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Luo, Jingqin; Agboola, Folasade; Grant, Elizabeth; Morris, John C.; Masters, Colin L.; Albert, Marilyn S.; Johnson, Sterling C.; McDade, Eric M.; Fagan, Anne M.; Benzinger, Tammie L. S.; Hassenstab, Jason; Bateman, Randall J.; Perrin, Richard J.; Wang, Guoqiao; Li, Yan; Gordon, Brian; Cruchaga, Carlos; Day, Gregory S.; Levin, Johannes; Voeglein, Jonathan; Ikeuchi, Takeshi; Suzuki, Kazushi; Allegri, Ricardo F. and Xiong, Chengjie (2022): Accelerated longitudinal changes and ordering of Alzheimer disease biomarkers across the adult lifespan. In: Brain, Vol. 145, No. 12: pp. 4459-4473

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The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-beta(42) (A beta(42)), A beta(40), total tau (Tau) and phosphorylated tau181 (pTau(181)), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-beta with PET using the C-11-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 A beta(42) and A beta(42)/A beta(40) ratio (with an increase) and for Tau, and pTau(181) (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 A beta(42)/A beta(40) ratio, Tau, pTau(181), 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 A beta(42) and A beta(42)/A beta(40) ratio and decreases in PiB SUVR occurred in APOE e4 non-carriers but not carriers. After age 45 years, APOE e4 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 e4. These findings may better inform the design of prevention trials on Alzheimer disease. Luo et al. characterize the temporal evolution of Alzheimer's disease biomarkers, as well as the modifying effects of APOE e4, across the entire adult lifespan in cognitively normal individuals. Different biomarkers exhibit accelerated change at different ages: information that could inform the design of Alzheimer's disease prevention trials.

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