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Front Neurosci. 2017 May 17;11:281. doi: 10.3389/fnins.2017.00281. eCollection 2017.

Time to Amyloid Positivity and Preclinical Changes in Brain Metabolism, Atrophy, and Cognition: Evidence for Emerging Amyloid Pathology in Alzheimer's Disease.

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Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund UniversityMalmö, Sweden.
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative DiseasesSan Francisco, CA, United States.
Department of Radiology and Biomedical Imaging, University of California, San FranciscoSan Francisco, CA, United States.
Department of Neurology and Alzheimercenter, Neuroscience Campus Amsterdam, VU University Medical CenterAmsterdam, Netherlands.
Alzheimer's Therapeutic Research Institute, University of Southern California, San DiegoSan Diego, CA, United States.
Helen Wills Neuroscience Institute, University of California, BerkeleyBerkeley, CA, United States.
Life Sciences Division, Lawrence Berkeley National Laboratory, BerkeleyBerkeley, CA, United States.
Memory Clinic, Skåne University HospitalMalmö, Sweden.
Department of Neurology, Skåne University HospitalLund, Sweden.


Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition. Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines. Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity. Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.


Alzheimer's disease; atrophy; cognition; metabolism; preclinical; β-amyloid

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