Protection against Alzheimer's disease (AD) dementia has two main components: protection against Alzheimer's disease pathology (ADP ? amyloid and tau) and protection against cognitive impairment despite ADP (cognitive reserve). Here, we propose an ?exceptional aging? hypothesis, where some subjects (>85 years of age) have no significant ADP and are cognitively normal due to protective factors against both ADP and cognitive decline across the lifespan. This is based on the idea that a combination of environmental, lifestyle, and genetic factors trigger the onset of AD dementia in the majority of individuals as they age but ?exceptional agers? are protected. To translate this knowledge to design successful personalized prevention and treatment trials, it is important to identify the parsimonious set(s) of protective factors and how certain individuals are able to outperform the average population trajectories, i.e., ?exceptionally age?. Our central hypothesis is that each individual's trajectory of amyloid, tau, and cognition will deviate from the average population trajectories, depending on the individual's genomic variation, lifestyle enrichment, and vascular health.
The aim of this proposal is to apply the unified theoretical framework proposed here to identify important protective factors against ADP and cognitive decline in a population-based sample and move towards personalized medicine by discovering paths to ?exceptional aging? using two independent mathematical models (association rule mining and structural equation models). We will utilize the existing infrastructure of the population-based, longitudinal Mayo Clinic Study of Aging (MCSA) (individuals aged 60-90 years) which collects imaging surrogates of amyloid (PiB PET) and tau (tau PET), neuropsychological exams, lifestyle enrichment (midlife cognitive and physical activity), and APOE gene status. We will also utilize the Rochester Epidemiology Project (REP) which maintains a comprehensive medical records-linkage system (since 1965), to abstract additional information from the electronic medical records: longitudinal lab tests (lipid panel), blood pressure, medications, BMI, and diagnosis of cardiac and metabolic conditions (CMCs) up to 20 years before the amyloid and tau scans. Lastly, we will add a comprehensive screen of genetic variation related to ADP, related neurodegenerative disorders, and aging with the latest SNP-based array (NeuroX2).

Public Health Relevance

While several research studies have demonstrated the positive impact of protective factors in Alzheimer's disease, this knowledge is yet to be translated into feasible dementia prevention trials. Understanding fundamental mechanisms through which important protective factors (lifestyle enrichment and vascular health) alter Alzheimer's disease trajectories is crucial to facilitate bench-to-bedside translation. In this proposal, we provide a theoretical framework to discover paths to ?exceptional aging?, i.e., outperforming the population average in the context of AD outcomes and apply it to the population-based sample of Mayo Clinic Study of Aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Anderson, Dallas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Vemuri, Prashanthi (2018) ""Exceptional brain aging"" without Alzheimer's disease: triggers, accelerators, and the net sum game. Alzheimers Res Ther 10:53
Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan et al. (2018) Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. J Alzheimers Dis 65:1345-1352
Vemuri, Prashanthi; Lesnick, Timothy G; Przybelski, Scott A et al. (2018) Development of a cerebrovascular magnetic resonance imaging biomarker for cognitive aging. Ann Neurol 84:705-716
Fatemi, Farzan; Kantarci, Kejal; Graff-Radford, Jonathan et al. (2018) Sex differences in cerebrovascular pathologies on FLAIR in cognitively unimpaired elderly. Neurology 90:e466-e473
Vemuri, Prashanthi; Lesnick, Timothy G; Przybelski, Scott A et al. (2017) Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann Neurol 82:706-718