Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment

Article type: Research Article

Authors: Clark, Alexandra L.^{a; b; c} | Weigand, Alexandra J.^{a; d} | Thomas, Kelsey R.^{a; c} | Solders, Seraphina K.^e | Delano-Wood, Lisa^{a; b; c} | Bondi, Mark W.^{a; b; c} | Bernier, Rachel A.^e | Sundermann, Erin E.^c | Banks, Sarah J.^e | Bangen, Katherine J.^{a; c; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Research Services, VA San Diego Healthcare System, San Diego, CA, USA | [b] Psychology Service, VA San Diego Healthcare System, San Diego, CA, USA | [c] University of California San Diego, School of Medicine, Department of Psychiatry, La Jolla, CA, USA | [d] San Diego State University/University of California, San Diego (SDSU/UCSD), La Jolla, CA, USA | [e] Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA

Correspondence: [*] Correspondence to: Katherine J. Bangen, Ph.D., VA San Diego Healthcare System (151B), 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel.: +1 858 552 8585 /Ex 5794; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer’s disease (AD), although their interactive effects have yet to be fully examined. Objective:The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). Methods:This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1–42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. Results:Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = –1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s < 0.05). Conclusion:PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

Keywords: Cerebrospinal fluid, inflammation, mild cognitive impairment, tau, vascular dysfunction

DOI: 10.3233/JAD-201382

Journal: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1451-1463, 2021