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 #
5R01AG033040-05
Application #
8403404
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Anderson, Dallas
Project Start
2009-01-15
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$889,503
Indirect Cost
$130,366
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Seiler, Stephan; Fletcher, Evan; Hassan-Ali, Kinsy et al. (2018) Cerebral tract integrity relates to white matter hyperintensities, cortex volume, and cognition. Neurobiol Aging 72:14-22
Nishtala, Arvind; Piers, Ryan J; Himali, Jayandra J et al. (2018) Atrial fibrillation and cognitive decline in the Framingham Heart Study. Heart Rhythm 15:166-172
Bangen, Katherine J; Preis, Sarah R; Delano-Wood, Lisa et al. (2018) 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 32:50-56
Tynkkynen, Juho; Chouraki, Vincent; van der Lee, Sven J et al. (2018) Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts. Alzheimers Dement 14:723-733
Li, Jinlei; Ogrodnik, Matthew; Devine, Sherral et al. (2018) Practical risk score for 5-, 10-, and 20-year prediction of dementia in elderly persons: Framingham Heart Study. Alzheimers Dement 14:35-42
Adams, Shayna; Conner, Sarah; Himali, Jayandra J et al. (2018) Vascular risk factor burden and new-onset depression in the community. Prev Med 111:348-350
Au, Rhoda; Piers, Ryan J; Devine, Sherral (2017) How technology is reshaping cognitive assessment: Lessons from the Framingham Heart Study. Neuropsychology 31:846-861
Weinstein, Galit; Preis, Sarah R; Beiser, Alexa S et al. (2017) Clinical and Environmental Correlates of Serum BDNF: A Descriptive Study with Plausible Implications for AD Research. Curr Alzheimer Res 14:722-730
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
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

Showing the most recent 10 out of 48 publications