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1.  Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure 
Background and Purpose
Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging (MRI).
Methods
Framingham Offspring Study participants who attended the seventh examination, were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter (PM2.5) and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age) and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends.
Results
A 2 μg/m3 increase in PM2.5 was associated with -0.32% (95%CI: -0.59, -0.05) smaller total cerebral brain volume and 1.46 (95%CI: 1.10, 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95%CI: 0.01, 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter.
Conclusions
Exposure to elevated levels of PM2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia-and stroke-free persons.
doi:10.1161/STROKEAHA.114.008348
PMCID: PMC4414870  PMID: 25908455
air pollution; white matter disease; brain imaging
2.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
BACKGROUND
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
doi:10.1016/j.biopsych.2014.08.027
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
3.  Low Cardiac Index is Associated with Incident Dementia and Alzheimer’s Disease: The Framingham Heart Study 
Circulation  2015;131(15):1333-1339.
Background
Cross-sectional epidemiological and clinical research suggest lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults.
Methods & Results
1039 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia formed our sample (69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, cardiovascular disease [CVD] history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac MRI-assessed cardiac index (cardiac output/body surface area) to incident all-cause dementia and Alzheimer’s disease (AD). Over the median 7.7 year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each one standard deviation unit decrease in cardiac index increased the relative risk of both dementia (HR=1.66; 95% confidence intervals [CI], 1.11–2.47; p=0.013) and AD (HR=1.65; 95% CI, 1.07–2.54; p=0.022). Compared to normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02–4.19; p=0.044). If participants with clinically prevalent CVD and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34–6.36; p=0.007) and AD (HR=2.87; 95% CI, 1.21–6.80; p=0.016) compared to individuals with normal cardiac index.
Conclusions
Lower cardiac index is associated with an increased risk for the development of dementia and AD.
doi:10.1161/CIRCULATIONAHA.114.012438
PMCID: PMC4398627  PMID: 25700178
blood circulation; brain; cardiac output; hemodynamics; dementia; Alzheimer disease
4.  Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis 
Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.
doi:10.3233/JAD-150543
PMCID: PMC4827707  PMID: 26639959
Alzheimer’s disease; cognition; dyslexia; learning disorders; memory disorders; mild cognitive impairment; neuropsychological tests
5.  Midlife Hypertension Risk and Cognition in the Non-Demented Oldest Old: Framingham Heart Study 
Midlife cardiovascular risk, hypertension (HTN) in particular, has been related cross-sectionally to poorer neuropsychological (NP) performance in middle age and older adults. This study investigated whether a similar relationship persists between midlife HTN or systolic blood pressure (SBP) and NP performance approximately 30 years later. 378 Framingham stroke and dementia-free Original cohort participants, with HTN and SBP ascertained between 50–60 years of age (mean age 55 ± 1, 65% women), were administered a NP assessment at age ≥80 years. Tests included Logical Memory, Visual Reproduction, Paired Associate, Hooper Visual Organization Test, Trail Making A & B, Digit Span Forward and Backward, Controlled Word Association Test (COWAT), and Similarities. Multivariable linear regression, adjusted for age, time interval between risk factor and NP testing, gender, and premorbid intelligence, assessed association between midlife HTN/SBP and NP outcomes. Midlife HTN was not significantly associated with NP outcome measures. Midlife SBP was associated with poorer Digit Span Forward and COWAT performance (p < 0.05). No significant interaction of age on HTN/SBP to NP associations was found. There was a significant interaction between ApoE4 status and SBP in their effects on COWAT (pinteraction = 0.074); SBP was negatively associated with COWAT only in those with the ApoE4 allele (p = 0.025). While midlife HTN is not associated with late life cognitive impairment, midlife SBP is related to late life attention and verbal fluency impairments, particularly among ApoE4+ individuals. These results offer insight into processes that are operative in the absence of overt cognitive impairment and dementia.
doi:10.3233/JAD-141881
PMCID: PMC4827717  PMID: 26402768
Apolipoprotein E4; blood pressure; cognition; executive function; hypertension; memory; neuropsychological assessment
6.  Midlife Cardiovascular Risk Impacts Memory Function: The Framingham Offspring Study 
Introduction
This study incorporates unique error response analyses with traditional measures of memory to examine the association between mid-life cardiovascular risk factors (CVRF) and later-life memory function.
Methods
The Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was assessed in 1755 Framingham Offspring participants (54% women, mean age=54±9 years) from 1991-1995. Memory tests including Logical Memory (LM) and Visual Reproductions (VR) were administered from 2005-2008. Linear and logistic regression examined the association between FSRP and memory measures. Interaction between presence of the ApoE4 allele and each FSRP component on the memory measures was also assessed.
Results
FSRP and the individual components of age, sex, and smoking were related to lower standard scores of memory. The new error response analyses reinforced the standard analyses and also identified new relationships. Participants with diabetes were found to make more errors on LM, and those with a history of smoking were found to make more errors on VR. Lastly, ApoE4+ smokers experienced significant verbal memory loss whereas ApoE4- smokers did not.
Conclusion
Middle-aged healthy adults with CVRF including diabetes, history of smoking, and ApoE4 positivity were found to have greater later-life memory impairments.
doi:10.1097/WAD.0000000000000059
PMCID: PMC4345145  PMID: 25187219
Neuropsychological assessment; Memory; Mild cognitive impairment; ApolipoproteinE allele 4
7.  Gender and incidence of dementia in the Framingham Heart Study from mid-adult life 
Background
Gender-specific risks for dementia and Alzheimer's Disease (AD) starting in midlife remain largely unknown.
Methods
Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD, based on the Kaplan-Meier method (Cumulative Incidence) or accounting for competing risk of death (lifetime risk, LTR).
Results
Overall, 777 incident dementia (601 AD) occurred in 7,901 participants (4,333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women >85. LTR of dementia/AD at age 45 was 1 in 5 in women, 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from ~6 at 45-54 to <2 after age 65.
Conclusion
Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.
doi:10.1016/j.jalz.2013.10.005
PMCID: PMC4092061  PMID: 24418058
incidence of dementia; Alzheimer's disease; gender; mortality; cardiovascular risk profile; selective survival; cohort/population-based cohort; prevention
8.  Plasma amyloid β and risk of Alzheimer’s disease in the Framingham Heart Study 
Background
Plasma amyloid β (Aβ) peptides levels have been examined as a low-cost, accessible marker for risk of incident Alzheimer’s disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date.
Methods
A total of 2189 dementia-free, Framingham Study participants over age 60 years (mean age 72±8; 56% women) had plasma Aβ1-42 and Aβ1-40 measured and were followed prospectively (mean 7.6±3.0 years) for dementia/AD.
Results
Increased plasma Aβ1-42 levels were associated with lower risk of dementia (Hazard ratios: Aβ1-42 HR=0.80 [0.71–0.90], p<0.001; Aβ1-42/Aβ1-40 ratio HR=0.86 [0.76–0.98], p=0.027) and AD (Aβ1-42 HR=0.79 [0.69–0.90], p<0.001; Aβ1-42/Aβ1-40 ratio HR=0.83 [0.72–0.96], p=0.012).
Conclusion
Our results suggest that lower plasma Aβ levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma Aβ levels as a biomarker for risk of developing clinical AD and dementia.
doi:10.1016/j.jalz.2014.07.001
PMCID: PMC4362883  PMID: 25217292
Aβ peptides; plasma biomarker; incident Alzheimer’s disease; incident dementia; Framingham heart study; epidemiology; meta-analysis
9.  APOE and mild cognitive impairment: the Framingham Heart Study 
Age and Ageing  2014;44(2):307-311.
Background: the risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI.
Setting: a community-based cohort study.
Methods: using two psychometric neuropsychological impairment definitions, we examined APOE4 and prevalent MCI among older adults or pre-MCI among middle-aged adults. Neuropsychological, clinical and genetic data were collected on 2,239 Framingham Offspring Cohort participants free from clinical stroke or dementia (62 ± 9 years; 54% women). Prevalent amnestic MCI was defined from neuropsychological performances ≥1.5 SD below the mean based on (i) age and education or (ii) age and Wide Range Achievement Test-3 Reading (WRAT-3 Reading) performance adjustment.
Results: in the entire sample, multivariable-adjusted logistic regressions found that APOE4 was associated with amnestic MCI when using the age and WRAT Reading definition (odds ratio [OR] = 1.7, P = 0.002) but not the age and education definition (OR = 1.0, P = 0.90). Results were modified by age, such that APOE4 was associated with amnestic MCI in participants ≥65 years using both the age and WRAT Reading definition (OR = 2.4, P < 0.001) and the age and education definition (OR = 1.7, P = 0.04).
Conclusion: APOE4 risk for prevalent amnestic MCI varies depending on the definition of objective neuropsychological impairment for MCI. Our findings support existing literature emphasising the need to refine MCI neuropsychological profiling methods.
doi:10.1093/ageing/afu183
PMCID: PMC4400527  PMID: 25497326
Alzheimer's disease; APOE; genetic risk; mild cognitive impairment; older people; risk factors
10.  Lipid and lipoprotein measurements and the risk of ischemic vascular events 
Neurology  2015;84(5):472-479.
Objectives:
To examine the relationship between plasma lipid measurements and incident ischemic vascular events (ischemic stroke [IS], and as a positive control, myocardial infarction [MI]) in a community cohort.
Methods:
In 6,276 stroke-free Framingham participants (aged 64 ± 10 years, 56% female), we related plasma lipid levels (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and TC/HDL-C ratio) measured at the original cohort 15th (1977–1979) and 20th examination cycles (1986–1990) and (TC, HDL-C, TC/HDL-C ratio, triglycerides [TG], and low-density lipoprotein cholesterol [LDL-C]) measured at the offspring fourth examination (1995–1998), to 10-year risk of incident IS and MI. Utilizing genome-wide genotyping in the same subjects, we used mendelian randomization methods to assess whether observed associations were incidental or causal.
Results:
During a mean follow-up of 9 years, 301 participants experienced incident IS. In multivariable-adjusted analyses, HDL-C ≤40 mg/dL and TC/HDL ratio ≥5 were associated with increased risk of IS (hazard ratio [95% confidence interval]: 1.59 [1.23–2.05], p < 0.001 and 1.47 [1.15–1.87], p < 0.001), but not TC or LDL-C. In adjusted analysis, a strong association between TG and IS was diminished. In the MI-free sample (n = 5,875, aged 64 ± 10 years, 58% female; 403 MI events), all lipid markers were associated with MI risk. A genetic risk score comprising 47 known determinants of circulating HDL-C was not associated with IS.
Conclusions:
In a middle-aged to elderly community sample, we observed that low HDL-C and high TC/HDL-C ratio, but not LDL-C or TG were associated with risk of incident IS. We observed the usual associations between lipids and risk of MI. Our findings suggest an important, but less likely causal, role of HDL-C over other lipid biomarkers for optimal stroke risk stratification.
doi:10.1212/WNL.0000000000001202
PMCID: PMC4336066  PMID: 25568296
11.  Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes 
European Heart Journal  2014;35(42):2980-2987.
Aims
Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD).
Methods and results
In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32–2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08–3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42–1.53; P = 0.51) of subclinical CVD (Pinteraction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure.
Conclusion
Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.
doi:10.1093/eurheartj/ehu052
PMCID: PMC4271053  PMID: 24574370
Carbon monoxide; Subclinical vascular disease; Cardiovascular outcomes
12.  Cognitive Performance after Stroke – The Framingham Heart Study 
Background
Individuals with a high risk of stroke are also more prone to cognitive impairment perhaps due to concomitant vascular risk factors. In addition, clinical stroke increases the risk of subsequent dementia. Nevertheless, the relationship between clinical stroke and subsequent cognitive function in initially non-demented individuals remains less clear as most prior studies examined case series without controls.
Aims
To specify among non-demented individuals the cognitive domains affected by clinical stroke, independently of vascular risk factors and pre-stroke cognition.
Methods
One hundred-thirty-two Framingham Study participants (mean age=77±9 years, 54% women) with prospectively validated initial strokes, as well as age- and sex-matched controls, underwent identical cognitive evaluations ~6 months after the stroke. Linear regression models were used to assess the differences in cognitive scores between stroke cases and controls adjusting for pre-stroke cognitive function as assessed by Mini-Mental State Examination scores, and with and without adjustment for vascular risk factors.
Results
Adjusting for pre-stroke cognition and vascular risk factors, persons with stroke had poorer cognitive function in the domains of immediate recall of logical and visual memories (β=−1.27±0.60; P=0.035, β=−1.03±0.47; P=0.028, respectively), verbal learning (paired associate test; β=−1.31±0.57; P=0.023), language (Boston naming test; β=−0.27±0.08; P=0.002), executive function (Digit span backwards; β=−0.53±0.21; P=0.015) and visuo-spatial and motor skills (block design; β=−3.02±1.06; P=0.005).
Conclusions
Clinical stroke is associated with subsequent poorer performance in multiple cognitive domains. This association cannot be entirely explained by the individual’s cognitive function prior to stroke or by concomitant vascular risk factor levels.
doi:10.1111/ijs.12275
PMCID: PMC4215163  PMID: 25352473
cerebrovascular disease; stroke related outcomes; cognitive function; vascular risk factors; neuropsychology matched cohort study
13.  Association between neuropathology and brain volume in the Framingham Heart Study 
Studies of clinical and community cohorts have shown that antemortem imaging measures of hippocampal volume have correlated with postmortem Alzheimer's pathology. Fewer studies have examined the relationship between both Alzheimer's and cerebrovascular pathology, and antemortem brain imaging. The aim of this study was to correlate antemortem brain magnetic resonance imaging (MRI) volumes with postmortem brain pathology (both Alzheimer-related and cerebrovascular) in a community-derived cohort from the Framingham Heart Study (FHS). Participants (n=59) from the FHS were included if they were enrolled in the brain autopsy program and underwent antemortem clinical evaluation, neuropsychological testing and brain MRI. Cortical neurofibrillary tangle pathology correlated with lower total cerebral brain (beta±SE=−0.04±0.01, p=0.004) and hippocampal volumes (beta±SE=−0.03±0.02, p=0.044) and larger temporal horns (log-transformed, beta±SE=0.05±0.01, p=0.001). Similar findings were seen between total/cortical neuritic plaques and total cerebral brain and temporal horn volume. White matter hyperintensities (also log-transformed) were best predicted by the presence of deep nuclei microinfarcts (beta±SE=0.53±0.21, p=0.016), whereas hippocampal volume was significantly decreased in the presence of hippocampal sclerosis (beta±SE =−1.23±0.30, p<0.001). This study showed that volumetric MRI measures correlated with postmortem Alzheimer-related and cerebrovascular neuropathology in this community-derived cohort, confirming that these MRI measures are important antemortem surrogates for these dementia-related pathologies.
doi:10.1097/WAD.0000000000000032
PMCID: PMC4139422  PMID: 24614264
14.  Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy 
Neurology  2014;82(18):1613-1619.
Objective:
To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages.
Methods:
Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity.
Results:
Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively).
Conclusion:
Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.
doi:10.1212/WNL.0000000000000382
PMCID: PMC4013812  PMID: 24706014
15.  Parental longevity is associated with cognition and brain ageing in middle-aged offspring 
Age and Ageing  2013;43(3):358-363.
Background: offspring of long-lived individuals have lower risk for dementia. We examined the relation between parental longevity and cognition and subclinical markers of brain ageing in community-dwelling adult offspring.
Methods: offspring participants with both parents in the Framingham Heart Study, aged ≥55 years and dementia-free underwent baseline and repeat neuropsychological (NP) testing and brain magnetic resonance imaging (MRI). Parental longevity was defined as having at least one parent survive to age ≥85 years. To test the association between parental longevity and measures of cognition and brain volumes, we used multivariable linear and logistic regression adjusting for age, sex, education and time to NP testing or brain MRI.
Results: of 728 offspring (mean age 66 years, 54% women), 407 (56%) had ≥1 parent achieve longevity. In cross-sectional analysis, parental longevity was associated with better scores on attention (beta 0.21 ± 0.08, P = 0.006) and a lower odds of extensive white matter hyperintensity on brain MRI (odds ratio 0.59, 95% CI: 0.38, 0.92, P = 0.019). The association with white matter hyperintensity was no longer significant in models adjusted for cardiovascular risk factors and disease. In longitudinal analysis (6.7 ± 1.7 years later), offspring with parental longevity had slower decline in attention (0.18 ± 0.08, P = 0.038), executive function (beta 0.19 ± 0.09, P = 0.031) and visual memory (beta −0.18 ± 0.08, P = 0.023), and less increase in temporal horn volume (beta −0.25 ± 0.09, P = 0.005). The associations persisted in fully adjusted models.
Conclusion: parental longevity is associated with better brain ageing in middle-aged offspring.
doi:10.1093/ageing/aft175
PMCID: PMC4001170  PMID: 24212919
brain ageing; brain imaging; cognition; longevity; neuropsychological testing; older people; parental longevity
16.  Risk Factors, Stroke Prevention Treatments, and Prevalence of Cerebral Microbleeds in the Framingham Heart Study 
Background and purpose
Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB.
Methods
We include 1,965 Framingham Original and Offspring participants (age 66.5±11.0years; 54%women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (APOE) risk factors and medication use to presence of CMB overall and stratified by brain location (deep, lobar or mixed).
Results
CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (p<0.0001) and was higher in men (p<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (p<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (p<0.05). Statin use increased risk of lobar and mixed location CMB (p<0.05). The latter association was not affected by adjustment for cholesterol levels, or concomitant medication use.
Conclusions
We observed the expected association of hypertension with deep CMB and low cholesterol and APOEε4 with lobar CMB. Additionally, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.
doi:10.1161/STROKEAHA.114.004130
PMCID: PMC4048617  PMID: 24713533
17.  Midlife Cardiovascular Risk Impacts Executive Function: Framingham Offspring Study 
Introduction
Novel error scores and traditional indices of executive function (EF) were related to cardiovascular risk factors (CVRF) measured 10–15 years earlier.
Methods
From 1991–1995, the Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was ascertained in 1755 Framingham Offspring participants (54% women, mean age= 54 ± 9 years). Participants were administered EF tests: FAS and Animals Fluency tests, Trail Making Test B (TrB), and Digit Span-Backwards (DS-B) in 2005–2009. Linear and logistic regression were used to relate the FSRP and its components to both error responses and traditional scores.
Results
Consistent with previous findings, the FSRP and the individual components diabetes and sex were associated with several traditional measures of EF. Of interest were relationships between the FSRP score and TrB Total Errors (p=0.04), DS-B % Total Errors (p=0.02) and DS-B Capacity Score (p=0.03), and prevalent CVD related to making FAS Perseverations in the 75th percentile (p=0.03). By comparison, FSRP and CVD were not related to the traditional DS-B or FAS scores. Additionally, age was associated with higher Animals % Total Errors and % Perseverations among ApoE4+ individuals and with higher TrB Total Errors among ApoE4− individuals.
Conclusion
For those middle-aged and healthy, including those ApoE4+, CVRF are related to impairments in EF as ascertained by novel errors as well as traditional measures.
doi:10.1097/WAD.0b013e3182a715bc
PMCID: PMC3945114  PMID: 23995818
Neuropsychological assessment; Executive function; Mild cognitive impairment; ApolipoproteinE allele 4
18.  APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline 
Vascular risk factors have been associated with cognitive decline, however, it remains unclear whether apolipoprotein E (APOE) genotype modifies this relationship. We aimed to further elucidate these relationships and extend previous findings by examining data from a more comprehensive cognitive assessment than used in prior studies. 1,436 participants from the prospective Framingham Offspring Cohort Study underwent health examination from 1991-1995, followed by a baseline neuropsychological assessment (1999-2003) and a repeat neuropsychological assessment approximately eight years later (2004-2009). Multivariate linear regression analyses were performed to examine the relationship between midlife vascular risk factors, presence of the APOE ε4 allele, and cognitive change. APOE genotype significantly modified the associations between both midlife hypertension and cardiovascular disease and decline in language abilities as well as midlife diabetes and decline in verbal memory, attention, and visuospatial abilities. Associations between increased midlife vascular risk burden and greater cognitive decline were observed among APOE ε4 carriers but not non-carriers. The present findings revealed a subgroup at increased risk for cognitive decline (APOE ε4 carriers with midlife exposure to vascular risk factors) and suggest that treatment of vascular risk factors during midlife may reduce the risk of cognitive impairment later in life, particularly among APOE ε4 carriers.
doi:10.1016/j.jstrokecerebrovasdis.2013.03.013
PMCID: PMC3849195  PMID: 23601373
Apolipoprotein E; Cognition; Vascular Risk; Aging; Diabetes; Hypertension; Cardiovascular Disease
19.  Defining MCI in the Framingham Heart Study Offspring: Education vs. WRAT-based norms 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827bde32.
Introduction
Psychometric definitions of mild cognitive impairment (MCI) typically use cut-off levels set at 1.5 standard deviations below age- and education-adjusted norms, assuming that the education adjustment accounts for premorbid abilities. However, non-cognitive factors impact educational attainment, potentially leading to incorrect categorization as MCI. We examined whether using an adjustment based on reading performance (Wide Range Achievement Test [WRAT] Reading) improved MCI diagnostic accuracy.
Methods
935 Framingham Offspring (mean age 72 ± 5) underwent tests of Memory, Executive Function, Abstraction, Language, and Visuospatial Function as part of a neuropsychological test battery. Domain-specific test scores were regressed onto age and WRAT score, or education, to define MCI. Survival analyses were used to relate baseline MCI to incident dementia.
Results
The two MCI definitions differed most for the lowest and highest education groups. The WRAT definition was more strongly associated with incident dementia for all five tests. MCI-level Abstraction performance was associated with incident dementia using the WRAT definition (HR = 3.20, p = .033), but not the education definition (HR = 1.19, p = .814).
Discussion
The WRAT should be considered along with the standard measure of years of education, as it may be a better surrogate marker of premorbid abilities.
doi:10.1097/WAD.0b013e31827bde32
PMCID: PMC3626741  PMID: 23314066
Mild cognitive impairment; premorbid abilities; neuropsychological assessment; Alzheimer's disease; longitudinal
20.  Serum BDNF and VEGF levels are associated with Risk of Stroke and Vascular Brain Injury: Framingham Study 
Stroke; a journal of cerebral circulation  2013;44(10):10.1161/STROKEAHA.113.001447.
Background and Purpose
BDNF, a major neurotrophin and VEGF, an endothelial growth factor have a documented role in neurogenesis, angiogenesis and neuronal survival. In animal experiments they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample.
Methods
In 3440 stroke/TIA-free FHS participants (mean age 65±11yrs, 56%W), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological (NP) tests available (N=1863 and 2104, respectively; mean age 61±9yrs, 55%W, in each) we related baseline BDNF and logVEGF to log-white matter hyperintensity volume (lWMHV) on brain MRI, and to visuospatial memory and executive function tests.
Results
During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age-, sex- and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (HR comparing BDNF Q1 versus Q2–4:1.47, 95%CI:1.09–2.00, p=0.012; and HR/SD increase in logVEGF:1.21, 95%CI:1.04–1.40, p=0.012). Persons with higher BDNF levels had less lWMHV (β±SE=−0.05±0.02; p=0.025), and better visual memory (β±SE=0.18±0.07; p=0.005).
Conclusions
Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.
doi:10.1161/STROKEAHA.113.001447
PMCID: PMC3873715  PMID: 23929745
BDNF; VEGF; Risk; Stroke; Brain MRI; Subclinical
21.  Brain Imaging and Cognitive Predictors of Stroke and Alzheimer Disease in the Framingham Heart Study 
Background and purpose
Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer’s disease (AD) risk.
Methods
A cognitive battery was administered to 1,679 dementia and stroke-free Framingham Offspring (age>55; mean=65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD during up to 10 years of follow-up. As a secondary analysis, we explored these associations in the FHS Original cohort (mean age 67.5±7.3 and 84.8±3.3 at the cognitive assessment and MRI examination, respectively).
Results
A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 standard-deviations below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (HR=2.27;95%CI:1.06–4.85) and AD (3.60;95%CI:1.52–8.52); additional cognitive tests also predicted AD. Participants with low (<20%ile) total brain volume and high (>20%ile) white matter hyperintensity volume had a higher risk of stroke (HR=1.97;95%CI:1.03–3.77 and HR=2.74;95%CI:1.51–5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the Offspring and Original cohorts (HR=4.41;95%CI:2.00–9.72 and HR=2.37;95%CI:1.12–5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imagingmarkers.
Conclusions
Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.
doi:10.1161/STROKEAHA.113.000947
PMCID: PMC3974341  PMID: 23920020
stroke; Alzheimer’s disease; cognitive function; brain MRI
22.  Relations of arterial stiffness and endothelial function to brain aging in the community 
Neurology  2013;81(11):984-991.
Objective:
To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.
Methods:
Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998–2001) and brain MRI and cognition (1999–2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).
Results:
Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
Conclusions:
Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.
doi:10.1212/WNL.0b013e3182a43e1c
PMCID: PMC3888200  PMID: 23935179
24.  APOE genotype and MRI markers of cerebrovascular disease 
Neurology  2013;81(3):292-300.
Objective:
We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.
Methods:
We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis.
Results:
APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size–weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008).
Conclusions:
APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.
doi:10.1212/WNL.0b013e31829bfda4
PMCID: PMC3770168  PMID: 23858411
25.  Lexical retrieval in discourse: An early indicator of Alzheimer's dementia 
Clinical linguistics & phonetics  2013;27(12):905-921.
We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS), and written description of the Cookie Theft Picture (CTP).
Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7–9 years prior to death and FAS and BNT only at 2–4 years. These results suggest that lexical-retrieval deficits in written discourse serve as an early indicator of AD.
doi:10.3109/02699206.2013.815278
PMCID: PMC4095845  PMID: 23985011
discourse; naming; early markers; neuropathology; Alzheimer's disease

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