CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease

• DOI: 10.1016/j.nbd.2022.105714
• Publication Date: 2022-03-28T15:54:31Z
• Authors: Jeremy F. Strain; Nicolas Barthelemy; Kanta Horie; Brian A. Gordon; Collin Kilgore; Andrew Aschenbrenner; Carlos Cruchaga; Chengjie Xiong; Nelly Joseph-Math...; Jason Hassenstab; Anne M. Fagan; Yan Li; Celeste M. Karch; Richard J. Perrin; Sarah B. Berman; Jasmeer P. Chhatwal; Neill R. Graff-Ra...; Hiroshi Mori; Johannes Levin; James M. Noble; Ricardo Allegri; Peter R. Schofield; Daniel S. Marcus; David M. Holtzman; John C. Morris; Tammie L.S. Benzi...; Eric M. McDade; Randall J. Bateman; Beau M. Ances
• Keywords: diagnostic imaging [Cognitive Dysfunction]; metabolism [White Matter]; 610; genetics [Alzheimer Disease]; CSF; Neurosciences. Biological psychiatry. Neuropsychiatry; tau Proteins; cerebrospinal fluid [Amyloid beta-Peptides]; Article; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; ddc:570; Medicine and Health Sciences; Humans; Cognitive Dysfunction; Phosphorylation; Psychiatry; PCA; Amyloid beta-Peptides; Phosphorylated tau; White matter; ICTS (Institute of Clinical and Translational Sciences); White Matter; metabolism [tau Proteins]; 3. Good health; cerebrospinal fluid [Alzheimer Disease]; Diffusion Tensor Imaging; cerebrospinal fluid [Biomarkers]; diagnostic imaging [Alzheimer Disease]; Biomarkers; ADAD; RC321-571

Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s).In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss.We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.