Mid-Career Mentoring and Research on Blood-Based Biomarkers of Alzheimer's Disease
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PROJECT SUMMARY: Modest effects of anti-amyloid therapies imply many paths to dementia across the stages of Alzheimer’s disease (AD), especially during the preclinical stage where different mechanisms and exposures modulate this trajectory. As an Associate Professor of Neurology and a clinical neuropsychologist, I conduct patient-oriented research in this area, elucidating white matter pathophysiology in preclinical AD and the effects of regular cannabis use on dementia risk in cognitively unimpaired older adults. As an AD researcher, I ensure my studies are standardized and harmonized so they can be synergized to yield new discoveries. To this end, this K24 combines these data to support new research that leverages banked plasma to assay emerging blood- based biomarkers (BBM). BBM are proteins detected in blood that indicate AD pathology (AB42/40, pTau-217), neuroinflammation (glial fibrillary acidic protein; GFAP), and neurodegeneration (neurofilament light). Despite recent FDA approval for 2 AD BBM, confounds such as demographic factors and medical comorbidities can physiologically alter BBM concentrations, impact their interpretation, and lead to false positive or negative results in real-world settings. Moreover, effects of exposures such as cannabis use on BBM have not been examined despite it being common among older adults (i.e. 6-18% report current, regular, or long-term use) and emerging data showing that cannabis adversely impacts cognition, conflicting with experimental evidence of its pro- cognitive effects. My preliminary data show that regular cannabis users have worse memory and unexpectedly higher AB42/40; while higher AB42/40 typically indicates less AD pathology, it correlates with higher GFAP in cannabis users, among whom cognition correlates with BBM only among women. These results suggest profound challenges to interpreting BBM in the context of this common exposure. As emerging studies show that newer BBM (i.e. pTau-217/brain-derived tau [BD-tau] ratio) can be more specific to AD pathology and less impacted by comorbidities, I will use single molecule array immunoassays to test the overall hypothesis that among community-dwelling older adults, BBM indicate greater AD pathology in regular cannabis users, which will be associated with cognitive deficits in women in particular. I will therefore determine risk for AD among regular cannabis users using BBM and cognitive test performance (Aim 1) and identify sex differences in the associations between BBM and cognitive test performance (Aim 2), accounting for demographic and comorbidity influences on BBM to inform their use in real-word settings. This project combines data from hundreds of participants in my ongoing longitudinal preclinical AD (R01AG054159) and cross-sectional cannabis use (U54DA016511-5804) studies. To maximize impact, I will learn data management and predictive modeling (Goal 1; Consultants: Mielke, Obeid) and apply for an AD training grant (Goal 2; Consultants: McRae-Clark, Feghali- Bostwick). Mentees will have access to these data, and with the additional support of professional coaching and Consultant expertise, they will be poised to succeed as patient-oriented researchers in the field of AD.
