Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment

Article type: Research Article

Authors: Malpas, Charles B.^{a; b; *} | Saling, Michael M.^{b; c; d} | Velakoulis, Dennis^{a; e; f} | Desmond, Patricia^{a; g; h} | O’Brien, Terence J.^{a; i} | for the Alzheimer’s Disease Neuroimaging Initiative

Affiliations: [a] Melbourne Brain Centre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Victoria, Australia | [b] Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia | [c] Department of Neuropsychology, Austin Health, Victoria, Australia | [d] Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Hospital, Australia | [e] Melbourne Neuropsychiatry Centre, Royal Melbourne Hospital, Victoria, Australia | [f] Department of Psychiatry, University of Melbourne, Melbourne, Australia | [g] Department of Radiology, University of Melbourne, Melbourne, Australia | [h] Department of Medical Imaging, Royal Melbourne Hospital, Victoria, Australia | [i] Department of Neurology, Royal Melbourne Hospital, Victoria, Australia

Correspondence: [*] Correspondence to: Charles Malpas, Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne 3010, Australia. Tel.: +61 (03) 8344 6377; Fax: +61 (03) 9347 6618; [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: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials.

Keywords: Amyloid-β, cerebrospinal fluid, cognition, mild cognitive impairment, tau

DOI: 10.3233/JAD-142643

Journal: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 965-975, 2015