Variant-dependent heterogeneity in amyloid beta burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study

Chhatwal, Jasmeer P.; Schultz, Stephanie A.; McDade, Eric; Schultz, Aaron P.; Liu, Lei; Hanseeuw, Bernard J.; Joseph-Mathurin, Nelly; Feldman, Rebecca; Fitzpatrick, Colleen; Sparks, Kathryn P.; Levin, Johannes; Berman, Sarah B.; Renton, Alan E.; Esposito, Bianca; Fernandez, Maria Vitoria; Sung, Yun Ju; Lee, Jae Hong; Klunk, William E.; Hofmann, Anna; Noble, James M.; Graff-Radford, Neill; Mori, Hiroshi; Salloway, Steven M.; Masters, Colin L.; Martins, Ralph; Karch, Celeste M.; Xiong, Chengjie; Cruchaga, Carlos; Perrin, Richard J.; Gordon, Brian A.; Benzinger, Tammie L. S.; Fox, Nick C.; Schofield, Peter R.; Fagan, Anne M.; Goate, Alison M.; Morris, John C.; Bateman, Randall J.; Johnson, Keith A. und Sperling, Reisa A. (2022): Variant-dependent heterogeneity in amyloid beta burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study. In: Lancet Neurology, Bd. 21, Nr. 2: S. 140-152

Abstract

Background Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid 13 (A13) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. Methods We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in A13 biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF A131-42 (A1342), and levels of A131-40 (A1340). Findings Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0.0001), despite similar progression on the clinical dementia rating (p>0.7), and CSF A1342 levels (codon-based grouping: p=0.49;domain-based grouping: p=0.095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. Interpretation Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using A13 PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of A13 levels are not interchangeable and might reflect different A13-driven pathobiological processes. Funding National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1474-4422
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198