TY - JOUR
T1 - Accelerated longitudinal changes and ordering of Alzheimer disease biomarkers across the adult lifespan
AU - Dominantly Inherited Alzheimer Network (DIAN)
AU - Dominantly Inherited Alzheimer Network (DIAN)
AU - Luo, Jingqin
AU - Agboola, Folasade
AU - Grant, Elizabeth
AU - Morris, John C.
AU - Masters, Colin L.
AU - Albert, Marilyn S.
AU - Johnson, Sterling C.
AU - McDade, Eric M.
AU - Fagan, Anne M.
AU - Benzinger, Tammie L.S.
AU - Hassenstab, Jason
AU - Bateman, Randall J.
AU - Perrin, Richard J.
AU - Wang, Guoqiao
AU - Li, Yan
AU - Gordon, Brian
AU - Cruchaga, Carlos
AU - Day, Gregory S.
AU - Levin, Johannes
AU - Vöglein, Jonathan
AU - Ikeuchi, Takeshi
AU - Suzuki, Kazushi
AU - Allegri, Ricardo F.
AU - Xiong, Chengjie
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5-6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18-45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45-50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50-55 years and an accelerated decrease for hippocampal volume at the baseline age of 55-60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65-70 years. Another acceleration in the rate of change occurred at the baseline age of 65-70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18-45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ϵ4 non-carriers but not carriers. After age 45 years, APOE ϵ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ϵ4. These findings may better inform the design of prevention trials on Alzheimer disease.
AB - The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5-6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18-45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45-50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50-55 years and an accelerated decrease for hippocampal volume at the baseline age of 55-60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65-70 years. Another acceleration in the rate of change occurred at the baseline age of 65-70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18-45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ϵ4 non-carriers but not carriers. After age 45 years, APOE ϵ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ϵ4. These findings may better inform the design of prevention trials on Alzheimer disease.
KW - Alzheimer disease
KW - accelerated rates of longitudinal change
KW - biomarkers
KW - temporal evolution and ordering
UR - http://www.scopus.com/inward/record.url?scp=85146361268&partnerID=8YFLogxK
U2 - 10.1093/brain/awac238
DO - 10.1093/brain/awac238
M3 - Article
C2 - 35925685
AN - SCOPUS:85146361268
SN - 0006-8950
VL - 145
SP - 4459
EP - 4473
JO - Brain
JF - Brain
IS - 12
ER -