) is linked to a lower risk of several chronic diseases, but its association with the risk of fractures is unclear. Our aim was to investigate the association between MeDi adherence and the risk of fractures in older persons. METHODS: The sample consisted of 1,482 individuals aged 67 years or older, from Bordeaux, France, included in the Three-City Study in 2001-2002. Occurrences of hip, vertebral and wrist fractures were self-reported every 2 years over 8 years, and 155 incident fractures were recorded. Adherence to the MeDi was evaluated at baseline by a MeDi score, on a 10-point scale based on a food frequency questionnaire and a 24-h recall. Multivariate Cox regression tests were performed to estimate the risk of fractures according to MeDi adherence. RESULTS: Higher MeDi adherence was associated with a non-significant increased risk of fractures at any site (hazard ratio [HR] per 1-point increase of MeDi score = 1.10, P = 0.08) in fully adjusted model. Among MeDi components, higher fruits consumption (>2 servings/day) was significantly associated with an increased risk of hip fractures (HR = 1.95, P = 0.04), while low intake of dairy products was associated with a doubled risk of wrist fractures (HR = 2.03, P = 0.007). An inverse U-shaped association between alcohol intake and risk of total fracture was observed (HR high vs. moderate = 0.61, P for trend = 0.03). CONCLUSIONS: Greater MeDi adherence was not associated with a decreased risk of fractures in French older persons. The widely recognized beneficial effects of the MeDi do not seem to apply to bone health in these people.

Nutrient patterns and risk of fracture in older subjects: results from the Three-City Study.

UNLABELLED: We investigated the association between nutrient patterns and risk of fractures in 1,482 older subjects. Patterns associated with higher intakes of Ca, P, vitamin B12, proteins and unsaturated fats, and moderate alcohol intake, provided by diets rich in dairies and charcuteries, were related to a lower risk of wrist and hip fractures. INTRODUCTION: The purpose of this study was to investigate the relationship between patterns of nutrient intake and the risk of fractures in older subjects. METHODS: Among 1,482 participants from the Bordeaux sample of the Three-City (3C) Study who completed a 24-h dietary recall and a food frequency questionnaire, we examined the association between patterns of nutrient intake derived from principal component analysis and 8-year incidence of self-reported fractures of the hip, the wrist, and the vertebrae. RESULTS: A "nutrient-dense" pattern rich in Ca and P, iron, vitamins B including B12, vitamins C and E, alcohol, proteins, and unsaturated fats, and characterized by a higher consumption of fruits and vegetables, meats and fish, cheese and milk, charcuteries, cereals, rice, pasta, and potatoes, was associated with a 19% (95% CI 2-34%, P=0.03) lower risk of wrist fractures. The same pattern was associated with a 14% (95% CI 2-25%) lower risk of fractures at any site. A "south-western French" pattern rich in Ca, P, vitamins D and B12, retinol, alcohol, proteins, and fats-including unsaturated fats; poor in vitamins C, E, and K, carotenes, folates, and fibers; and related to a higher consumption of cheese, milk, and charcuterie and a lower consumption of fruits and vegetables was related to a 33% lower risk of hip fractures (95% CI 3-39%, P=0.03). CONCLUSIONS: Higher intakes of Ca, P, vitamin B12, proteins, and unsaturated fats and moderate alcohol, provided by dietary patterns rich in cheese, milk, and charcuteries, were related to a lower risk of wrist and hip fractures in our cohort.

Ten Years after the National Alzheimer's Plan: Dementia Remains a Hidden Syndrome in France.

Ten years after the implementation of the French Plan on Alzheimer's Disease (2008-2012), the present study aimed at describing the situation of the persons living with dementia in terms of diagnosis and high-risk situations (living alone, continuing driving, inability to handle budget and to manage medication). Among the 115 dementia cases followed-up in the AMI population-based cohort on aging in 2018 (i.e. ten years after the launch of the Plan), the prevalence of under-diagnosis was similar to the one estimated ten years earlier (53.0% vs. 55.6%). Almost all cases (95.3%) were concerned by high-risk situations (61.2% were unable to handle finances, 48.2% were living alone, 27.1% continued driving). Being diagnosed as demented was not associated with a lower frequency of high-risk situations, excepting for driving (16.7% vs. 37.2%). Ten years after the beginning of the French Alzheimer's Plan, dementia remains a hidden syndrome, with a frequent inadequate management of high-risk situations.

Co-Occurrence of Geriatric Syndromes and Diseases in the General Population: Assessment of the Dimensions of Aging.

OBJECTIVES: The co-occurrence of multiple medical or psycho-social conditions (geriatric syndromes (GS) and age-related diseases) is a growing concern in older people. Given the diversity of these conditions and their complex interactions, our aim was to determine whether they could be structured into synthetic dimensions in order to facilitate the management of multimorbidity. DESIGN: The underlying structure of 10 GSs and 8 age-related diseases was identified using a multiple correspondence analysis (MCA), and confronted to subjective and objective health outcomes. SETTING: community residents from Bordeaux City (France) older than 75 years in 2010. PARTICIPANTS: 630 adults aged 75+ years who lived in Bordeaux and participated in the 10-year follow-up of the Three-City study. MEASUREMENTS: GSs included physical frailty, cognitive impairment and dementia, dependency, depressive symptoms, polymedication, thinness, falls, sensory deficit, social isolation, incontinence. Age-related diseases were cancer, cardiac diseases, peripheral vascular diseases, diabetes, hypertension, pulmonary diseases, osteoporosis, other chronic diseases. Association of the MCA-derived independent dimensions was assessed with 10-year visit subjective health and well-being, and with incident death and entry into institution during the remaining cohort follow-up. RESULTS: Most of the participants (82%) had at least two age-related syndromes or diseases. The MCA structured the 18 conditions into three major dimensions: Degradation (D) driven by GS, Vascular (V), and Psychosocial (P) representing 68.7%, 7.4%, and 5.7% of the total variance, respectively. Dimension D was a strong predictor of future death and institutionalization. Dimensions D and P were strongly associated with current well-being. CONCLUSIONS: This work confirmed that multimorbidity is very common among older adults, and demonstrated the essential role of GS as manifestations of aging, even more than age-related diseases.

Older People Facing the Crisis of COVID-19: Between Fragility and Resilience.

The health crisis we are facing is challenging seniors' resources and capacities for adaptation and resilience. The PACOVID survey, set up a few days after containment, investigates their psychological and social experiences with regard to the COVID-19 crisis and to what extent these characteristics, representations and attitudes have an impact on health and mortality. A telephone survey is being carried out on 935 people already followed up in the framework of ongoing epidemiological studies. As we are writing this article, the interviews conducted during the containment have just ended. Even though we will have to wait for the analysis of the results to draw conclusions, words collected by the psychologists during the interviews already illustrate a great heterogeneity in the way older adults lived this experience: social isolation, anxiety, the importance of family and the difficulty of being deprived of it, but also remarkable coping skills and resilience capacities.

Ginkgo Biloba Extract Consumption and Long-Term Occurrence of Death and Dementia.

OBJECTIVES: To study the benefit of Ginkgo Biloba Extract (GBe) consumption on the long term risk of dementia and death in elderly people. DESIGN: The Paquid study is a population-based cohort with regular follow-up screenings up to twenty-two years and systematic detection of incident cases of dementia. Statistical analysis was conducted with an illness-death model dealing with interval censoring of dementia and competing risk of death. SETTING: The sample was randomly selected from electoral rolls in two administrative areas of southwestern France in 1988-1989. PARTICIPANTS: 3,777 subjects aged 65 years or older at baseline who were living at home. MEASUREMENT: Participants were visited at home by a trained psychologist at baseline in 1988/1989, and then again approximately every two years. Drug consumption for the treatment of cognitive or neurosensory impairment was collected at baseline. Participants were classified as GBe consumers, other drug (OD) consumers and untreated controls (UC) for this motive. RESULTS: After adjustment for sociodemographic factors and cognitive measures at baseline the risk for dementia was not significantly different in GBe consumers and UC (Hazard Ratio (HR)=1.21, 95% Confidence Interval (95% CI)=0.95-1.55, p=0.42) and it was of the same magnitude but significantly increased in the OD group versus UC (HR=1.25, 95% CI=1.06-1.46, p=0.004). With the same adjustment, the risk of dying in non-demented subjects was reduced in GBe consumers versus UC (HR=0.67, 95% CI=0.49-0.93, p=0.02) while it was the same as the reference group in OD consumers. The mean lifetimes without dementia was of 11.2 years in the UC group (95% CI=10.9-11.5), 11.1 years in the GBe group (10.2-11.9) and 9.1 years for the OD group (8.7-9.6). CONCLUSION: GBe consumers have a lower risk of dying before dementia and a longer lifetime without dementia than participants taking other drugs for the same indication.

Analysis of the effect of aluminum in drinking water and transferrin C2 allele on Alzheimer's disease.

Although highly controversial, the hypothesis of a link between aluminum (Al) in drinking water and Alzheimer's disease (AD) has been supported by several epidemiological studies. Transferrin (Tf) is a major transport protein for both iron and Al. Moreover, it has been demonstrated that defective binding of iron and Al to the Tf variant C2 could be present in AD. Individuals carrying the Tf C2 allele might therefore be at greater risk of developing AD. We investigated whether the Tf C2 allele might be responsible for susceptibility to AD in a sample of 292 subjects (with 55 AD) aged > or = 75 years from south-west France, some exposed to high levels of Al in tap water (n = 181 subjects) and others to low levels of Al (n = 111 subjects). We also examined the combined genetic effects of Tf C2 and epsilon4 allele of apolipoprotein E gene (ApoE). Logistic regression analysis showed that neither Tf C2 nor its interaction with Al or with the epsilon4 allele of the ApoE were significantly associated with the risk of AD.

Why Is Later Age at Retirement Beneficial for Cognition? Results from a French Population-based Study.

OBJECTIVE: To determine whether and how age at retirement influences the risk of dementia. The association between the age at retirement, the number of working years and the risk of dementia was evaluated over 12 years of follow-up. DESIGN: A prospective population-based study. SETTING: Three-City cohort, a French population-based study of community-dwelling individuals aged 65 to 95. PARTICIPANTS: The sample consisted of 1,658 non-demented participants at baseline. MEASUREMENTS: All participants were evaluated at home at the initial visit and at two years interval for a period of 12 years. An active research of dementia was conducted at each follow-up; all suspected cases were analysed by an independent committee of neurologists. Information regarding retirement age and number of working years was collected at baseline using a structured questionnaire. RESULTS: The multivariate Cox model, including both the age at retirement and the number of working years and adjusted for potential confounders, revealed that the risk of dementia was independently associated with the age at retirement (p=0.022) but not with the number of working years (p=0.296). CONCLUSION: Although our results are in accordance with previous studies (i.e., older age at retirement is associated with decreased risk of dementia), it provides additional information regarding the possible explanation for such results. Given that a longer working life did not reduce the risk of dementia, the age at retirement cannot be considered as a new factor of cognitive reserve but rather seems to be a psycho-social vulnerability factor. Further evidence is necessary to identify work and retirement related factors that influence the association between the age at retirement and the risk of dementia.

Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells.

BACKGROUND: Inadequate retinoid status has often been described as occurring with aging. Moreover, subclinical hypothyroid status has also been evoked in the elderly. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain. OBJECTIVE: The aim of the present study was to clarify whether aging modifies retinoid and thyroid signalling in humans. METHODS: Using real-time RT-PCR the relative amount of mRNA of the retinoid (RARalpha, RARgamma and RXRalpha) and thyroid (TRalpha and TRbeta) nuclear receptors in peripheral blood mononuclear cells (PBMC) of young (24-57 years old, n = 22) compared with elderly (69-90 years old, n = 24) healthy subjects was quantitated. Classical plasma parameters used to characterize the retinoid and thyroid status - retinol (ROH), retinol-binding protein (RBP), free triiodothyronine (FT3) and thyroxine (FT4), thyroid-stimulating hormone (TSH) and transthyretin (TTR) - were also assessed. RESULTS: RARgamma expression was significantly decreased in elderly versus young subjects while no modification of the retinoid-related plasma parameters ROH and RBP were emphasized by aging. Concerning thyroid criteria, the elderly exhibited an increase in TSH concentration (+39%) without significant modifications of FT3 and FT4, which indicated an age-related sub-clinical hypothyroidism. Concurrently, the amount of TR mRNA (alpha as well as beta subtypes) was significantly decreased in the elderly. CONCLUSION: These data constitute the first evidence of an age-related hypo-activation of the retinoid and thyroid nuclear pathways in PBMC. Further study of the possible association between the expression of the retinoid and thyroid nuclear receptors and age-related cognitive alterations in humans would be interesting.

Correlates of regular fish consumption in French elderly community dwellers: data from the Three-City study.

OBJECTIVE: Several studies have found an inverse association between fish consumption and risk of dementia. The objective of this study was to describe the characteristics of older fish consumers, in order to identify potential confounders in this relationship. DESIGN: Cross-sectional analysis of the baseline data of a prospective cohort study. SETTING: Bordeaux, Dijon, and Montpellier (France) in 1999-2000. SUBJECTS: A total of 9280 community dwellers aged 65 y and above participating in the baseline examination of the Three-City Study. INTERVENTIONS: All participants answered a face-to-face interview and underwent a physical examination. Cross-sectional analyses were performed by logistic regressions. RESULTS: Regular fish consumers (at least weekly) had a higher education (OR from 1.19 to 1.65, P = 0.0003) and income (OR from 1.37 to 1.89, P < 0.0001). Controlling for age, sex, education, and city, they had a higher consumption of pulses, fruit, and vegetables (P < 0.001). They were more often alcohol drinkers (P < 0.0001). They felt in better health (P < 0.05), exhibited less depressive symptoms (P < 0.001), and scored higher on the Mini Mental Status Examination (P < 0.05). However, their objective physical health status was not better, except that they were leaner. They suffered more often from hypertension and past stroke. CONCLUSIONS: Socioeconomic status, dietary habits, depression, and vascular risk factors could act as confounders in the relationship between fish consumption and risk of dementia.

[Validity of the five-word screening test for Alzheimer's disease in a population based study]. / Le test des 5 mots: validité dans la détection de la maladie d'Alzheimer dans la population générale.

INTRODUCTION: In general medicine lack of time impairs screening for Alzheimer's disease (AD). The five word test (FWT) enables rapid assessment of verbal episodic memory in accordance with Grober and Buschke neuropsychological concept. The main steps of the FWT are: induce specific semantic processing, control of encoding to avoid attention deficits, free and cued recall. Cued recall helps to distinguish a recall impairment from storage impairment which is evocative of AD. OBJECTIVE: Evaluate FWT total score (sum of free and cued recalls), FWT total weighed score which give a higher coefficient for free recalls than cued recalls and present the ability of these two scores for AD screening. METHOD: Evaluation performed with 4116 subjects (of whom 73 MA) aged from 65 years and more, randomly selected in two French towns for the "Three Cities" Study, a population-based cohort. RESULTS: The total score was more specific than sensitive with a maximal sensitivity (Se) at 63 percent with specificity (Sp) at 91.1 percent. The total weighed score significantly increased Se (83.6 percent) with control of specificity (84.9 percent) and positive predictive value (9.1 percent). CONCLUSION: The FWT allows quick screening of patients for whom further neuropsychological evaluation is needed to diagnose AD. The ability of is simple test to screen for AD is improved by a simple weighting procedure: the total weighted score.

Dementia in Parkinson's disease: a population-based study in ambulatory and institutionalized individuals.

We examined the frequency of dementia and depressive symptomatology in 60 Parkinson's disease (PD) patients, identified in a large representative sample of the population, aged 65 years and older, living at home or in institutions in Gironde, France. Dementia, diagnosed according to DSM-III-R criteria, was present in 17.6%, and depressive symptomatology, assessed by the Center for Epidemiologic Studies-Depression Scale, was present in 32.7%. The frequency of dementia in PD increased strongly with age and was higher in institutionalized PD patients than in those living at home. PD was significantly associated with dementia for individuals living at home (odds ratio = 8.2, adjusted for age and symptoms of depression.

Occupation during life and memory performance in nondemented French elderly community residents.

Using data obtained during the baseline screening of the PAQUID cohort, an epidemiologic study on brain aging conducted in the Bordeaux area of France, we studied the relationship between lifetime occupation and memory performance in visual recognition (Benton Visual Retention Test; BVRT) and verbal induced recall (Wechsler Paired Associates Test; WPAT) in 2,720 elderly community residents. Occupational category was strongly correlated with poor memory performance for both the BVRT and the WPAT. Independent of the educational level, the risk of having poor memory performance was two to three times greater for farmers, domestic service employees, and blue-collar workers than for professionals/managerials. Occupational category should be taken into account in future cross-national studies on brain aging.

Marital status and risk of Alzheimer's disease: a French population-based cohort study.

OBJECTIVE: To analyze the relationship between marital status and risk of AD or dementia. METHODS: This study was carried out from the Personnes Agées QUID (PAQUID) cohort, an epidemiologic study on normal and pathologic aging after age 65 years. The PAQUID cohort began in 1988. Individuals were followed up at 1, 3, and 5 years, with an active detection of dementia. Marital status was divided into four categories: widowed, never married, divorced or separated, and the reference category, married or cohabitant. The longitudinal relationship between marital status and risk of incident AD or dementia was analyzed by a Cox model with delayed entry. RESULTS: Among the 3,675 individuals initially not demented, 2,106 were married or cohabitants, 1,287 were widowers, 179 were never married, and 103 were divorced or separated. Among the 2,881 individuals reevaluated at least once for the risk of dementia during the 5-year follow-up, 190 incident cases of dementia were identified, including 140 with AD. The relative risks (RRs) of dementia (RR = 1.91, p = 0.018) and of AD (RR = 2.68, p<0.001) were increased for the never-married individuals compared with those who were married or cohabitants. This excess of risk was specifically associated with AD. Adjustment for other risk factors of dementia (education, wine consumption), or for factors reflecting social environment, leisure activities, and depression, did not modify the risk of AD for never-married individuals (RR = 2.31, p = 0.02). CONCLUSIONS: We confirmed an association between marital status and AD, with an excess risk observed among never-married individuals. This association may provide clues about the pathogenesis of AD.

Incidence and outcome of mild cognitive impairment in a population-based prospective cohort.

OBJECTIVE: To estimate the age-specific incidence rate of mild cognitive impairment (MCI) according to sex and educational level and to explore the course of MCI, particularly its progression to AD, in a population-based cohort. METHODS: A community-based cohort of nondemented elderly people (Personnes Agées QUID [PAQUID]) was followed longitudinally for 5 years. MCI was defined as memory complaints with objective memory impairment, without dementia, impairment of general cognitive functioning, or disability in activities of daily living. Incidence rates were calculated using the person-years method. A descriptive analysis at the different follow-up times was performed to study the course of MCI. RESULTS: At baseline, there were 58 prevalent cases of MCI (2.8% of the sample). During a 5-year follow-up, 40 incident cases of MCI occurred in 1,265 subjects at risk. The global incidence rate of MCI was 9.9/1,000 person-years. MCI was a good predictor of AD with an annual conversion rate of 8.3% and a good specificity, but it was very unstable over time: Within 2 to 3 years, only 6% of the subjects continued to have MCI, whereas >40% reverted to normal. CONCLUSIONS: Conventionally defined MCI has reasonable predictive value and specificity for AD. However, MCI was very unstable across time in this study. Furthermore, the definition of MCI seems to be too restrictive and should probably be extended to other categories of individuals also at high risk of developing AD.

Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia.

OBJECTIVE: To investigate the risk of AD associated with a family history of dementia, female gender, low levels of education, smoking, and head trauma. BACKGROUND: These putative factors have been identified in cross-sectional studies. However, those studies are prone to bias due to systematic differences between patients and control subjects regarding survival and how risk factors are recalled. METHODS: The authors performed a pooled analysis of four European population-based prospective studies of individuals 65 years and older, with 528 incident dementia patients and 28,768 person-years of follow-up. Patients were detected by screening the total cohort with brief cognitive tests, followed by a diagnostic assessment of those who failed the screening tests. Dementia was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (revised), and AD was diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Incident rates and relative risk (95% CI) express the association of a risk factor for dementia. RESULTS: Incident rates for dementia and AD were similar across studies. The incidence of AD increased with age. At 90 years of age and older the incidence was 63.5 (95% CI, 49.7 to 81.0) per 1,000 person-years. Female gender, current smoking (more strongly in men), and low levels of education (more strongly in women) increased the risk of AD significantly. A history of head trauma with unconsciousness and family history of dementia did not increase risk significantly. CONCLUSION: Contrary to previous reports, head trauma was not a risk factor for AD, and smoking did not protect against AD. The association of family history with the risk of AD is weaker than previously estimated on the basis of cross-sectional studies. Female gender may modify the risk of AD, whether it be via biological or behavioral factors.