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Shapes of the Trajectories of 5 Major Biomarkers of Alzheimer Disease
Open accessAbstract
OBJECTIVE: To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score. DESIGN AND SETTING: Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative. PATIENTS: Two different samples (n = 343 and n = 598) were created that spanned the cognitive spectrum from normal to Alzheimer disease dementia. Subgroup analyses were performed in members of both cohorts (n = 243 and n = 328) who were amyloid positive at baseline. MAIN OUTCOME MEASURES: The shape of biomarker trajectories as a function of MMSE score, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging. RESULTS: Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model. CONCLUSIONS: Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants.
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“So far, biomarker studies demonstrated the successive development of primary pathologies including amyloid-β and tau (as measured by biofluid and molecular PET markers) followed by alterations of medial temporal and parietal grey matter (as measured by volumetric MRI and FDG-PET) in both sporadic late-onset Alzheimer’s disease (Jack et al., 2012) and genetically-caused Alzheimer’s disease (Bateman”
From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Jack et al., 2012
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Metadata
- Authors
- Jack, C. R., Vemuri, P., Wiste, H. J., Weigand, S. D., Lesnick, T. G., Lowe, V., Kantarci, K., Bernstein, M. A., Senjem, M. L., Gunter, J. L., Boeve, B. F., Trojanowski, J. Q., Shaw, L. M., Aisen, P. S., Weiner, M. W., Petersen, R. C., Knopman, D. S., & Alzheimer's Disease Neuroimaging Initiative, F. T.
- Affiliations
- Mayo Clinic (US)
- University of Pennsylvania (US)
- University of California San Diego (US)
- University of California, San Francisco (US)
- Corresponding author
- Jack, Clifford R.
- ORCID
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2012-07-01
- Volume
- 69
- Issue
- 7
- Pages
- 856-67
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC3595157
- OpenAlex
- W2014117421
- Cited by
- 145
- References
- 66
- Citations by year
- 2026: 12 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 17 · 2019: 6 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 11 · 2014: 20 · 2013: 23 · 2012: 6
- FWCI
- 13.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Mayo Foundation for Medical Education and Research (AG16574)
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, R01AG11378, P50‐AG16574, U01AG06786, U01AG006786, R01AG011378, U19AG010483, R01AG041851, P50AG016574)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, biomarker trajectories, Mini-Mental State Examination, cerebrospinal fluid amyloid-beta 42, tau protein, amyloid PET, FDG-PET, hippocampal volume, apolipoprotein E, cognitive decline, amyloid-positive
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Aniline Compounds, Cognition Disorders, Cross-Sectional Studies, Female, Hippocampus, Humans, Immunoassay, Magnetic Resonance Imaging, Male, Mental Status Schedule, Peptide Fragments, Thiazoles, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Nonlinear Dynamics, Fluorodeoxyglucose F18, Positron-Emission Tomography, Apolipoprotein E4
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