Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer’s Disease

Article type: Research Article

Authors: Pillai, Jagan A.^{a; b; *} | Bonner-Jackson, Aaron^a | Bekris, Lynn M.^c | Safar, Jiri^{d; e} | Bena, Jim^f | Leverenz, James B.^{a; b}

Affiliations: [a] Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA | [b] Department of Neurology, Cleveland Clinic, Cleveland, OH, USA | [c] Department of Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA | [d] Department of Pathology, Cleveland, OH, USA | [e] Department of University Hospitals Cleveland Medical Center, Cleveland, OH, USA | [f] Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

Correspondence: [*] Correspondence to: Jagan A Pillai, MBBS, PhD, Staff Neurologist, Lou Ruvo Center for Brain Health, Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Ave/U10, Cleveland, OH 44195, USA. Tel.: +1 216 636 9467; Fax: +1 216 445 7013; E-mail: pillaij@ccf.org.

Abstract: Background:Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer’s disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels. Objective:We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD. Methods:Retrospective comparative case study of 97 patients evaluated in a memory clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOE ɛ4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates. Results:Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOE ɛ4, MoCA, and CSF Aβ42. Logopenic AD had higher t-tau and p-tau levels compared to other variants. Conclusions:Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant.

Keywords: Alzheimer’s disease, atypical variant, biomarkers, cerebrospinal fluid, cortical atrophy, hippocampal atrophy, mild cognitive impairment, tau

DOI: 10.3233/JAD-190519

Journal: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1051-1058, 2019