Tau Protein is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer’s Disease Cerebrospinal Fluid Biomarker Levels

Article type: Research Article

Authors: Tort-Merino, Adrià^a | Olives, Jaume^a | León, María^a | Peñaloza, Claudia^b | Valech, Natalia^a | Santos-Santos, Miguel A.^b | Càmara, Estela^b | Grönholm-Nyman, Petra^c | Martínez-Lage, Pablo^d | Fortea, Juan^{e; f} | Molinuevo, José L.^{a; g} | Sánchez-Valle, Raquel^{a; h} | Laine, Matti^c | Rodríguez-Fornells, Antoni^{b; i; j} | Rami, Lorena^{a; h; *}

Affiliations: [a] Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain | [b] Cognition and Brain Plasticity Group, Bellvitge Biomedical Research Institute- IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain | [c] Department of Psychology, Åbo Akademi University, Turku, Finland | [d] Neurología, Fundación CITA-Alzhéimer Fundazioa, Centro de Investigación y Terapias Avanzadas, San Sebastián, Guipúzcoa, España | [e] Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau and Institute of Biomedical Research, Barcelona, Spain | [f] Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain | [g] Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain | [h] August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain | [i] Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain | [j] Department of Cognition, Development and Education Psychology, University of Barcelona, L’Hospitalet de Llobregat, Spain

Correspondence: [*] Correspondence to: Lorena Rami, PhD, Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, IDIBAPS. Villarroel 170. 08036. Barcelona. Spain. Tel.: +34 932275785; Fax: +34 932275783; E-mail: [email protected].

Abstract: Background:We investigated a sample of cognitively healthy subjects with normal Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. Objective:Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline. Methods:Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau < 228.64 pg/ml; n = 16) and CBN-Tau↑ (tau > 228.64 pg/ml; n = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. Results:Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B = –0.17, p < 0.05; r = –0.414; p < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. Conclusions:The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects.

Keywords: Aging, biomarkers, cognition, early detection, memory decline, tau, voxel-based morphometry

DOI: 10.3233/JAD-190046

Journal: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 211-225, 2019