Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer’s Disease and Vascular Pathology

Article type: Research Article

Authors: Shir, Dror^a | Mielke, Michelle M.^{b; e} | Hofrenning, Ekaterina I.^b | Lesnick, Timothy G.^b | Knopman, David S.^a | Petersen, Ronald C.^{a; b} | Jack Jr, Clifford R.^c | Algeciras-Schimnich, Alicia^d | Vemuri, Prashanthi^c | Graff-Radford, Jonathan^{a; *}

Affiliations: [a] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [b] Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA | [c] Department of Radiology, Mayo Clinic, Rochester, MN, USA | [d] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA | [e] Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Correspondence: [*] Correspondence to: Dr. Jonathan Graff-Radford, Department of Neurology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA. Tel.: +1 507 284 2111; [email protected].

Abstract: Background:The National Institute on Aging-Alzheimer’s Association Research Framework proposes defining Alzheimer’s disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. Objective:To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer’s disease pathology measured by Aβ42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). Methods:Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aβ42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). Results:Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aβ42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). Conclusion:The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, neurodegeneration, neurofilament light chain, neurogranin, total tau, white matter integrity

DOI: 10.3233/JAD-221015

Journal: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 887-898, 2023