Digital Accessible Remote Olfactory Mediated Health Assessments for Lewy Body Disease

Abstract Approximately 60% of the 6.9 million Americans with Alzheimer’s Disease (AD) pathology have Lewy Body (LB) pathology and 1.4 million Americans have been diagnosed with Lewy Body Disease (LBD). Like AD pathology, which emerges up to two decades prior to the onset of memory symptoms, LB pathology accumulates in asymptotic individuals. A consensus to test disease modifying therapies for dementias at preclinical stages of the disease is emerging. It is critical to know if patients have LB pathology in preclinical LBD trials or in preclinical AD trials (to prevent heterogenous treatment effects driven by covert LBD). Efficient recruitment and validated outcomes within the asymptomatic phase of the disease are challenges for preclinical studies. The olfactory bulb is an early site for LB pathology, and two different odor identification tests predicted the presence of LB pathology in asymptomatic individuals. Current olfactory tests are administered by research assistants, requiring a face-to-face meeting. A self-administered, multi-lingual, validated olfactory test battery would afford scaling of this promising surveillance strategy for Lewy body pathology into the home setting, and make recruitment more efficient for both preclinical LBD and pure AD trials. To address this unmet need, we propose to examine the utility of the AROMHA Brain Health Test, a web-based app paired with smell cards using proprietary naturalistic odors. This validated at home olfactory battery consists of self-administered tests of odor identification, odor memory, and odor discrimination. In Phase I, we will tailor the multilingual AROMHA Brain Health Test for early detection of LBD. In Aim 1, we will query patient reported outcomes of known risk factors for LB pathology, such as REM sleep behavioral disorder, subjective smell loss, constipation, and orthostatic hypotension, and pair this app with our validated, mailable bilingual smell cards. In Aim 2, we will pilot this battery in the DLB arm of the longitudinal cohort of Mass. ADRC, which includes deeply phenotyped patients at the dementia (n = 30) or mild cognitive impairment stages of LBD (n = 30) as well as age-matched controls (n=20). In addition, we will obtain skin biopsies for phospho-synuclein staining and the Brief Smell Identification Test (B-SIT) (Aim 2). We will model olfactory performance to predict the diagnosis of a clinical diagnosis of DLB vs. age-matched controls, and to predict the presence of LB pathology seen in skin biopsies collected from these participants, with a particular focus on seeking sensitivity and specificity of olfactory changes related to aging and early LBD. Successful completion of these aims will afford a Phase II application for longitudinal smell testing of recruited patients, and further validation in multiple patient cohorts with a deeper phenotyping of LBD and other neurodegenerative disease biomarkers (plasma, neuroimaging, CSF). Used alone or together with other non-invasive measures, a remote test to screen cognitively normal people harboring olfactory dysfunction - and possible LB pathology - who are at risk of developing LBD is an important tool to efficiently recruit participants for clinical trials testing therapies for preclinical LBD and/or AD.