It is increasingly recognized that although clinical manifestations of many neurological disorders occur in later decades, an individual's susceptibility to disease is determined early in life. In the Framingham Heart Study, we have identified genetic, cardiovascular risk factor and biomarker data related to the subsequent development of AD in our Original Gen1, elderly cohort that are also associated with structural and cognitive endophenotypes (heritable intermediate phenotypes) in our Offspring Gen2, middle aged cohort. In the proposed MRI, Genetic, Cognitive &Biomarker Precursors of AD &Dementia in Young Adults grant we hypothesize that the structural and cognitive continuum we have observed in our younger Gen2 participants represents the lengthening of a continuum that begins even earlier in life and will be extended to this still younger Gen3 cohort. Gen 3 represents a richly characterized group of young-adults in whom dense genotyping, comprehensive biomarker and abundant vascular risk factor, documented family occurrence of disease such as AD and dementia, and subclinical atherosclerosis data are available. Our primary goal is to characterize brain morphology on MRI and cognitive function in the Gen3 cohort, specifically previously identified endophenotypes of AD and dementia (such as total and regional brain volumes, white matter lesions, and regional quantitative measures of the hippocampal and entorhinal cortex as well as memory and executive function.) We predict within this younger Gen3 cohort there is an identifiable continuum of structural and cognitive indices linked to dementia and brain aging. We will also relate previously measured vascular, metabolic, inflammatory, family occurrence of AD/dementia and other risk factor data already available on these subjects to the range of structural and functional AD/dementia endophenotypes. We posit that a subset of the risk factors previously identified in the older Gen2 cohort will show similar associations in Gen 3. Further we anticipate uncovering additional risk factors related to AD/dementia endophenotypes unique to this younger cohort. Finally, we will utilize the extensive genetic resources currently available in all three generations of the Framingham cohorts to uncover age-specific genetic effects, gene environment interactions and novel genetic relationships. This application represents a resource-effective mechanism to leverage the wealth of genetic, risk factor and biomarker data collected in this younger adult community-based population to greatly enrich our understanding of preclinical AD and pathophysiology of disease.

Public Health Relevance

The primary objective of the proposed project, MRI, Cognitive, Genetic &Biomarker Precursors of AD &Dementia in Young Adults is to identify the earliest indicators of a propensity to develop AD and dementia in later life. To accomplish this goal we seek to establish, within the Framingham Heart Study's third generation cohort, baseline measures of brain morphology and cognitive function that have been linked to AD/dementia. We will relate these data to previously measured risk factors and biomarkers already available on these subjects to determine a """"""""pre-MCI"""""""" continuum of structural and functional indices of AD and dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033040-02
Application #
7756617
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Anderson, Dallas
Project Start
2009-01-15
Project End
2013-12-31
Budget Start
2010-03-15
Budget End
2010-12-31
Support Year
2
Fiscal Year
2010
Total Cost
$1,357,609
Indirect Cost
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Neu, Scott C; Pa, Judy; Kukull, Walter et al. (2017) Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol 74:1178-1189
Pase, Matthew P; Seshadri, Sudha; Jacques, Paul F (2017) Response by Pase et al to Letter Regarding Article, ""Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study"". Stroke 48:e181
Romero, José R; Beiser, Alexa; Himali, Jayandra J et al. (2017) Cerebral microbleeds and risk of incident dementia: the Framingham Heart Study. Neurobiol Aging 54:94-99
Saber, Hamidreza; Himali, Jayandra J; Beiser, Alexa S et al. (2017) Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study. Stroke 48:1760-1765
Bangen, Katherine J; Preis, Sarah R; Delano-Wood, Lisa et al. (2017) Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study. Alzheimer Dis Assoc Disord :
Chibnik, Lori B; Wolters, Frank J; Bäckman, Kristoffer et al. (2017) Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. Eur J Epidemiol 32:931-938
Dufouil, Carole; Beiser, Alexa; McLure, Leslie A et al. (2017) Revised Framingham Stroke Risk Profile to Reflect Temporal Trends. Circulation 135:1145-1159
Maillard, Pauline; Mitchell, Gary F; Himali, Jayandra J et al. (2017) Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity: A Continuum of Injury. Stroke 48:1567-1573
Adams, Shayna; Conner, Sarah; Himali, Jayandra J et al. (2017) Vascular risk factor burden and new-onset depression in the community. Prev Med :
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

Showing the most recent 10 out of 41 publications