δ-Related Biomarkers Attenuate Multiple Alzheimer’s Disease Conversion Risks and OfferTargets for Intervention

Background: We tested certain serum proteins’ ability to mediate the effects of demographic variables on prospective 5-year conversion to clinical “Alzheimer’s disease” from non-demented states (i.e. normal control and mild cognitive impairment). The proteins were rationally selected from previously published mediators of those same variables’ (plural posessive) association with the latent variable “δ,” a novel omnibus dementia severity metric. Methods: Each protein’s attenuation of its risk factor’s independent association with conversion was performed using logistic regression, adjusted for education, ethnicity, self-reported diabetes mellitus, and hypertension, among initially non-demented Mexican American and non-Hispanic white (N = 772) participants in the Texas Alzheimer’s Research and Care Consortium. Results: A total of 70 (9.1%) non-demented participants at baseline converted to “Alzheimer’s disease”, with a mean follow-up of 5.4 years. Age >80 years (odds ratio = 3.1), 30-item Geriatric Depression Scale >10/30 (odds ratio = 2.3), female gender (odds ratio = 2.2), and the presence of an apolipoprotein E ε4 allele (odds ratio = 2.4) were independently associated with prospective conversion. These effects were fully attenuated by five serum proteins: age: insulin-like growth factor-binding protein 2 and epidermal growth factor receptor 1; depression: resistin; gender: thrombopoietin; and apolipoprotein E: C-reactive protein. Conclusion: Clinical dementia arises from the sum of independent δ-related processes. This analysis provides proof of concept for the rational selection of antidementia targets and offers a foundation for precision antidementia therapy.