Journal Article

α‐Synuclein seed amplification assay detects Lewy body co‐pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Höglinger, Günter U., Lopera, Francisco, Berman, Sarah B., Daniels, Alisha, Giese, Armin, Hansson, Oskar, Vöglein, Jonathan, Chhatwal, Jasmeer P., Xiong, Chengjie, Preische, Oliver, Cruchaga, Carlos, Day, Gregory S., Frosch, Matthew P., Bernhardt, Alexander, Noble, James M., Gordon, Brian A., Jucker, Mathias, Huey, Edward D., Cairns, Nigel J., Llibre‐Guerra, Jorge, McLean, Catriona, Ryan, Natalie S., Goate, Alison M., Roh, Jee Hoon, Franklin, Erin E., Lee, Jae‐Hong, Levin, Johannes, Masters, Colin L., Mammana, Angela, Supnet‐Bell, Charlene, Sanchez‐Valle, Raquel, Perrin, Richard J., Ibanez, Laura, Bateman, Randall J., Keene, C. Dirk, Quadalti, Corinne, Morris, John C., Rossi, Marcello, Baiardi, Simone, Karch, Celeste M., Schofield, Peter R., Renton, Alan E., McDade, Eric, Parchi, Piero, Hofmann, Anna, Chrem, Patricio

2024

Overview

INTRODUCTION Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS Using an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo. DISCUSSION Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity. Highlights Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants. LBP develops late in the disease course in ADAD. CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP.

• Publisher: John Wiley and Sons Inc
• Subject: Aged / alpha-Synuclein - cerebrospinal fluid / alpha-Synuclein - genetics / alpha‐synuclein seed amplification assay / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - diagnosis / Alzheimer Disease - genetics / Alzheimer Disease - pathology / Amyloid beta-Peptides - cerebrospinal fluid / Amyloid beta-Peptides - metabolism / Brain - pathology / Clinical Medicine / Disease Progression / Dominantly Inherited Alzheimer Network / Female / Humans / Klinisk medicin / Lewy Bodies - pathology / Lewy body pathology / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Middle Aged / Mutation / Neurologi / Neurology / real‐time quaking‐induced conversion / Short Report / Short Reports