Adverse Vascular Risk Relates to Cerebrospinal Fluid Biomarker Evidence of Axonal Injury in the Presence of Alzheimer’s Disease Pathology

Article type: Research Article

Authors: Osborn, Katie E.^a | Alverio, Jonathan M.^b | Dumitrescu, Logan^a | Pechman, Kimberly R.^a | Alzheimer’s Disease Neuroimaging Initiative¹ | Gifford, Katherine A.^a | Hohman, Timothy J.^{a; c} | Blennow, Kaj^{d; e} | Zetterberg, Henrik^{d; e; f; g} | Jefferson, Angela L.^{a; *}

Affiliations: [a] Vanderbilt Memory & Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA | [b] Vanderbilt University School of Medicine, Nashville, TN, USA | [c] Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA | [d] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [e] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [f] Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK | [g] UK Dementia Research Institute at UCL, London, UK

Correspondence: [*] Correspondence to: Angela L. Jefferson, PhD, Vanderbilt Memory & Alzheimer’s Center, 1207 17th Avenue South, Suite 204, Nashville, TN 37212, USA. Tel.: +1 615 322 8676; Fax: +1 615 343 1302; 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:Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer’s disease pathology influences the brain’s vulnerability in this regard is not well understood. Objective:Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer’s disease. Methods:Among Alzheimer’s Disease Neuroimaging Initiative participants with normal cognition (n = 117), mild cognitive impairment (n = 190), and Alzheimer’s disease (n = 95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42, hyperphosphorylated tau, and total tau. Results:Vascular risk and neurofilament light were not related in the main effect model (p = 0.08). However, interactions emerged for total tau (p = 0.01) and hyperphosphorylated tau (p = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer’s disease biomarker profiles (p = 0.046) where in comparison to the referent ‘normal’ biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light. Conclusion:Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer’s disease pathology.

Keywords: Alzheimer’s disease, cerebrovascular, neurodegeneration, neurofilament light, vascular risk

DOI: 10.3233/JAD-190077

Journal: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 281-290, 2019