Over 5.5 million Americans are currently affected by Alzheimer's disease (AD) with an economic burden estimated at > $250 billion/year in 2017 that is projected increase at least four fold over next several decades. In spite of the dearth of pharmacological options to modify the course of the disease at present, the field has developed accurate biomarkers that demonstrate that the pathology of AD is present 15 years of more prior to the onset of memory symptoms. There is converging opinion at the national level and within pharmaceutical companies that our best strategy to develop disease modifying therapies is to design clinical trials during this asympomatic, preclinical period. The accurate biomarkers that detect individuals in the 15-year preclinical period of AD (prior to the onset of memory symptoms) have limitations. They are largely radiological indicators, which are expensive and require the subject to travel to a remote location. Moreover, with the advent of a disease modifying therapeutic, screening the 75 million people above the age of 50 to determine who would benefit from this therapy is prohibitively expensive. To address this critical unmet medical need, we developed an algorithm of olfactory tests that functionally probe two vulnerable neural circuits with early signs of pathology (olfactory and memory circuits). In clinically normal elderly individuals, who have undergone longitudinal neuropsychological testing and radiographic phenotyping, the Percepts of Odor Episodic Memory (POEM) algorithm identified clinical normal individuals with selective odor memory deficits, normalized to other aspects of their individual olfactory function (odor discrimination and odor identification). Those clinically normal elderly individuals with a selective odor memory deficit were enriched in the 3 key AD risk factors: ApoE4, the strongest genetic risk factor for AD, evidence of neurodegeneration in a key memory and olfactory processing area of the brain, and, most importantly, a significant decline in cognitive function over time. In order to fully explore the potential of this finding, here we seek to expand our participant pool by creating a digital olfactory battery that couples with the POEM algorithm, with the ultimate goal that this can be self administered independently at home. To accomplish this goal, we have partnered with a leading digital health company, the ADK group, to develop a mobile app and Scentovations, a company taking an innovative approach to the design and manufacturing of odor delivery devices that are either reusable or disposable. The mobile app will organize the subject's experience with instructions and cues, will collect the response data generated in response to the tests, and will send it securely to a central location. In addition, proprietary naturalistic odors developed by International Flavors and Fragrances will be incorporated into this battery to improve the perceptual salience of odors and performance across different cultures and continents. Following the development of this prototype, we will seek to validate it in both a clinical and home setting. Used alone or together with other non-invasive measures that probe function of different brain regions, a remote test to identify cognitively normal people harboring AD pathology and at risk of developing clinical AD is an essential step to developing and clinically managing therapies that will impact the growing epidemic of AD.

Public Health Relevance

Detecting clinically normal elderly individuals with AD pathology and following their disease progression in a non-invasive, affordable manner is a critical step to developing and monitoring disease modifying therapies. We developed the POEM (Percepts of Odor Episodic Memory) algorithm to identify cognitively healthy elderly individuals with neurodegeneration in their memory circuits and significant cognitive decline over time. To seek further validation of this promising methodology, we have teamed with a leading digital health company and propose to develop a digital olfactory battery for remote assessment of the POEM algorithm using novel odor diffusers and naturalistic odors.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1)
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St Hillaire-Clarke, Coryse
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Massachusetts General Hospital
United States
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