Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or ...artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.
We studied 2888 participants aged >45 years for incident stroke (mean age 62 SD, 9 years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 SD, 6 years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer's disease).
After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer's disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26-6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18-7.07) for Alzheimer's disease. Sugar-sweetened beverages were not associated with stroke or dementia.
Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia.
The association between vascular risk factors and dementia varies with age, making generalizability of dementia risk prediction rules to individuals of different ages challenging. We determined the ...most important vascular risk factors for inclusion in age-specific dementia risk scores.
Framingham Heart Study Original and Offspring cohort participants with available data on the Framingham Stroke Risk Profile (FSRP) at midlife (age 55; n = 4,899, 57% women), late life (ages 65 or 70), or later life (ages 75 or 80 n = 2,386, 62% women) were followed for 10-year incident dementia risk from ages 65, 70, 75, and 80.
Age- and sex-adjusted midlife risk factors associated with 10-year risk of dementia from age 65 included FSRP (hazard ratio HR 1.16, 95% CI 1.06-1.26, per 1 SD increment in log-transformed score), diabetes mellitus (DM; HR 4.31, 95% CI 1.97-9.43), and systolic blood pressure (SBP; HR 1.12, 95% CI 1.02-1.24, per 10 mm Hg increment). Late-life risk factors associated with 10-year incident dementia from ages 65 or 70 included FSRP (age 65 only: HR 1.06, 95% CI 1.02-1.10), antihypertensive use (age 65 reported: HR 1.66, 95% CI 1.12-2.46), DM (age 65 reported: HR 1.96, 95% CI 1.09-3.52), atrial fibrillation (age 65 reported: HR 2.30, 95% CI 1.00-5.27), nonstroke cardiovascular disease (nsCVD; age 65 reported: HR 1.95, 95% CI 1.24-3.07), and stroke (age 70 only: HR 3.61, 95% CI 2.21-5.92). Later-life risk factors associated with 10-year incident dementia from ages 75 or 80 included antihypertensive use (age 80 only: HR 0.74, 95% CI 0.62-0.89), DM (age 80 reported: HR 1.40, 95% CI 1.04-1.89), atrial fibrillation (age 80 reported: HR 1.43, 95% CI 1.07-1.92), and stroke (age 80 reported: HR 1.63, 95% CI 1.13-2.35). In stepwise models, SBP and DM at age 55, nsCVD at age 65, DM and stroke at ages 70 and 75, and DM, stroke, and use of antihypertensives (protective) at age 80 were the most important vascular risk factors for dementia.
Our findings support the use of age-specific dementia risk scores, which should prioritize including, at age 55, SBP and DM; at age 65, nsCVD; at ages 70 and 75, DM and stroke; and at age 80, DM, stroke, and antihypertensive use.
Heart failure is a risk factor for Alzheimer's disease and cerebrovascular disease. In the absence of heart failure, it was hypothesized that left ventricular ejection fraction (LVEF), an indicator ...of cardiac dysfunction, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected from 1,114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (aged 40 to 89 years, mean age 67 ± 9 years, 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI–assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p values >0.15). However, LVEF quintile analyses yielded several U-shaped associations. Compared to the referent (quintile 2 to 4), the lowest quintile (quintile 1) LVEF was associated with lower mean cognitive performance, including Visual Reproduction Delayed Recall (β = −0.27, p <0.001) and Hooper Visual Organization Test (β = −0.27, p <0.001). Compared to the referent, the highest quintile (quintile 5) LVEF values also were associated with lower mean cognitive performance, including Logical Memory Delayed Recall (β = −0.18, p = 0.03), Visual Reproduction Delayed Recall (β = −0.17, p = 0.03), Trail Making Test Part B − Part A (β = −0.22, p = 0.02), and Hooper Visual Organization Test (β = −0.20, p = 0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although these observational cross-sectional data cannot establish causality, they suggest a nonlinear association between LVEF and measures of accelerated cognitive aging.
To determine the joint role of ideal cardiovascular health (CVH) and genetic risk on risk of dementia.
We categorized CVH on the basis of the American Heart Association Ideal CVH Index and genetic ...risk through a genetic risk score (GRS) of common genetic variants and the
ε4 genotype in 1,211 Framingham Heart Study (FHS) offspring cohort participants. We used multivariable Cox proportional hazards regression models to examine the association between CVH, genetic risk, and incident all-cause dementia with up to 10 years of follow-up (mean 8.4 years, 96 incident dementia cases), adjusting for age, sex, and education.
We observed that a high GRS (>80th percentile) was associated with a 2.6-fold risk of dementia (95% confidence interval CI of hazard ratio HR 1.23-5.29;
= 0.012) compared with having a low GRS (<20th percentile); carrying at least 1
ε4 allele was associated with a 2.3-fold risk of dementia compared with not carrying an
ε4 allele (95% CI of HR 1.49-3.53;
= 0.0002), and having a favorable CVH showed a 0.45-fold lower risk of dementia (95% CI of HR 0.20-1.01;
= 0.0527) compared to having an unfavorable CVH when all 3 components were included in the model. We did not observe an interaction between CVH and GRS (
= 0.99) or
ε4 (
= 0.16).
We observed that both genetic risk and CVH contribute additively to dementia risk.
To assess the association of early morning serum cortisol with cognitive performance and brain structural integrity in community-dwelling young and middle-aged adults without dementia.
We evaluated ...dementia-free Framingham Heart Study (generation 3) participants (mean age 48.5 years, 46.8% men) who underwent cognitive testing for memory, abstract reasoning, visual perception, attention, and executive function (n = 2,231) and brain MRI (n = 2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear and logistic regression to assess the relations of cortisol (categorized in tertiles, with the middle tertile as referent) to measures of cognition, MRI volumes, presence of covert brain infarcts and cerebral microbleeds, and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex,
, and vascular risk factors.
Higher cortisol (highest tertile vs middle tertile) was associated with worse memory and visual perception, as well as lower total cerebral brain and occipital and frontal lobar gray matter volumes. Higher cortisol was associated with multiple areas of microstructural changes (decreased regional FA), especially in the splenium of corpus callosum and the posterior corona radiata. The association of cortisol with total cerebral brain volume varied by sex (
for interaction = 0.048); higher cortisol was inversely associated with cerebral brain volume in women (
= 0.001) but not in men (
= 0.717). There was no effect modification by the
genotype of the relations of cortisol and cognition or imaging traits.
Higher serum cortisol was associated with lower brain volumes and impaired memory in asymptomatic younger to middle-aged adults, with the association being evident particularly in women.
We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease.
We performed a cross-sectional study relating a panel of 15 biomarkers, ...representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor α, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoprotein-associated phospholipase A2 mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 ± 9.1 years, 53.7% women).
We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio OR 2.2, 95% confidence interval CI 1.1-4.1 and OR 1.5, 95% CI 1.1-2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0-1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1-2.5), and lipoprotein-associated phospholipase A2 mass (OR 1.5, 95% CI 1.1-2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7-1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts.
Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD.
We tested whether abnormal arterial stiffness and blood pressure would be associated with progression of brain aging measured by brain MRI and neurocognitive testing.
Framingham Offspring Cohort ...participants (n = 1,223, 61 ± 9 years, 56% women) without previous stroke or dementia underwent applanation tonometry, brain MRI, and neurocognitive testing at examination 7 (1998-2001). Follow-up brain MRI and neurocognitive testing was performed at examination 8 (2005-2008, mean interval 6.4 ± 1.3 years). We related examination 7 inverse-transformed carotid-femoral pulse wave velocity (iCFPWV), central pulse pressure (CPP), and mean arterial pressure to changes in the following variables between examinations 7 and 8: total cerebral brain volume, white matter hyperintensity volume, and performance on executive function and abstraction tasks, the Trail Making Test, Parts B and A (ΔTrails B-A), and Similarities tests.
Higher baseline iCFPWV and CPP were associated with greater progression of neurocognitive decline (iCFPWV and ΔTrails B-A association: SD unit change in outcome variable per SD change in tonometry variable β ± SE = 0.10 ± 0.04, p = 0.019; CPP and ΔSimilarities association: -0.08 ± 0.03, p = 0.013). Higher mean arterial pressure, but not iCFPWV or CPP, was associated with increase in white matter hyperintensity volume (β ± SE 0.07 ± 0.03, p = 0.017). No tonometry measures were associated with change in cerebral brain volume.
In middle-aged and older adults without evidence of clinical stroke or dementia, elevated arterial stiffness and pressure pulsatility are associated with longitudinal progression of subclinical vascular brain injury and greater neurocognitive decline. Treatments to reduce arterial stiffness may potentially reduce the progression of neurovascular disease and cognitive decline.
In animal studies, brain-derived neurotrophic factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels ...increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset.
To examine whether higher serum BDNF levels in cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
Framingham Study original and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as related BDNF genetic variants to AD risk. This community-based, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean SD age, 72 7 years; 56% women).
Ten-year incidence of dementia and AD.
During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95% CI, 0.28-0.85; P = .01; and hazard ratio, 0.46; 95% CI, 0.24-0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, 95% CI, 0.50-0.85, P = .001; 0.63 95% CI, 0.47-0.85, P = .002; and 0.27 95% CI, 0.11-0.65, P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
Higher serum BDNF levels may protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons.
INTRODUCTION
Early risk stratification for clinical dementia could lead to preventive therapies. We identified and validated a magnetic resonance imaging (MRI) signature for Alzheimer's disease (AD) ...and related dementias (ARDR).
METHODS
An MRI ADRD signature was derived from cortical thickness maps in Framingham Heart Study (FHS) participants with AD dementia and matched controls. The signature was related to the risk of ADRD and cognitive function in FHS. Results were replicated in the University of California Davis Alzheimer's Disease Research Center (UCD‐ADRC) cohort.
RESULTS
Participants in the bottom quartile of the signature had more than three times increased risk for ADRD compared to those in the upper three quartiles (P < 0.001). Greater thickness in the signature was related to better general cognition (P < 0.01) and episodic memory (P = 0.01). Results replicated in UCD‐ADRC.
DISCUSSION
We identified a robust neuroimaging biomarker for persons at increased risk of ADRD. Other cohorts will further test the validity of this biomarker.
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