Baseline Neurodegeneration Influences the Longitudinal Effects of Tau on Cognition

Article type: Research Article

Authors: Ng, Kok Pin^{a; b} | Cheng, Grand H.-L.^c | Yatawara, Chathuri^a | Rosa-Neto, Pedro^{d; e} | Gauthier, Serge^e | Kandiah, Nagaendran^{a; b; f; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, National Neuroscience Institute, Singapore, Singapore | [b] Duke-NUS Medical School, Singapore, Singapore | [c] School of Arts and Social Sciences, The Open University of Hong Kong, Hong Kong, China | [d] Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, Canada | [e] Alzheimer’s Disease Research Unit, The McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada | [f] Lee Kong Chian School of Medicine –Imperial College London, Nanyang Technological University, Singapore, Singapore

Correspondence: [*] Correspondence to: A/Prof Nagaendran Kandiah, FRCP, Senior Consultant Neurologist, Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore. Tel.: +65 6357 7199; Fax: +65 6357 7137; 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:Cerebrospinal fluid t-tau (CSF t-tau) is a measure of neurodegeneration in Alzheimer’s disease (AD) and has been increasingly demonstrated to be a non-specific biomarker within the AD continuum. Objective:We sought to test whether t-tau influences the longitudinal effects of amyloid-β (Aβ) and phospho-tau (p-tau) on memory and executive function (EF) in mild cognitive impairment (MCI). Methods:319 MCI individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with baseline and 2-year CSF Aβ, p-tau, t-tau, and neuropsychological assessments were studied. Mediation and moderation analyses evaluated the role of t-tau in the effects of Aβ and p-tau on memory and EF over 2 years. Results:We found that high baseline p-tau but not Aβ was associated with higher t-tau and lower memory scores at 2 years follow-up. The association between p-tau and memory impairment was partially mediated by t-tau, whereby higher p-tau was indirectly associated with lower memory via higher t-tau. t-tau also moderated the association between p-tau and memory. When t-tau level was relatively lower, higher p-tau was associated with lower memory scores at 2 years. When t-tau level was higher, the memory scores were low regardless of the p-tau level. Conclusion:Tau-induced neurodegeneration is one key pathway by which AD pathology (p-tau) affects memory impairment. Furthermore, in individuals with lower levels of tau-induced neurodegeneration, higher levels of p-tau were required for memory impairment. Our findings suggest that t-tau plays a significant role in how early AD pathology affects cognitive outcomes.

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, cognitive dysfunction, executive function, memory, mild cognitive impairment

DOI: 10.3233/JAD-201425

Journal: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 159-167, 2021