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ImportanceIncident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain.ObjectiveTo evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline.Design, Setting, and ParticipantsIndividual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023.ExposuresTime-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels.Main Outcomes and MeasuresThe primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.ResultsA total of 1120 eligible dementia-free individuals with incident stroke were identified; 982 (87.7%) had available covariate data and 138 (12.3%) were excluded for missing covariate data. Of the 982, 480 (48.9%) were female individuals, and 289 (29.4%) were Black individuals. The median age at incident stroke was 74.6 (IQR, 69.1-79.8; range, 44.1-96.4) years. Cumulative mean poststroke SBP and LDL cholesterol levels were not associated with any cognitive outcome. However, after accounting for cumulative mean poststroke SBP and LDL cholesterol levels, higher cumulative mean poststroke glucose level was associated with faster decline in global cognition (−0.04 points/y faster per each 10–mg/dL increase [95% CI, −0.08 to −0.001 points/y]; P = .046) but not executive function or memory. After restricting to 798 participants with apolipoprotein E4 (APOE4) data and controlling for APOE4 and APOE4 × time, higher cumulative mean poststroke glucose level was associated with a faster decline in global cognition in models without and with adjustment for cumulative mean poststroke SBP and LDL cholesterol levels (−0.05 points/y faster per 10–mg/dL increase [95% CI, −0.09 to −0.01 points/y]; P = .01; −0.07 points/y faster per 10–mg/dL increase [95% CI, −0.11 to −0.03 points/y]; P = .002) but not executive function or memory declines.Conclusions and RelevanceIn this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.

ImportanceEnlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain.ObjectiveToperform a whole-brain investigation of ePVSs in a large community-based cohort.Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included.Main Outcomes and MeasuresEnlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models.ResultsIn the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (β = 3.59 × 10−3; 95% CI, 2.80 × 10−3 to 4.39 × 10−3), systolic blood pressure (β = 8.35 × 10−4; 95% CI, 5.19 × 10−4 to 1.15 × 10−3), use of antihypertensives (β = 3.29 × 10−2; 95% CI, 1.92 × 10−2 to 4.67 × 10−2), and negatively associated with Black race (β = −3.34 × 10−2; 95% CI, −5.08 × 10−2 to −1.59 × 10−2). Thalamic ePVS volume was positively associated with age (β = 5.57 × 10−4; 95% CI, 2.19 × 10−4 to 8.95 × 10−4) and use of antihypertensives (β = 1.19 × 10−2; 95% CI, 6.02 × 10−3 to 1.77 × 10−2). Insular region ePVS volume was positively associated with age (β = 1.18 × 10−3; 95% CI, 7.98 × 10−4 to 1.55 × 10−3). Brainstem ePVS volume was smaller in Black than in White participants (β = −5.34 × 10−3; 95% CI, −8.26 × 10−3 to −2.41 × 10−3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (β = 1.14 × 10−4; 95% CI, 3.38 × 10−5 to 1.95 × 10−4) and negatively associated with age (β = −3.38 × 10−4; 95% CI, −5.40 × 10−4 to −1.36 × 10−4). Temporal region ePVS volume was negatively associated with age (β = −1.61 × 10−2; 95% CI, −2.14 × 10−2 to −1.09 × 10−2), as well as Chinese American (β = −2.35 × 10−1; 95% CI, −3.83 × 10−1 to −8.74 × 10−2) and Hispanic ethnicities (β = −1.73 × 10−1; 95% CI, −2.96 × 10−1 to −4.99 × 10−2).Conclusions and RelevanceIn this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

ImportanceLittle is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers.ObjectiveTo investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF).Design, Setting, and ParticipantsThe Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target InterventionsAt baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment.Main Outcomes and MeasuresThe main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest).ResultsAt baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]).Conclusions and RelevanceThis study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control.Trial RegistrationClinicalTrials.gov Identifier: NCT01206062

Key Points Question What is the association of different forms of social support with an early neuroanatomical marker of Alzheimer disease vulnerability and cognitive function? Findings In this cross-sectional study, high (vs low) availability of supportive listening was associated with cognitive resilience, which indicated better global cognitive function than expected for lower cerebral volume. This association was absent for other forms of social support. Meaning In psychosocial interventions and related public health strategies to promote neurocognitive health, precise targeting of specific forms of social support, such as supportive listening, may be warranted., Importance Cognitive resilience refers to the general capacity of cognitive processes to be less susceptible to differences in brain structure from age- and disease-related changes. Studies suggest that supportive social networks reduce Alzheimer disease and related disorder (ADRD) risk by enhancing cognitive resilience, but data on specific social support mechanisms are sparse. Objective To examine the association of individual forms of social support with a global neuroanatomical measure of early ADRD vulnerability and cognition. Design, Setting, and Participants This retrospective cross-sectional analysis used prospectively collected data from Framingham Study participants without dementia, stroke, or other neurological conditions who underwent brain magnetic resonance imaging and neuropsychological testing at the same visit. Data from this large, population-based, longitudinal cohort were collected from June 6, 1997, to December 13, 1999 (original cohort), and from September 11, 1998, to October 26, 2001 (offspring cohort). Data were analyzed from May 22, 2017, to June 1, 2021. Exposures Total cerebral volume and, as a modifying exposure variable, self-reported availability of 5 types of social support measured by the Berkman-Syme Social Network Index. Main Outcomes and Measures The primary outcome was a global measure of cognitive function. Cognitive resilience was defined as the modification of total cerebral volume’s association with cognition, such that smaller β estimates (presented in SD units) indicate greater cognitive resilience (ie, better cognitive performance than estimated by lower total cerebral volume). Results The study included 2171 adults (164 in the original cohort and 2007 in the offspring cohort; mean [SD] age, 63 [10] years; 1183 [54%] female). High listener availability was associated with greater cognitive resilience (β = 0.08, P, This cross-sectional study uses data from the Framingham Study to examine whether different forms of social support are associated with Alzheimer disease vulnerability and cognitive function.

IMPORTANCE: Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population. OBJECTIVE: To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1). EXPOSURES: Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort). MAIN OUTCOMES AND MEASURES: The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017. RESULTS: Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P

Importance Intracerebral hemorrhage (ICH) has the highest mortality of all stroke types and is the most serious complication of anticoagulation. Data regarding trends in ICH incidence and location-specific risk factors on the population level are conflicting. Objective To assess long-term population-based trends in the incidence of ICH, examine incidence rates stratified by deep and lobar locations, and characterize location-specific risk factors. Design, Setting, and Participants This longitudinal prospective community-based cohort study comprised 10 333 original participants (n = 5209; age range, 28-62 years) and offspring participants (n = 5124; age range, 5-70 years) from the Framingham Heart Study who were followed up from January 1, 1948, to December 31, 2016. Original and offspring patient cohorts were confirmed to have experienced a spontaneous ICH event through imaging or pathologic testing. A total of 129 participants were identified with a primary incident of ICH. After exclusions, the remaining 99 patients were divided into 2 nested case-control samples, which were created by stratifying the first incident of ICH by brain region (lobar ICH or deep ICH), with 55 patients included in the lobar ICH sample and 44 patients included in the deep ICH sample. Patients were matched by age and sex (1:4 ratio) with 396 individuals without any stroke event (the control group). No participant in the patient samples was excluded or approached for consent, as their initial consent to participate in the Framingham Heart Study included consent to follow-up of cardiovascular outcomes. Data were analyzed in October 2019. Main Outcomes and Measures The unadjusted and age-adjusted ICH incidence rates, assessed in 3 periods (period 1, from 1948-1986; period 2, from 1987-1999; and period 3, from 2000-2016) to study incidence trends. Nested case-control samples were used to examine baseline risk factors and medication exposures with the incidence of ICH events located in the lobar and deep brain regions within the 10 years before participants experienced a stroke event. Results Of 10 333 original and offspring participants in the Framingham Heart Study, 129 patients (72 women [55.8%]; mean [SD] age, 77 [11] years) experienced a primary ICH incident during a follow-up period of 68 years (301 282 person-years), with an incidence rate of 43 cases per 100 000 person-years. The unadjusted incidence rate increased over time, but the age-adjusted incidence rate decreased slightly between periods 2 and 3. An age-stratified analysis indicated a continued increase in ICH incidence among patients 75 years and older, reaching 176 cases per 100 000 person-years in period 3. A concurrent 3-fold increase in the use of anticoagulant medications was observed, from 4.4% in period 2 to 13.9% in period 3. The incidence rate increased substantially with age for both lobar and deep ICH. Higher systolic and diastolic blood pressure and statin medication use (odds ratio [OR], 4.07; 95% CI, 1.16-14.21;P = .03) were associated with the incidence of deep ICH. Higher systolic blood pressure and apolipoprotein E e4 allele homozygosity (OR, 3.66; 95% CI, 1.28-10.43;P = .02) were associated with the incidence of lobar ICH. Conclusions and Relevance This study found that the incidence of ICH increased in the oldest patients. Hypertension is a treatable risk factor for both deep and lobar ICH, while the use of statin medications is associated with the risk of a deep ICH event.

IMPORTANCE: 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. OBJECTIVE: To investigate the use of plasma total tau as a blood biomarker for dementia and related endophenotypes. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Plasma total tau level measured using single-molecule array technology. MAIN OUTCOMES AND MEASURES: Incidence of dementia of any cause (all dementia) and dementia due to clinical Alzheimer disease (AD dementia). RESULTS: 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

Importance Dementia risk may be attenuated by physical activity (PA); however, the specific activity levels optimal for dementia prevention are unclear. Moreover, most older adults are unable to meet the nationally recommended PA guidelines, set at 150 minutes of moderate to vigorous PA per week. Objective To assess the association of total steps walked per day and total dose (intensity × duration) of PA with brain volumes on magnetic resonance imaging (MRI) among Framingham Heart Study participants. Design, Setting, and Participants This cross-sectional, community-based cohort study of the association of accelerometry-determined PA with brain MRI measures in Framingham, Massachusetts, included the Framingham Heart Study third-generation (examination 2, 2008-2011) and offspring (examination 9, 2011-2014) cohorts. Of 4021 participants who agreed to wear an accelerometer and had valid data (≥10 hours/day for ≥3 days), 1667 participants who did not undergo brain MRI (n = 1604) or had prevalent dementia or stroke (n = 63) were excluded. Data analysis began in 2016 and was completed in February 2019. Exposures Physical activity achieved using accelerometry-derived total activity (steps per day) and 2 intensity levels (light intensity and moderate to vigorous intensity). Main Outcomes and Measures Differences in total brain volume and other MRI markers of brain aging. Results The study sample of 2354 participants had a mean (SD) age of 53 (13) years, 1276 (54.2%) were women, and 1099 (46.7%) met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging (β estimate, 0.22; SD, 0.07;P = .003). Among individuals not meeting the PA guidelines, each hour of light-intensity PA (β estimate, 0.28; SD, 0.11;P = .01) and achieving 7500 steps or more per day (β estimate, 0.44; SD, 0.18;P = .02) were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume. Conclusions and Relevance Every additional hour of light-intensity PA was associated with higher brain volumes, even among individuals not meeting current PA guidelines. These data are consistent with the notion that the potential benefits of PA on brain aging may accrue at a lower, more achievable level of intensity or duration.

Background Elevated plasma total homocysteine (tHcy) levels have been associated with increased risk of dementia and stroke, but it is uncertain whether the mediating mechanisms are predominantly cellular, vascular, or both. Objective To evaluate the relationship between tHcy levels and findings at brain magnetic resonance imaging (MRI) in a community-based sample. Design Our sample comprised 1965 participants in the Framingham Offspring Study (1050 women; mean [SD] age, 62 [9] years) who were free of clinical stroke, dementia, or other neurologic disease affecting brain MRI and for whom at least 1 measurement of plasma tHcy level (1991-2001) and a brain MRI (1999-2002) were available. We used multivariate regression analysis to relate initial (1991-1995) and concurrent (1998-2001) plasma tHcy levels to total cerebral brain volume and lobar volumes as measures of neuronal loss and atrophy and to the presence or absence of silent brain infarcts and extensive white matter hyperintensity (log–white matter intensity ≥1 SD above the age-adjusted mean) as separate measures of vascular injury. Results Mean total cerebral brain volume was 78%. At MRI, 218 participants had silent brain infarcts and 250 demonstrated extensive white matter hyperintensity. Participants with a plasma tHcy level in the highest age- (−0.37%, P = .01) or sex-specific (−0.48%, P P = .02) and concurrent tHcy levels, with smaller frontal (−0.14%, P = .001) and temporal lobar (−0.10%, P = .04) volumes. Prevalence of extensive white matter hyperintensity did not differ according to initial or concurrent plasma tHcy levels (relative risk, both 1.0; 95% confidence interval, 0.7-1.4 and 0.8-1.4, respectively). Conclusions Higher plasma tHcy levels are associated with smaller brain volume and the presence of silent brain infarcts at MRI, even in healthy, middle-aged adults. Thus, both cellular and vascular mechanisms may underlie the association of plasma tHcy level with brain aging, as reflected by the effects on both subclinical and overt disease.

ContextThe long-term risk for developing hypertension is best described by the lifetime risk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown.ObjectivesTo estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk.Design, Setting, and ParticipantsCommunity-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline (1976-1998).Main Outcome MeasuresResidual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of antihypertensive medications.ResultsThe residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (≥140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants. The lifetime probability of receiving antihypertensive medication was 60%. The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residual lifetime risk for stage 2 high blood pressure or higher (≥160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure.ConclusionThe residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension.

Importance 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. Objective 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. Design, Setting, and Participants 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). Main Outcomes and Measures Ten-year incidence of dementia and AD. Results 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. Conclusions and Relevance 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.

Objective To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A 2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. Design Prospective cohort study. Setting Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. Participants Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. Main Outcome Measures We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ϵ4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. Results Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P = .054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P = .050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P = .04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P = .01) as compared with those with values less than the median. Conclusion In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Context The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes β-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). Objective To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. Design, Setting, and Participants Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. Main Outcome Measure Incidence of dementia and AD during follow-up until December 31, 2007. Results During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. Conclusion Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.

Background Clinical hypo- and hyperthyroidism are recognized causes of reversible dementia but prior studies relating thyroid stimulating hormone (TSH) levels to cognitive performance in clinically euthyroid persons have yielded inconsistent results.

Objective To examine the relationship between white matter hyperintensity (WMH) volume on magnetic resonance images and cognitive tests in a large, population-based sample. Methods Quantitative magnetic resonance imaging and neuropsychological evaluations were performed in 1820 dementia- and stroke-free participants from the Framingham Offspring Cohort. The WMH volume relative to total cranial volume was computed; WMH volumes more than 1 SD above the age-predicted mean were defined as large. Adjusting for age, sex, education, height, and Framingham Stroke Risk Profile, we examined the relationship between WMH and 3 cognitive factors derived from a neuropsychological test battery (verbal memory, visuospatial memory and organization, and visual scanning and motor speed) and 3 individual measures of new learning, abstract reasoning, and naming. Results Compared with those with no or little WMH volume, participants with large WMH volume performed worse on the cognitive factors of visuospatial memory and organization (P = .04) and visual scanning and motor speed (P = .01), as well as on new learning (P = .04), but not on verbal memory (P = .52). Conclusions In this younger community-based population of nondemented individuals, those with large WMH volume, as compared with those with less or no WMH volumes, performed significantly worse in cognitive domains generally associated with frontal lobe systems and, to a lesser extent, the medial temporal area. Further study will clarify whether large WMH volume and associated cognitive impairment lead to future risk of stroke or dementia.

Background Some, but not all, studies have suggested that estrogen replacement therapy has a beneficial effect on cognition in postmenopausal women. Bone mineral density (BMD) is a potential surrogate marker for cumulative estrogen exposure and has been associated with cognitive performance and risk of cognitive deterioration. Objective To examine whether low BMD in elderly individuals is associated with an increased risk of developing Alzheimer disease (AD). Design, Setting, and Participants Community-based prospective cohort study of 987 subjects (610 women) who were cognitively intact and had baseline BMD measured at the femoral neck, the trochanter, and the radial shaft between 1988 and 1989. Main Outcome Measures Incidence of AD and all-cause dementia during an 8-year follow-up period. Results Women in the lowest quartile of femoral neck BMD had more than twice the incidence of AD (hazard ratio, 2.04; 95% confidence interval, 1.11-3.75) and all-cause dementia (hazard ratio, 2.01; 95% confidence interval, 1.16-3.49) compared with those in higher quartiles after adjusting for age, sex, apolipoprotein E e4, baseline homocysteine level, education, estrogen use, smoking, and stroke. A similar but statistically nonsignificant relationship was observed between BMD of the femoral trochanter and AD, while no such relationship was seen between radial BMD and AD or all-cause dementia. In men, there was a trend toward an inverse relationship between BMD and the risk of AD, but the relationship was not statistically significant at any of the 3 sites. Conclusions Low femoral neck BMD was associated with approximately 2 times the risk of AD and all-cause dementia in women but not men, suggesting the possibility that cumulative estrogen exposure may influence the risk of developing AD. Additional studies are needed to confirm this correlation.

Background Previous studies examining the association of plasma cholesterol levels with the risk for development of Alzheimer disease (AD) have been inconclusive. We examined the impact of baseline and lifetime plasma total cholesterol levels averaged across many years on the risk for AD in a large, population-based cohort. Methods Five thousand two hundred nine subjects from the Framingham Study original cohort underwent biennial evaluation for cardiovascular risk factors since 1950, with estimations of serum total cholesterol levels at 19 of these 25 biennial examinations. The study sample consisted of 1026 subjects from this cohort who were alive and free of stroke and dementia at examination cycle 20 (1988-1989) and had undergone apolipoprotein E (APOE) genotyping. The main outcome measure was incident AD diagnosed using standard criteria, according to average total cholesterol levels across biennial examination cycles 1 to 15 and baseline total cholesterol level measured at the 20th biennial examination cycle. Results Alzheimer disease developed in 77 subjects from 1992 to 2000. After adjustment for age, sex,APOEgenotype, smoking, body mass index (calculated as weight in kilograms divided by the square of height in meters), coronary heart disease, and diabetes, we found no significant association between the risk for incident AD and average cholesterol level at biennial examination cycles 1 to 15 (hazard ratio per 10-mg/dL [0.3-mmol/L] rise, 0.95; 95% confidence interval, 0.87-1.04) or baseline total cholesterol level at examination 20 (hazard ratio, 0.97; 95% confidence interval, 0.90-1.05). Conclusion In this large, population-based cohort, baseline and long-term average serum total cholesterol levels were not associated with the risk for incident AD.