Funded by NIA since 1989, the Epidemiology of Dementia Study has focused on identifying incident cases of dementia and determining the risk factors associated with clinical dementia, particularly Alzheimer's disease (AD) in the large prospective community-based Framingham Study. Beginning with the establishment of a dementia-free cohort in 1976-78, this study has documented >600 subjects with incident dementia, largely from the Original cohort recruited in 1948. In recent years, with the aging of the children of the Original cohort (and their spouses), a number of these Generation 2 subjects have been documented to have cognitive decline, and MRI markers of brain injury as well as Mild Cognitive Impairment (MCI) and dementia. We have provided community-based estimates of incidence and lifetime risk of AD, the risk of dementia following stroke, and have identified a number of lifestyle, vascular, novel biomarker and more recently genetic risk factors for AD. Through an ongoing brain donation program established in 1995, we have performed detailed neuropathologic examination of approximately 140 brains. In this application we will focus on identifying persons with subclinical disease by intensifying surveillance to identify subjects with probable MCI and will follow them with annual assessments. We will relate a wealth of previously collected risk factors to the risk of incident AD and all-dementia, to AD endophenotypes, and to the risk of conversion from MCI to clinical AD. These risk factors include genetic (genome-wide, candidate gene and gene expression) and environmental (lifestyle, vascular, metabolic measures gathered repeatedly since midlife) data, circulating biomarker levels and baseline imaging data. To this array of putative risk markers we propose to add: (1) a key biomarker, circulating beta-amyloid (A240 and A242) levels;(2) a third round of quantitative brain MRI and NP testing to more precisely document change, and distinguish those with consistent signs of brain atrophy and cognitive decline at highest risk of transitioning to MCI and/or dementia;and, (3) detailed post-processing MR analyses of additional regions of interest from prior and newly acquired MRI images to enhance detection of subtle changes in brain morphology over time. The goal is to incorporate these new and existing data into a risk prediction score for AD and dementia and validate it in an independent epidemiological cohort.
The aim of this risk profile is to identify persons at highest risk for developing AD, thus permitting targeted preventive and therapeutic interventions, including enrollment of susceptible subjects for clinical trials of promising therapies.

Public Health Relevance

Funded by NIA since 1989, the Epidemiology of Dementia Study has focused on determining the incidence and risk factors predisposing to dementia generally, and Alzheimer's disease (AD) specifically, in a large, multi-generational, community-based prospective epidemiologic study. Since detecting early disease is important for effective prevention, we have recently focused on identifying persons with Mild Cognitive Impairment (MCI). We have studied participants, with two sets of brain MRI and cognitive tests done 5 years apart. In this renewal we have added a key biomarker (beta-amyloid), better imaging and cognitive data. We propose to develop a dementia (and AD) risk score based on these new data, and on the genetic, lifestyle, vascular, metabolic, biomarker and imaging data already available (collected over 4-6 decades). The purpose of this risk score is to accurately identify high-risk persons for enrollment in preventive and treatment trials.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-PSE-H (03))
Program Officer
Anderson, Dallas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Pase, Matthew P; Beiser, Alexa; Enserro, Danielle et al. (2016) Association of Ideal Cardiovascular Health With Vascular Brain Injury and Incident Dementia. Stroke 47:1201-6
Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17
Konukoglu, Ender; Coutu, Jean-Philippe; Salat, David H et al. (2016) Multivariate statistical analysis of diffusion imaging parameters using partial least squares: Application to white matter variations in Alzheimer's disease. Neuroimage 134:573-86
Ibrahim-Verbaas, C A; Bressler, J; Debette, S et al. (2016) GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Mol Psychiatry 21:189-97
Hankee, Lisa D; Preis, Sarah R; Piers, Ryan J et al. (2016) Population Normative Data for the CERAD Word List and Victoria Stroop Test in Younger- and Middle-Aged Adults: Cross-Sectional Analyses from the Framingham Heart Study. Exp Aging Res 42:315-28
Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; Stroke Genetics Network (SiGN); International Stroke Genetics Consortium (ISGC) (2016) Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol 15:695-707
Romero, José R; Preis, Sarah R; Beiser, Alexa et al. (2016) Carotid Atherosclerosis and Cerebral Microbleeds: The Framingham Heart Study. J Am Heart Assoc 5:e002377
Spartano, Nicole L; Himali, Jayandra J; Beiser, Alexa S et al. (2016) Midlife exercise blood pressure, heart rate, and fitness relate to brain volume 2 decades later. Neurology 86:1313-9
Satizabal, Claudia L; Beiser, Alexa S; Chouraki, Vincent et al. (2016) Incidence of Dementia over Three Decades in the Framingham Heart Study. N Engl J Med 374:523-32
Weinstein, Galit; Beiser, Alexa S; Preis, Sarah R et al. (2016) Plasma clusterin levels and risk of dementia, Alzheimer's disease, and stroke. Alzheimers Dement (Amst) 3:103-9

Showing the most recent 10 out of 227 publications