Impaired LC-NE System-A Novel Molecular Mechanism Underlying Health Disparity and Increased Prevalence of Alzheimer's Disease Among African Americans.

Background: The current biomarker classification system does not fully explain the increased prevalence of both Alzheimer's disease (AD) and vascular risk factors for AD-such as diabetes and hypertension--among African Americans (AAs) compared to White participants. Research on cognitive aging has traditionally focused on how declines in cortical and hippocampal regions influence cognition. However, tau pathology emerges decades before amyloid pathology, initially appearing in the brainstem, particularly in the locus coeruleus (LC), the primary source of the brain's norepinephrine (NE). Further, postmortem studies suggest that the loss of LC neurons is a better predictor of AD symptom severity than amyloid-beta/neurofibrillary tangle pathology in any other brain region. Methods: Our decade-long studies in humans using a norepinephrine transporter (NET)-selective radiotracer ([11C]MRB) have demonstrated that LC is uniquely vulnerable to aging and stress. In this retrospective study, regression slopes with age (RSAs) for regional NET availability were compared across groups and tested for statistical significance. Results: In our primary analysis, higher NET availability was observed in AAs (N = 14; 7 males aged 23-49), particularly at younger ages, as compared to White (N = 16; 11 males aged 24-55) participants. Our preliminary data also suggest that the rate of decline in NET availability is faster in AAs, with a potential trend toward a more pronounced effect in AA males as compared to White males (e.g., in the left thalamus, RSA was -3.03%/year [95%CI: -5.80% to 1.19%] for AA males vs. RSA = -0.14 for White males [95%CI: -0.79% to 0.47%]. Additionally, in the right anterior cingulate cortex, RSA was -3.4%/year [95%CI: -4.6% to -1.4%] for AA males, compared to RSA = 0.3%/year [95%CI: 0.04% to 1.03%] for White males). Conclusions: This report reveals that NET availability (measured with [11C]MRB) can serve as a biomarker to index the function of the LC-NE system and that the fast-decline rate of NET in AAs implicates a potential molecular mechanism underlying health disparities observed in the disproportionate AD prevalence.