Summary Background Comprehensive long-term data on atrial fibrillation trends in men and women are scant. We aimed to provide such data through analysis of the Framingham cohort over 50 years. ...Methods We investigated trends in incidence, prevalence, and risk factors for atrial fibrillation and its association with stroke and mortality after onset in 9511 participants enrolled in the Framingham Heart Study between 1958 and 2007. We analysed trends within 10 year groups (1958–67, 1968–77, 1978–87, 1988–97, and 1998–2007), stratified by sex. Findings During 50 years of observation (202 417 person-years), 1544 cases of new-onset atrial fibrillation occurred (of whom 723 47% were women). Between 1958–67 and 1998–2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20·4 to 96·2 cases per 1000 person-years in men and from 13·7 to 49·4 cases per 1000 person-years in women; age-adjusted incidence increased from 3·7 to 13·4 new cases per 1000 person-years in men and from 2·5 to 8·6 new cases per 1000 person-years in women (ptrend <0·0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1000 person-years increased (12·6 in 1958–67 to 25·7 in 1998–2007 in men, ptrend =0·0007; 8·1 to 11·8 in women, ptrend =0·009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 74% (95% CI 50–86%) decrease in stroke (hazards ratio HR 3·77, 95% CI 1·98–7·20 in 1958–1967 compared with 1998–2007; ptrend =0·0001) and a 25% (95% CI −3–46%) decrease in mortality (HR 1·34, 95% CI 0·97–1·86 in 1958–1967 compared with 1998–2007; ptrend =0·003) in 20 years following atrial fibrillation onset. Interpretation Trends of increased incidence and prevalence of atrial fibrillation in the community were probably partly due to enhanced surveillance. Measures are needed to enhance early detection of atrial fibrillation, through increased awareness coupled with targeted screening programmes and risk factor-specific prevention. Funding NIH, NHLBI, NINDS, Deutsche Forschungsgemeinschaft.
The prevalence of dementia is expected to soar as the average life expectancy increases, but recent estimates suggest that the age-specific incidence of dementia is declining in high-income ...countries. Temporal trends are best derived through continuous monitoring of a population over a long period with the use of consistent diagnostic criteria. We describe temporal trends in the incidence of dementia over three decades among participants in the Framingham Heart Study.
Participants in the Framingham Heart Study have been under surveillance for incident dementia since 1975. In this analysis, which included 5205 persons 60 years of age or older, we used Cox proportional-hazards models adjusted for age and sex to determine the 5-year incidence of dementia during each of four epochs. We also explored the interactions between epoch and age, sex, apolipoprotein E ε4 status, and educational level, and we examined the effects of these interactions, as well as the effects of vascular risk factors and cardiovascular disease, on temporal trends.
The 5-year age- and sex-adjusted cumulative hazard rates for dementia were 3.6 per 100 persons during the first epoch (late 1970s and early 1980s), 2.8 per 100 persons during the second epoch (late 1980s and early 1990s), 2.2 per 100 persons during the third epoch (late 1990s and early 2000s), and 2.0 per 100 persons during the fourth epoch (late 2000s and early 2010s). Relative to the incidence during the first epoch, the incidence declined by 22%, 38%, and 44% during the second, third, and fourth epochs, respectively. This risk reduction was observed only among persons who had at least a high school diploma (hazard ratio, 0.77; 95% confidence interval, 0.67 to 0.88). The prevalence of most vascular risk factors (except obesity and diabetes) and the risk of dementia associated with stroke, atrial fibrillation, or heart failure have decreased over time, but none of these trends completely explain the decrease in the incidence of dementia.
Among participants in the Framingham Heart Study, the incidence of dementia has declined over the course of three decades. The factors contributing to this decline have not been completely identified. (Funded by the National Institutes of Health.).
To determine the association between blood pressure during midlife (40-64 years) to late life (≥65 years) and risk of incident dementia.
This study included 1,440 (758 women, mean age 69 ± 6 years) ...Framingham Offspring participants who were free of dementia and attended 5 consecutive examinations at 4-year intervals starting at midlife (1983-1987, mean age 55 years) until late life (1998-2001, mean 69 years) and subsequently were followed up for incident dementia (mean 8 years). We determined the effect of midlife hypertension (≥140/90 mm Hg), late life hypertension, lower late life blood pressure (<100/70 mm Hg), persistence of hypertension during mid- to late life, and steep decline in blood pressure from mid- to late life over an 18-year exposure period.
During the follow-up period, 107 participants (71 women) developed dementia. Using multivariable Cox proportional hazards models, we found that midlife systolic hypertension (hazard ratio HR 1.57, 95% confidence interval CI 1.05-2.35) and persistence of systolic hypertension into late life (HR 1.96, 95% CI 1.25-3.09) were associated with an elevated risk of incident dementia. However, in individuals with low to normal blood pressure (≤140/90 mm Hg) at midlife, a steep decline in systolic blood pressure during mid- to late life was also associated with a >2-fold increase in dementia risk (HR 2.40, 95% CI 1.39-4.15).
Elevated blood pressure during midlife, persistence of elevated blood pressure into late life, and, among nonhypertensives, a steep decline in blood pressure during mid- to late life were associated with an increased dementia risk in a community-based cohort. Our data highlight the potential sustained cognitive benefits of lower blood pressures in midlife but also suggest that declining blood pressure in older adults with prehypertension or normotension, but not in those with hypertension, may be a risk marker for dementia.
The autonomic nervous system has been implicated in stroke and dementia pathophysiology. High resting heart rate and low heart rate variability indicate the effect of autonomic imbalance on the ...heart. We examined the associations of resting heart rate and heart rate variability with incident stroke and dementia in a community-based cohort of middle- and old-aged adults.
The study sample included 1581 participants aged >60 years and 3271 participants aged >45 years evaluated for incident dementia and stroke, respectively, who participated in the Framingham Offspring cohort third (1983–1987) examination and had follow-up for neurology events after the seventh (1998–2001) examination. Heart rate variability was assessed through the standard deviation (SD) of normal-to-normal RR intervals and the root mean square of successive differences between normal heartbeats from 2-hour Holter monitor. Participants were followed-up for stroke and dementia incidence from exam 7 to a maximum of 10 years. Cox regression models were used to assess the link of resting heart rate and heart rate variability with stroke and dementia risk while adjusting for potential confounders, and interactions with age and sex were assessed.
Of the dementia (mean age, 55±6 years, 46% men) and stroke (mean age, 48±9 years, 46% men) samples, 133 and 127 developed dementia and stroke, respectively, during the follow-up. Overall, autonomic imbalance was not associated with dementia risk. However, age modified the associations such that SD of normal-to-normal intervals and root mean square of successive differences were associated with dementia risk in older people (hazard ratio HR 95% CI per 1SD, 0.61 0.38–0.99 and HR 95% CI per 1SD, 0.34 0.15–0.74, respectively). High resting heart rate was associated with increased stroke risk (HR 95% CI per 10 bpm, 1.18 1.01–1.39), and high SD of normal-to-normal intervals was associated with lower stroke risk in men (HR 95% CI per 1SD, 0.46 0.26–0.79) but not women (HR 95% CI per 1SD, 1.25 0.88–1.79; P for interaction=0.003).
Some measures of cardiac autonomic imbalance may precede dementia and stroke occurrence, particularly in older ages and men, respectively.
Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation ...into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population.
Several longitudinal studies found an inverse relationship between levels of physical activity and cognitive decline, dementia, and/or Alzheimer's disease (AD), but results have been inconsistent. We ...followed an older, community-based cohort for over a decade to examine the association of physical activity with the risk of incident dementia and subclinical brain MRI markers of dementia.
The physical activity index (PAI) was assessed in the Framingham Study Original and Offspring cohorts, aged 60 years or older. We examined the association between PAI and risk of incident all-cause dementia and AD in participants of both cohorts who were cognitively intact and had available PAI (n = 3,714; 54% women; mean age = 70±7 years). We additionally examined the association between PAI and brain MRI in the Offspring cohort (n = 1,987).
Over a decade of follow-up, 236 participants developed dementia (188 AD). Participants in the lowest quintile of PAI had an increased risk of incident dementia compared with those in higher quintiles (hazard ratio HR = 1.50, 95% confidence interval CI = 1.04-1.97, p = .028) in a multivariable-adjusted model. Secondary analysis revealed that this relation was limited to participants who were apolipoprotein (APO)E ε4 allele noncarriers (HR = 1.58, 95% CI = 1.08-2.32; p = .018) and strongest in participants aged 75 years or older. PAI was also linearly related to total brain and hippocampal volumes (β ± SE = 0.24±0.06; p < .01 and 0.004±0.001; p = .003, respectively).
Low physical activity is associated with a higher risk for dementia in older individuals, suggesting that a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.
To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.
Findings were pooled from 5 ...population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.
After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.
Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.
Blood-based biomarkers have the potential to improve the identification of persons with the greatest dementia risk for inclusion in dementia prevention trials through low-cost and minimally invasive ...screening.
To investigate the use of plasma total tau as a blood biomarker for dementia and related endophenotypes.
This prospective cohort study used data from the US community-based Framingham Heart Study with replication in the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France. Total tau levels were measured from stored plasma samples in Framingham Heart Study participants during 2004 to 2011. Dementia follow-up occurred across a median of 6 years (interquartile range, 5-8 years) for persons 65 years and older who were dementia free at baseline. Plasma and/or cerebrospinal fluid samples were obtained from Memento study participants from April 19, 2011, to June 22, 2016. Dementia follow-up took place over a median of 4 years (interquartile range, 3-5 years). Data analysis was performed from January to November 2018.
Plasma total tau level measured using single-molecule array technology.
Incidence of dementia of any cause (all dementia) and dementia due to clinical Alzheimer disease (AD dementia).
Among the 1453 participants in the Framingham dementia study sample, the mean (SD) age was 75 (7) years; 792 (54.5%) were female. Among the 367 individuals in the replication cohort, the mean (SD) age was 69 (9) years; 217 (59.1%) were female. Of 134 cases of incident all dementia in the Framingham sample, 105 were AD dementia. After adjustment for age and sex, each SD unit increase in the log of plasma total tau level was associated with a 35% increase in AD dementia risk (hazard ratio HR, 1.35; 95% CI, 1.10-1.67). The addition of plasma total tau to a model including age and sex improved the stratification of participants for risk of AD dementia (net reclassification improvement, 0.382; 95% CI, 0.030-0.716). Higher plasma total tau level was associated with poorer cognition across 7 cognitive tasks (P < .05) and smaller hippocampi (hippocampal volume: β SE = 0.002 0.001; P = .003) as well as neurofibrillary tangles (β SE = 0.95 0.45; P = .04) and microinfarcts (odds ratio, 3.04; 95% CI, 1.26-7.37) at autopsy. In the replication cohort, plasma total tau level weakly correlated with cerebrospinal fluid total tau level (Spearman correlation coefficient, 0.16; P = .07), but plasma total tau was at least as strongly associated with incident AD dementia as cerebrospinal fluid total tau (log plasma total tau: HR, 2.33; 95% CI, 1.00-5.48; log cerebrospinal fluid total tau: HR, 2.14; 95% CI, 1.33-3.44) after adjustment for age and sex.
The findings suggest that plasma total tau levels may improve the prediction of future dementia, are associated with dementia endophenotypes, and may be used as a biomarker for risk stratification in dementia prevention trials.
To assess the risk of incident epilepsy among participants with prevalent dementia and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS).
We ...analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy, we used separate, nested, case-control designs and matched each case to 3 age-, sex- and FHS cohort-matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and
ε4 allele status in modifying the association between epilepsy and dementia.
A total of 4,906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1,980 dementia-free controls, there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases vs controls yielded a hazard ratio (HR) of 1.82 (95% confidence interval 1.05-3.16,
= 0.034). Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases vs controls yielded a HR of 1.99 (1.11-3.57,
= 0.021). In this group, among participants with any post-high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia (HR 4.67 1.82-12.01,
= 0.001) compared to controls of the same educational attainment.
There is a bi-directional association between epilepsy and dementia. with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.
Summary Background Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure ...in the brain are evident as early as the fifth decade of life. Methods In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders. Findings 579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmann's area 48 on the medial surface of the temporal lobe and Brodmann's area 21 of the middle temporal gyrus. Interpretation Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure. Funding National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
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