Smaller Head Circumference Combined with Lower Education Predicts High Risk of Incident Dementia: The Shanghai Aging Study.

INTRODUCTION: An important index of brain reserve is the maximal attained brain size, which can be estimated by measuring the head circumference (HC). We investigated the association of HC and education with incident dementia in a population-based study of Chinese older adults. METHODS: We conducted a prospective follow-up study of 1,659 non-demented participants with a mean age of 71.5 years. Characteristics and anthropometry of the participants were collected at baseline. Consensus diagnoses for dementia were made using DSM-IV criteria based on functional, neurological, and neuropsychological assessments. RESULTS: We identified 168 new-onset dementia cases after a mean of 5.2 years of follow-up. Participants with smaller HC combined with low educational attainment had a significantly higher risk of incident dementia than those with larger HC who had completed more than 12 years of education (adjusted hazard ratio 4.48, 95% CI 2.47-8.12). DISCUSSION/CONCLUSION: Our results suggest that smaller HC in combination with low education leads to a markedly increased risk of dementia.

Prevalence of mild cognitive impairment in an urban community in China: a cross-sectional analysis of the Shanghai Aging Study.

BACKGROUND: Substantial variations in the prevalence of mild cognitive impairment (MCI) have been reported, although mostly in Western countries. Less is known about MCI in the Chinese population. METHODS: We clinically and neuropsychologically evaluated 3141 community residents ≥60 years of age. Diagnoses of MCI and its subtypes were made using standard criteria via consensus diagnosis. RESULTS: Among 2985 nondemented individuals, 601 were diagnosed with MCI, resulting in a prevalence of 20.1% for total MCI, 13.2% for amnestic MCI (aMCI), and 7.0% for non-amnestic MCI (naMCI). The proportions of MCI subtypes were: aMCI single domain (SD), 38.9%; aMCI multiple domains (MD), 26.5%; naMCI-SD, 25.0%; and naMCI-MD, 9.6%. The prevalence of aMCI-MD increased rapidly with age in women APOE ε4 carriers (from 60 to 69 years to ≥80 years, 3.1%-33.3%, P < .001). CONCLUSIONS: Our findings suggest that 20% of Chinese elderly are affected by MCI. Prospective studies in China are needed to examine progression to dementia and related risk factors.

The Shanghai Aging Study: study design, baseline characteristics, and prevalence of dementia.

BACKGROUND: To establish a prospective cohort to enumerate the prevalence, incidence and risk factors for dementia and mild cognitive impairment (MCI) among residents aged ≥60 in an urban community of Shanghai, China. METHODS: Participants received clinical evaluations including physical measurements, demographic and lifestyle questionnaires, physical and neurologic examinations, and neuropsychological testing. Urine and blood samples were collected, aliquoted, and stored. DNA was extracted for Apolipoprotein (APOE) genotyping. Diagnoses of dementia and MCI were made using standard criteria via consensus diagnosis. RESULTS: Among 3,141 participants aged ≥60, 1,438 (45.8%) were men. The average age of participants was 72.3 years (SD 8.1), and they had an average of 11.6 years (SD 4.4) of education. The most common chronic disease of participants was hypertension (56.4%). The frequencies of APOE-​ε2, ε3 and ε4 were 7.9, 82.7 and 9.4%, respectively. We diagnosed 156 (5.0%, 95% CI 4.3-5.8%) participants with dementia. The prevalence rates of Alzheimer's disease and vascular dementia were 3.6% (95% CI 3.0-4.3%) and 0.8% (95% CI 0.5-1.1%). CONCLUSIONS: The Shanghai Aging Study is the first prospective community-based cohort study of cognitive impairment in China, with a comparable study design, procedures, and diagnostic criteria for dementia and MCI to most previous cohort studies in developed countries.

Dementia: a barrier to receiving percutaneous coronary intervention for elderly patients with ST-elevated myocardial infarction.

OBJECTIVE: Percutaneous coronary intervention (PCI) is the first line of treatment for ST-elevated myocardial infarction (STEMI). This study evaluates the role of dementia in diagnostic cardiac catheterization (to receive PCI) in STEMI patients ≥65 years old admitted to high annual volume PCI hospitals. METHODS: Participants were registered in Florida's comprehensive inpatient surveillance system for the years 2006-2007 with principal diagnosis of STEMI. Dementia was defined using ICD-9 codes for presenile, senile, and Alzheimer's type dementia. RESULTS: Data from 8331 STEMI patients were used. Of these, 77.2% were catheterized, 67.2% received PCI, and 9.3% had coronary artery bypass graft (CABG). The mean age of the cohort was 76.3 years (SD 7.8 years.); with 43.3% female, 83.4% white, 4.6% black, and 12% Hispanic/other. Of the 248 (3%) patients with dementia, 42% were catheterized. After adjustment for age, gender, and race/ethnicity, patients with dementia were less likely to be catheterized (RR 0.30, 95% CI 0.30-0.50) than non-demented patients. However, among patients who were catheterized, there was no difference in the use of PCI or CABG for patients with versus without dementia (p = 0.56). Of those with dementia, being older and arriving to the hospital in the afternoon were associated with lower likelihood of being catheterized (RR 0.08, 95% CI 0.02-0.28, and RR 0.30, 95% CI 0.10-0.88, respectively). However, having hyperlipidemia increased the probability of catheterization (RR 3.60, 95% CI 1.86-6.98). CONCLUSION: ST-elevated myocardial infarction patients with dementia were much less likely to receive diagnostic cardiac catheterization, thereby limiting the possibility for receiving optimal care including PCI or CABG.

The association of physical and mental health with sexual activity in older adults in a retirement community.

INTRODUCTION: Understanding sexual behavior is important when evaluating the health needs of older adults. Little research has addressed the effect of specific health conditions on sexual inactivity in this growing population. AIM: The study aims to assess the association of mental and physical health conditions with sexual inactivity among adults 55 and older living in The Villages, Florida. METHODS: Exposure data for 22 self-reported health conditions were assessed in relation to sexual inactivity in 22,654 participants ages 55 and older, including 1,879 participants over age 80 in a community-based cross-sectional study. Logistic regression analyses were conducted separately for men and women to evaluate the likelihood of being sexually active for each health condition. Covariates included age, race, education, income, self-reported overall health, and marital status. MAIN OUTCOME MEASURES: The odds ratio and 95% confidence intervals for sexual activity status were calculated separately for men and women. RESULTS: Fifty-five percent of men and 45% of women reported being sexually active. Significant positive correlates of sexual activity included walking at least 1-2 times per week, participating in at least two registered clubs, engaging in physical and social activities, no tobacco use, fewer medications, increased alcohol consumption, and reporting a good quality of life, psychological well-being, or social support. Sexual inactivity was significantly related to cancer, bladder/bowl problems, major surgery, poor vision, mental health conditions, and cardiovascular disease and its risk factors including diabetes, hypertension, and high cholesterol. Additional associations with sexual inactivity included hearing loss and dementia for men, and dermatologic conditions, problems with the joints, bone or back, gastrointestinal problems, alcohol misuse, chronic wound care, and gum disease in women. CONCLUSIONS: Mental and physical health conditions have very similar associations with sexual inactivity in men and women. Increased sexual activity was associated with positive physical, social, and emotional health indicators.

Associations of circulating saturated long-chain fatty acids with risk of mild cognitive impairment and Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

BACKGROUND: No study has examined the associations between peripheral saturated long-chain fatty acids (LCFAs) and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This study aimed to examine whether circulating saturated LCFAs are associated with both risks of incident MCI from cognitively normal (CN) participants and incident AD progressed from MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We conducted analysis of data from older adults aged 55-90 years who were recruited at 63 sites across the USA and Canada. We examined associations between circulating saturated LCFAs (i.e., C14:0, C16:0, C18:0, C20:0) and risk for incident MCI in CN participants, and incident AD progressed from MCI. FINDINGS: 829 participants who were enrolled in ADNI-1 had data on plasma saturated LCFAs, of which 618 AD-free participants were included in our analysis (226 with normal cognition and 392 with MCI; 60.2% were men). Cox proportional-hazards models were used to account for time-to-event/censor with a 48-month follow-up period for the primary analysis. Other than C20:0, saturated LCFAs were associated with an increased risk for AD among participants with MCI at baseline (Hazard ratios (HRs) = 1.3 to 2.2, P = 0.0005 to 0.003 in fully-adjusted models). No association of C20:0 with risk of AD among participants with MCI was observed. No associations were observed between saturated LCFAs and risk for MCI among participants with normal cognition. INTERPRETATION: Saturated LCFAs are associated with increased risk of progressing from MCI to AD. This finding holds the potential to facilitate precision prevention of AD among patients with MCI. FUNDING: National Institutes of Health.

Dietary calcium and magnesium intake and risk for incident dementia: The Shanghai Aging Study.

Introduction: Calcium (Ca), magnesium (Mg), or the calcium to magnesium (Ca:Mg) ratio may affect the risk of dementia via complex mechanisms. The aim of this study was to evaluate the association of dietary Ca, Mg, and Ca:Mg ratio with dementia risk at the prospective phase of the Shanghai Aging Study. Methods: We analyzed data from 1565 dementia-free participants living in an urban community who had measurements of dietary Ca and Mg intake derived from a food frequency questionnaire at baseline and incident dementia during follow-up. Results: Over the 5-year follow-up, 162 (10.4%) participants were diagnosed with incident dementia by Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Participants with the lowest tertile of dietary Ca (<339.1 mg/day) and Mg (<202.1 mg/day) had the highest incidence rates of dementia (3.3/100 person-years for Ca, 3.3/100 person-years for Mg) compared to those with higher Ca and Mg intake. In the subgroup with Ca:Mg ratios ≤ 1.69, Mg intake >267.5 mg/day was related to an increased risk for dementia (adjusted hazard ratio: 3.97, 95% confidence interval: 1.29-12.25). Conclusions: Our findings suggest that high dietary intake of Mg is associated with an increased risk of dementia mainly among older adults with low Ca:Mg intake ratios. Proper balance of Ca to Mg in the diet may be critical to the relationship between Mg intake and risk of dementia. Highlights: Participants with the lowest tertile of dietary calcium (Ca) and magnesium (Mg) had the highest incidence rates of dementia.In the subgroup with Ca:Mg ratios ≤1.69, Mg intake >267.5 mg/day was related to an increased risk for dementia.Balance of Ca to Mg in diet may be critical to the relationship between Mg intake and risk of dementia.

Midlife fruit and vegetable consumption and risk of dementia in later life in Swedish twins.

OBJECTIVE: Diet may be associated with risk of dementia and Alzheimer disease (AD). The authors examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD. METHODS: Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years before cognitive screening and full clinical evaluation for dementia as part of the study of dementia in Swedish Twins (HARMONY) study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins and with conditional logistic regression for the co-twin control design. RESULTS: In fully adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared with no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but nonsignificant, odds ratios were found in the co-twin control analyses. CONCLUSION: The findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.

High normal fasting blood glucose is associated with dementia in Chinese elderly.

BACKGROUND: Diabetes is a risk factor for mild cognitive impairment (MCI) and dementia. However, the association between high normal fasting blood glucose (FBG) and dementia has not been studied. METHODS: Polytomous logistic regression was used to assess the association of dementia and MCI with FBG in an age- and sex-matched sample of 32 dementia patients, 27 amnestic MCI (aMCI) patients, and 31 normal controls (NC). Analyses were repeated for those with normal FBG. Correlations between FBG and cognitive test scores were obtained. RESULTS: Controlling for age, gender, education, body mass index, Hachinski Ischemic Score, magnetic resonance imaging (MRI) stroke, and normalized brain, hippocampal, and white matter hyperintensity MRI volumes; higher FBG was associated with dementia versus aMCI status (OR = 3.13; 95% CI, 1.28-7.69). This association remained (OR = 7.75; 95% CI, 1.10-55.56) when analyses were restricted to subjects with normal FBG. When dementia patients were compared with NC adjusting for age, gender, and education, a significant association with FBG also was seen (OR = 1.83; 95% CI, 1.09-3.08), but it was lost when vascular covariates were added to the model. FBG was not associated with aMCI status versus NC. Higher FBG was correlated with poorer performance on the Trailmaking Test Part B (P = .003). The percentage of dementia patients with high normal FBG (90%) was significantly higher than that of aMCI patients with high normal FBG (32.9%) (χ(2) = 13.9, P < .001). CONCLUSIONS: Higher FBG was associated with dementia (vs. aMCI) independent of vascular risk factors and MRI indicators of vascular disease, and remained a significant risk factor when analyses were restricted to subjects with normal FBG. The results of this cross-sectional study suggest that a high normal level of FBG may be a risk factor for dementia.

The effect of APOE-epsilon4 on dementia is mediated by Alzheimer neuropathology.

The degree to which the association of epsilon4 with dementia is mediated by AD lesions in comparison with vascular lesions is controversial. The present study was undertaken to determine the roles of Alzheimer disease (AD) and vascular pathology in mediating the effect of apolipoprotein E (APOE)-epsilon4 alleles on dementia. Clinicopathologic correlations were studied in 267 Catholic sisters participating in the Nun Study. The extent to which AD and vascular pathologies mediated the effect of APOEepsilon4 on dementia was investigated using multiple logistic regression. Adjusted for age at death and education, possession of 1 or more epsilon4 alleles was an important risk factor for dementia (odds ratio=2.98; 95% confidence interval, 1.62-5.48). This association was lost (odds ratio=1.38; 95% confidence interval, 0.68-2.80) when an index of the severity of AD-related neuropathology was added to the model, but changed little when measures of the severity of vascular pathology were added. The findings suggest that the effect of epsilon4 on dementia is mediated by the severity of AD pathology. Although infarcts and atherosclerosis contribute to the occurrence of dementia, this contribution seems unrelated to APOE genotype.

Health-related quality of life in community-dwelling older Whites and African Americans.

OBJECTIVE: This study assesses structural and functional characteristics of Short Form-36 Health Survey (SF-36) domains using community-based samples of older Whites and African Americans. Although the eight domains of the SF-36 have by convention been collapsed into two summary categories- physical health and mental health-the authors examine a three-factor model including physical health, mental health, and general well-being. They hypothesized that the general well-being factor would be a mediator between physical and mental health in both groups. METHOD: Analyses using structural equation modeling provide support for the approach. RESULTS: In both White and African American samples, the three-factor model demonstrated a better fit than the two-factor model. Also, in both groups, general well-being mediated the relationship between physical health and mental health. DISCUSSION: Findings suggest that general well-being serves as an intervening step between physical and mental health in both White and African American older adults.

Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes.

STUDY OBJECTIVES: To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aß42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer's disease (AD) elderly. METHODS: Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aß42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA. RESULTS: In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B = .06, 95% CI = .02, .11 and B = .08, 95% CI = .05, .12, respectively) and decrease in CSF Aß42 levels (B = -2.71, 95% CI = -3.11, -2.35 and B = -2.62, 95% CI = -3.23, -2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group. CONCLUSIONS: In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Small head circumference is associated with less education in persons at risk for Alzheimer disease in later life.

Studies suggest that individuals who are at increased risk for Alzheimer disease (AD) in late life differ on measures of cognition, linguistic performance, and brain metabolism in earlier adult life compared with those with lower risk of this illness. The present study was undertaken to determine whether smaller head circumference (HC), a predictor of AD in late life, could influence educational attainment earlier in life, specifically among individuals at increased risk for AD. Data from the Nun Study, a longitudinal clinicopathologic study of dementia, were analyzed using logistic regression to assess the association between HC and attainment of less than a bachelor's degree. Modification of this association was studied by comparing those with and without evidence of increased AD risk, including possession of apolipoprotein E (APOE)-epsilon 4 alleles, occurrence of dementia before death, and satisfaction of AD neuropathologic criteria at autopsy. Small HC was associated with lower educational attainment in those carrying an APOE-epsilon 4 allele [odds ratio (OR)=6.27, 1.21 to 32.48], those who became demented (OR=3.23, 1.27 to 8.21), and those who fulfilled AD neuropathologic criteria (OR=5.03, 1.29 to 19.66), but not in those without these characteristics. These findings suggest that small HC limits educational attainment only among individuals who have greater risk of AD owing to their APOE genotype or who are destined to develop this illness later in life.

The association between social resources and cognitive change in older adults: evidence from the Charlotte County Healthy Aging Study.

We examined associations between multiple aspects of social resources and 5-year change in performance on different domains of cognitive function. Results indicated that lower satisfaction with support was associated with decline in episodic memory performance over 5 years. We also found significant interactions between age and social networks of family and friends and satisfaction with support for the separate cognitive domains. The results suggest that social resources may be differentially important for cognitive change but that different cognitive domains respond in a similar pattern to social resources.

Characteristics of the Florida cognitive activities scale in older African Americans.

Substantial research effort has recently focused on the potential protective effect of cognitively demanding activities on cognitive decline in late life. A significant methodological issue in this effort has been the lack of consistency in approaches to the operational measurement of cognitive activity. In this study, data in support of the reliability and construct validity of the recently developed Florida Cognitive Activities Scale (FCAS) in a sample of 223 African American older adults are provided. Consistent with the findings of the Schinka et al. study using a sample of Whites, the FCAS full scale showed a reasonably high level of internal consistency, small negative correlations with age and a measure of depressive symptomatology, and moderate positive correlations with years of education and neuropsychological measures of overall cognitive functioning, memory, and executive functioning. Even after controlling for the effects of age, education, and gender, the full scale score contributed significantly to the prediction of global cognitive functioning. The results of this study suggest that the FCAS is a reliable and valid measure of cognitive activities in older African Americans and provides additional, although not causative, evidence in support of the hypothesis of a protective effect of cognitive activity against cognitive decline regardless of ethnicity or race.

Role of genes and environments for explaining Alzheimer disease.

CONTEXT: Twin studies using selected samples have shown high heritability for Alzheimer disease (AD). OBJECTIVE: To evaluate genetic and environmental influences on AD in a fully ascertained population of older twins, including like- and unlike-sex pairs. DESIGN: Five-group quantitative genetic model: male monozygotic twins, female monozygotic twins, male dizygotic twins, female dizygotic twins, and unlike-sex twins. SETTING AND PARTICIPANTS: All twins in the Swedish Twin Registry aged 65 years and older. The study included 11,884 twin pairs, among whom were 392 pairs in which 1 or both members had AD. MAIN OUTCOME MEASURES: All individuals were screened for cognitive dysfunction. Suspected cases of dementia and their co-twins received complete clinical diagnostic evaluations for AD. Estimates of heritability, shared environmental influences, and nonshared environmental influences, adjusting for age, were derived from the twin data. RESULTS: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantly greater in dizygotic than in monozygotic pairs, suggesting genetic influences on timing of the disease. CONCLUSIONS: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset.

Accounting for the relationship between low education and dementia: a twin study.

We evaluated whether the association between low education and greater risk of dementia is explained by genetic influences, using three different types of analyses. The HARMONY study (Swedish for "health" (Hälsa), "genes" (ARv), "environment" (Miljö), "and" (Och), and "new" (NY)) includes members of the Swedish Twin Registry who were aged 65 and older and alive in 1998, and who were screened and clinically assessed for dementia. There were 394 cases with dementia and 7786 unrelated controls. Analyses included co-twin control, tests for association between education and a measured genotype, and bivariate twin modeling. Low education was a significant risk factor for dementia both in case-control analyses (odds ratio=1.77, 95% confidence interval 1.38 to 2.28) and co-twin control analyses with monozygotic twin pairs (odds ratio=3.17, 95% confidence interval 1.26 to 7.93). Apolipoprotein E genotype was not associated with education and did not account for the relationship between education and dementia. Bivariate twin modeling showed that the association between education and dementia was not mediated by genetic influences in common between education and dementia. The association was mediated by shared environmental influences that were related to both dementia and to education. Low education is confirmed as a risk factor for dementia. Findings from three different analytic approaches showed that genetic influences did not explain this association.

Negative life events and cognitive performance in a population of older adults.

OBJECTIVE: This study examined the association between negative life events in the past year and cognitive performance in a population of older adults. METHODS: Secondary data analysis was conducted on 428 participants from the Charlotte County Healthy Aging Study. Participants completed tests of episodic memory, attention, and psychomotor speed and endorsed the presence and severity of 24 life events. Life events were examined in the aggregate as well as individually. RESULTS: Hierarchical multiple regression results suggest no significant relationship between the aggregate frequency and severity measures of negative life events and cognitive performance. At the individual-event level, individuals who experienced the injury or illness of a friend during the past year and rated it as having more of an effect on their lives performed better on all three cognitive tasks. However, individuals who reported having less money to live on over the past year and rated the event as having more of an effect on their lives performed more poorly on the psychomotor speed tasks. DISCUSSION: The findings support previous research indicating that using estimates of individual stressors rather than aggregate stress measures increases the predictive validity of stress measurement. Furthermore, the individual negative life events can have both a positive and a negative effect, which nullify one another when using the sum score of events.

Apolipoprotein E and cognition in community-based samples of African Americans and Caucasians.

To compare relative frequencies of apolipo-protein E (APOE) alleles in African-American and Caucasian populations and test associations with cognition, we studied two community-based samples: one of 253 African Americans and another of 466 Caucasians age 60-84 years. Logistic regression, adjusting for age, sex, education, and history of hypertension and diabetes was used to associate APOE with five cognitive measures. The APOE-epsilon4 allele frequency was 29.5% in African Americans and 12.1% in Caucasians. In the African Americans, no association was found between the presence of the APOE-epsilon4 allele and any of the cognitive measures. Among Caucasians, APOE-epsilon4 carriers performed more poorly on three of the five tests. We also report a considerably higher frequency of the APOE-epsilon4 allele in our African-American sample compared to other US-based studies.

Potentially modifiable risk factors for dementia in identical twins.

BACKGROUND: The purpose of this study was to test nongenetic factors that might explain discordance for dementia in monozygotic twin pairs. Risk factors included education, engaged lifestyle in midlife, and early life circumstances indexed by tooth loss, short adult height, and parental social class. METHODS: Data are from the HARMONY study, including members of the Swedish Twin Registry age 65 and older and alive in 1998, who were screened and assessed clinically for dementia. Analyses included a case-control design to evaluate the risk factors and a co-twin control design that permits testing nongenetic risk factors while controlling for genetic influences. Case-control analyses included 310 dementia cases and 3,063 nondemented controls. There were 106 monozygotic twin pairs discordant for dementia. Risk factors were assessed independently by the Swedish Twin Registry three decades previously. RESULTS: Case-control findings showed that history of tooth loss before age 35 and low educational attainment were significant risk factors for Alzheimer's disease, with short adult height also contributing to risk for total dementia. In co-twin control analyses, only history of tooth loss before age 35 was a significant risk factor for Alzheimer's disease, whereas low educational attainment also contributed to risk for total dementia and lack of physical exercise to risk for non-Alzheimer's dementias. CONCLUSIONS: Potentially modifiable risk factors from early and midlife, with a cumulative detrimental effect on the brain, contribute to risk of dementia. Based on the association with tooth loss, further investigation of inflammatory load as a risk factor for Alzheimer's disease is warranted.