title: Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment.
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.
authors.affiliation: Melbourne Brain Centre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Victoria, Australia.|Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Malpas
authors.affiliation: Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia.|Department of Neuropsychology, Austin Health, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Hospital, Australia.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Saling
authors.affiliation: Melbourne Brain Centre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Victoria, Australia.|Melbourne Neuropsychiatry Centre, Royal Melbourne Hospital, Victoria, Australia.|Department of Psychiatry, University of Melbourne, Melbourne, Australia.
authors.forename: Dennis
authors.initials: D
authors.lastname: Velakoulis
authors.affiliation: Melbourne Brain Centre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Victoria, Australia.|Department of Radiology, University of Melbourne, Melbourne, Australia.|Department of Medical Imaging, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Desmond
authors.affiliation: Melbourne Brain Centre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Victoria, Australia.|Department of Neurology, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003071:Cognition / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000523:psychology*; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007858:Learning / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D012044:Regression Analysis; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Amyloid-β; cerebrospinal fluid; cognition; mild cognitive impairment; tau