Persons with similar amount of Alzheimer's or vascular brain pathology on imaging or autopsy may have had very different clinical and functional experiences during life. One possible reason could be varying amounts of cognitive reserve, or brain health which protects them from clinical manifestations. Thus, just as a healthy bone mass through life protects from osteoporosis and fractures, having a healthy brain at age 65-85, a consequence of genetic propensity and lifelong environmental, behavioral and disease-related factors, will protect from development of AD, dementia and stroke. How do we define a healthy brain phenotype? Brain health is typically characterized using quantitative measurements MRI and PET brain imaging, cognitive testing and at autopsy. Other dimensions of brain health, often altered in aging, prior to cognition, include retinal structure and vasculature, olfactory, visual, auditory, tactile and sensory perception and motor abilities. Sensory-motor measures are promising early biomarkers of AD and may play a causal role in the development or progression of dementia. An NIA workshop titled “Sensory and Motor dysfunctions in Aging and AD” concluded that comprehensive sensory motor testing would provide key mechanistic insights into AD pathogenesis. We propose to incorporate multiple such sensory-motor measures in the recently funded 10th exam for 1874 Framingham Heart Study (FHS) Offspring and Omni 1 cohort participants and develop a multi-dimensional sensory-motor Brain Health Index (smBHI), as well as a composite BHI (cBHI) that additionally includes brain MRI and cognitive measures. Predictors and outcomes related to the BHI will be identified using the extensive profiling of risk factors, repeated measures of brain structure and function, information on MCI, dementia (AD and VCID) and stroke outcomes already available in FHS. It will be validated in 3 additional population samples, 200 African- Americans in Jackson, MS, 400 Hispanic participants in San Antonio, Texas and 1650 European ancestry participants in the Great Age Study in Barri, Italy (LOS only, will collect and analyze data with Italian funding. Aim 1: To characterize individual brain health using a multidimensional sensory-motor `Brain Health Index' by assessing olfaction, retina, vision, auditory function, vestibular function, touch sensation, motor function, and examine its association with (i) cross-sectional MRI, PET and cognitive function and (ii) incident mild cognitive impairment (MCI), dementia including AD, VCID, TIA, stroke and all-cause mortality over 3-5 years and subsequent follow-up Aim 2: To investigate the effect of lifelong (20-40+ years) social, behavioral and vascular/metabolic factors, measured previously on these participants, on individual sensory-motor functions, smBHI and cBHI and brain reserve (difference between BH age and chronological age) Aim 3: To examine the association between (1) genetic, (2) putative circulating biomarkers and (3) epigenetic aging and `brain health' Aim 4: To replicate the associations observed in Aims 1, 2 and 3 in our three replication samples.

Project Narrative Persons with good brain health at the beginning of old age may be able to protect themselves from the development of dementia. Brain health is typically measured using brain imaging and cognitive tests. We are proposing a new way of capturing brain health – by assessing “sensory- motor” function using measurements of smell, vision, hearing, gait, touch and balance using non-invasive tests. These changes are typically considered part of normal aging, but recent research has shown that these could be early warning signs of dementia. In this study, we will examine how brain health measured using these sensory-motor measures can predict protection from or risk for dementia and increase our understanding of the many genetic and lifestyle, vascular factors that determine sensory-motor brain health.