SBIR-STTR Award

Over 5.5 million Americans are currently affected by Alzheimer's disease (AD) with an economic burden estimated at more than $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 Statement:
Project Narrative 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.

NIH Spending Category:
Acquired Cognitive Impairment; Aging; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Behavioral and Social Science; Brain Disorders; Clinical Research; Dementia; Neurodegenerative; Neurosciences; Prevention

Project Terms:
Address; Adopted; Affect; Age; Algorithms; Alleles; Alzheimer's Disease; Alzheimer's disease risk; American; Android; apolipoprotein E-4; Area; base; Biological Markers; Brain; Brain region; Cerebrospinal Fluid; Cerebrovascular Disorders; Clinical; Clinical Management; Clinical Research; Clinical Trials Design; Cognitive; cognitive function; Communities; Comorbidity; Couples; Cues; Data; Data Aggregation; design; Detection; Development; Devices; Diabetes Mellitus; Diagnostic; Diagnostic radiologic examination; Diffuse; digital; Discrimination; Disease; Disease Pathway; Disease Progression; Economic Burden; Elderly; entorhinal cortex; Epidemic; Episodic memory; Exhibits; experience; Feedback; field study; Generations; genetic risk factor; Goals; Grant; Health; health assessment; Home environment; Impaired cognition; improved; Independent Living; Individual; Inflammatory; innovation; Instruction; International; Lewy Bodies; Lewy Body Dementia; Libraries; Location; loss of function; Manufacturer Name; Measures; Mediating; Medical; meetings; Memory; Memory impairment; Methodology; Microglia; mobile application; molecular pathology; Monitor; Nerve Degeneration; neural circuit; Neurobehavioral Manifestations; Neurofibrillary Tangles; neuroimaging; Neurons; Neuropsychological Tests; non-demented; novel; Odors; olfactory bulb; operation; Outcome; Parkinson Disease; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Performance; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Play; Population Study; pre-clinical; Probability; Process; protein TDP-43; prototype; Psychophysics; Publishing; Radiology Specialty; relating to nervous system; remote location; Research Assistant; response; Risk; Risk Factors; Role; Sampling; screening; Secure; Self-Administered; Senile Plaques; Specificity; Supervision; Symptoms; Syndrome; System; Testing; Therapeutic; Time; Travel; university student; Validation; Writing

Over 5.8 million Americans are currently affected by Alzheimer's disease (AD) with an economic burdenestimated at > $270 billion/year in 2020 that is projected to increase at least four fold over the next severaldecades. Accurate biomarkers have been developed that demonstrate that AD pathology is present 15 years ofmore prior to the onset of memory symptoms. There is converging opinion that the best strategy to developdisease modifying therapies is to design clinical trials during this asymptomatic, preclinical period. The currentbiomarkers that detect individuals in the 15-year preclinical period of AD (prior to the onset of memorysymptoms) have limitations. They are largely radiological indicators, which are expensive and require thesubject to travel to a remote location or are invasive or expensive. To address this critical unmet medical need,we developed and tested the AROMHA web-based app that conducts the odor tests needed for the POEMalgorithm in our Phase I STTR grant. The POEM algorithm sets personalized thresholds to define selectiveodor memory loss in cognitively normal elderly individual by normalizing each individual's olfactory functionusing odor discrimination and odor identification test. Clinically normal elderly individuals with a selective odormemory deficit are enriched in the 3 key AD risk factors: ApoE4, neurodegeneration in a key memory andolfactory processing area of the brain, a significant decline in cognitive function over time. Recently, thisselective odor memory loss was found to increase risk of progression to MCI over the next 4 years with a HR >3.3. In order to fully realize the potential of the POEM algorithm, in this Phase II application we seek to expandour AROMHA products by creating a digital olfactory battery that couples with the POEM algorithm, with theultimate goal that this can be self administered independently at home. To accomplish this goal, we willdevelop standalone apps in the iOS and Android ecosystems and continue working with Scentovation, acompany taking an innovative approach to the design and manufacturing of odor delivery devices, that arereusable or and International Flavors and Fragrances (IFF) who has developed smell cards that are mailableand disposable. The mobile app will organize the subject's experience with instructions and cues, will collectthe response data generated in response to the tests, and will send it securely to a central location. In addition,proprietary naturalistic odors developed by IFF will be incorporated into this battery to improve the perceptualsalience of odors and performance across different cultures and continents. Following the development ofthese new products, we will seek to field test them in both clinical and home settings. Used alone or togetherwith other non-invasive measures that probe function of different brain regions, a remote test to identifycognitively normal people harboring AD pathology and at risk of developing clinical AD is an essential step todeveloping and clinically managing therapies that will impact the growing epidemic of AD.

Public Health Relevance Statement:
Project Narrative 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 have incorporated the POEM (Percepts of Odor Episodic Memory) battery and algorithm into a web-based app to identify cognitively healthy elderly individuals at risk for progression to MCI. To seek further validation of this promising methodology, we propose to develop digital AROMHA standalone apps in the iOS and Android ecosystems to conduct this olfactory battery for remote assessment of the POEM algorithm using novel odor diffusers and disposable scent cards to emit naturalistic odors.

Project Terms:
Affect ; Elderly ; advanced age ; elders ; geriatric ; late life ; later life ; older adult ; older person ; senior citizen ; Algorithms ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Anosmia ; anosphrasia ; loss of smell ; olfactory loss ; Bar Codes ; barcode ; Brain ; Brain Nervous System ; Encephalon ; Couples ; Cues ; Data Aggregation ; Aggregated Data ; Discrimination ; Cognitive Discrimination ; Disease ; Disorder ; Epidemic ; Feedback ; Follow-Up Studies ; Followup Studies ; Goals ; Grant ; Libraries ; Memory ; Methodology ; Names ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Odors ; Online Systems ; On-Line Systems ; online computer ; web based ; Parkinson Disease ; Paralysis Agitans ; Parkinson ; Parkinson's disease ; Parkinsons disease ; Primary Parkinsonism ; Pathology ; Patients ; Radiology Specialty ; General Radiology ; Radiology ; Research ; Research Personnel ; Investigators ; Researchers ; Risk ; Risk Factors ; Running ; Self Administration ; Self-Administered ; Smell Perception ; Olfaction ; Smell ; odor perception ; olfactory perception ; Specificity ; Supervision ; Syndrome ; Testing ; Time ; Travel ; Writing ; apolipoprotein E-4 ; APOE e4 ; APOE-ε4 ; APOEε4 ; apo E-4 ; apo E4 ; apo epsilon4 ; apoE epsilon 4 ; apoE-4 ; apoE4 ; apolipoprotein E epsilon 4 ; apolipoprotein E4 ; Measures ; Neurofibrillary Tangles ; neurofibrillary degeneration ; neurofibrillary lesion ; neurofibrillary pathology ; tangle ; Mediating ; Ecosystem ; Ecologic Systems ; Ecological Systems ; base ; improved ; Area ; Clinical ; Diffuse ; Phase ; Medical ; Psyche structure ; mental ; Memory impairment ; Memory Deficit ; memory dysfunction ; Individual ; Disease Progression ; TAR DNA-binding protein 43 ; TDP-43 ; TDP43 ; protein TDP43 ; protein TDP-43 ; clinical Diagnosis ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; cognitive function ; Clinic ; Location ; Cognitive Manifestations ; Cognitive Symptoms ; Neurobehavioral Signs and Symptoms ; neurobehavioral symptom ; Neurobehavioral Manifestations ; meetings ; Episodic memory ; American ; experience ; field based data ; field learning ; field test ; field study ; impression ; molecular pathology ; Performance ; college student ; university student ; novel ; Participant ; population-based study ; population-level study ; studies of populations ; study of the population ; Population Study ; Devices ; memory decline ; Memory Loss ; response ; Manufacturer ; Manufacturer Name ; Brain region ; Address ; Symptoms ; Data ; Detection ; Disease Pathway ; Economic Burden ; International ; Clinical Management ; Clinical Trials Design ; Cognitive ; Observational Study ; Observation research ; Observation study ; Observational research ; Small Business Technology Transfer Research ; STTR ; Validation ; Pathologic ; Monitor ; pre-clinical ; preclinical ; Instruction ; digital ; neuroinflammation ; neuroinflammatory ; design ; designing ; Population ; innovation ; innovate ; innovative ; Alzheimer's disease risk ; Alzheimer risk factor ; alzheimer risk ; prototype ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; new product development ; Secure ; operation ; mild cognitive impairment ; mild cognitive disorder ; mobile application ; mobile app ; mobile device application ; Alzheimer's disease pathology ; AD pathology ; Alzheimer's pathology ; Research Assistant ; biomarker panel ; marker panel ; brain health ; Android ; biomarker evaluation ; marker evaluation ; remote location ; amnestic mild cognitive impairment ; health assessment ; web-based assessment ; web-based screening ; self testing ; Dementia with Lewy Bodies ; pre-clinical assessment ; preclinical assessment ; Home ;