Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease
-
Published:2023-12-19
Issue:1
Volume:18
Page:
-
ISSN:1750-1326
-
Container-title:Molecular Neurodegeneration
-
language:en
-
Short-container-title:Mol Neurodegeneration
Author:
Millar Peter RORCID, Gordon Brian A, Wisch Julie K, Schultz Stephanie A, Benzinger Tammie LS, Cruchaga Carlos, Hassenstab Jason J, Ibanez Laura, Karch Celeste, Llibre-Guerra Jorge J, Morris John C, Perrin Richard J, Supnet-Bell Charlene, Xiong Chengjie, Allegri Ricardo F, Berman Sarah B, Chhatwal Jasmeer P, Chrem Mendez Patricio A, Day Gregory S, Hofmann Anna, Ikeuchi Takeshi, Jucker Mathias, Lee Jae-Hong, Levin Johannes, Lopera Francisco, Niimi Yoshiki, Sánchez-González Victor J, Schofield Peter R, Sosa-Ortiz Ana Luisa, Vöglein Jonathan, Bateman Randall J, Ances Beau M, McDade Eric M,
Abstract
Abstract
Background
“Brain-predicted age” estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.
Methods
We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.
Results
Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.
Conclusions
We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.
Funder
BrightFocus Foundation National Institute on Aging Alzheimer’s Association
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Molecular Biology
Reference81 articles.
1. Raz N, Gunning FM, Head D, Dupuis JH, Mcquain J, Briggs SD, Loken WJ, Allen E, Acker JD. Selective aging of the Human Cerebral Cortex Observed in vivo: Differential vulnerability of the prefrontal Gray Matter. Cereb Cortex. 1997;7:268–82. 2. Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C. Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J Neurosci. 2003;23:3295–301. 3. Bethlehem RAI, Seidlitz J, White SR, et al. Brain charts for the human lifespan. Nature. 2022. https://doi.org/10.1038/s41586-022-04554-y. 4. Franke K, Ziegler G, Klöppel S, Gaser C. Estimating the age of healthy subjects from T1-weighted MRI scans using kernel methods: exploring the influence of various parameters. NeuroImage. 2010;50:883–92. 5. Cole JH, Leech R, Sharp DJ. Prediction of brain age suggests accelerated atrophy after traumatic brain injury. Ann Neurol. 2015;77:571–81.
|
|