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Do rates of memory decline vary by the amyloid, tau, and neurodegeneration biomarker profiles described in the recent National Institute on Aging–Alzheimer’s Association Research Framework?
In this longitudinal cohort study that included 480 participants without dementia, the addition of amyloid positron emission tomography, tau positron emission tomography, and magnetic resonance imaging cortical thickness to a model that included clinical and genetic variables resulted in a small but statistically significant improvement in predictive accuracy for memory decline (R2, 0.31 vs 0.26).
Amyloid, tau, and neurodegeneration biomarkers may provide incremental prognostic value in addition to more readily available clinical and genetic variables, but the clinical importance of this difference is uncertain.
A National Institute on Aging and Alzheimer’s Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers.
To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information.
Design, Setting, and Participants
Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018.
Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (−), resulting in 8 AT(N) profiles.
Main Outcomes and Measures
Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only.
Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A−T−(N)− group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)−, and A+T−(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were −0.13 (95% CI, −0.17 to −0.09), −0.10 (95% CI, −0.16 to −0.05), and −0.10 (95% CI, −0.13 to −0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier.
Conclusions and Relevance
Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.
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Corresponding Author: Clifford R. Jack Jr, MD, Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (firstname.lastname@example.org).
Accepted for Publication: May 13, 2019.
Author Contributions: Dr Jack and Ms Wiste had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Jack, Lowe, Graff-Radford, Jones, Petersen.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Jack.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Wiste, Therneau, Weigand, Schwarz.
Obtained funding: Jack, Lowe, Vemuri, Roberts, Petersen.
Administrative, technical, or material support: Jack, Lowe, Schwarz, Gunter, Senjem, Graff-Radford, Jones, Roberts, Petersen.
Supervision: Jack, Lowe.
Conflict of Interest Disclosures: Dr Jack reported receiving grants from the National Institutes of Health (NIH) and Alexander Family Professorship of Alzheimer’s Disease Research during the conduct of the study, consulting for Eli Lily, and serving on an independent data monitoring board for Roche outside the submitted work but receives no personal compensation from any commercial entity. Drs Therneau, Vemuri, Machulda, and Schwarz reported receiving grants from the NIH. Dr Knopman reported receiving personal fees from the Dominantly Inherited Alzheimer Network–Trials Unit data and safety monitoring board; serving as an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California; and receiving research support from the NIH/National Institute on Aging (NIA) outside the submitted work. Dr Mielke reported receiving grants from the NIH/NIA during the conduct of the study and grants from Biogen, Lundbeck, and Roche and personal fees from Eli Lilly outside the submitted work. Dr Lowe reported consulting for Bayer Schering Pharma, Piramal Life Science, and Merck Research and receiving research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH. Dr Senjem reported owning shares of the following medical-related stocks, unrelated to the current work, at the time of manuscript submission: Align Technology Inc, LHC Group Inc, Mesa Laboratories Inc, Natus Medical Inc, and Varex Imaging Corp. Within the past 3 years, he reported owning the following medical-related stocks, unrelated to the current work: CRISPR Therapeutics, Gilead Sciences Inc, Globus Medical Inc, Inovio Biomedical Corp, Ionis Pharmaceuticals, Johnson & Johnson, Medtronic Inc, and Parexel International Corp. Dr Graff-Radford reported receiving grants from the NIA during the conduct of the study. Dr Jones reported receiving grants from the NIH and State of Minnesota during the conduct of the study. Dr Petersen reported receiving personal fees from Hoffman-La Roche Inc, Merck Inc, Genentech Inc, Biogen Inc, GE Healthcare, and Eisai Inc and royalties from Oxford University Press for “Mild Cognitive Impairment: Aging to Alzheimer’s Disease” outside the submitted work. No other disclosures were reported.
Funding/Support: Study funding was provided by the NIH (grants R37 AG011378, RO1 AG041851, R01 AG056366, R01 NS097495, U01 AG06786, and R01 AG034676), the Alexander Family Professorship of Alzheimer’s Disease Research, and the GHR Foundation.
Role of Funder/Sponsor Statement: The funding organizations/sponsors had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank AVID Radiopharmaceuticals Inc for its support in supplying AV-1451 ([18F]flortaucipir) precursor, chemistry production advice and oversight, and Food and Drug Administration regulatory cross-filing permission and documentation needed for this study.
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