The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease
Open accessAbstract
Objective To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. Methods We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals9 estimated years to symptom onset and to compare mutation carriers and noncarriers. Results Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7–10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations. Conclusion These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.
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“Cross-sectional and longitudinal data analyses of DIAN and other large Alzheimer’s disease cohorts have demonstrated that the pathological processes in Alzheimer’s disease begin more than two decades before the onset of clinical symptoms.”
From Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019) · cites this paper as [22]
In the citing paper
“However, atrophy of individual cortical regions occurs earlier1,2,22,25.”
From Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019) · cites this paper as [22]
In the citing paper
“The accumulation of amyloid-β in the brain (estimated 15–20 years before clinical onset) is followed by declines in cortical metabolism (estimated 10–15 years before clinical onset) and brain atrophy (5–10 years before clinical onset)1,2,22,25.”
From Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019) · cites this paper as [22]
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“A change in CSF Aβ levels can be detected even up to 25 years before a patient begins to show symptoms.478”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [478]
In the citing paper
“not only CSF P-tau217 but also P-tau181 may be increased very early (in preclinical stages) and then reach a plateau [and in very late stages, perhaps even a decrease, as has also been suggested by findings from autosomal dominant AD (35)].”
From Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease (2020) · cites this paper as [35]
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Self-citationClinical and biomarker changes in dominantly inherited Alzheimer's disease
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Self-citationBiomarker Modeling of Alzheimer’s Disease
Jack, C. R., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.12.003 · Cited by 1,002
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The A4 Study: Stopping AD Before Symptoms Begin?
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Self-citationCleveland, W. S., Devlin, S. J., & Grosse, E. (1988) · Journal of Econometrics · doi:10.1016/0304-4076(88)90077-2 · Cited by 607
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Self-citationSymptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis
Ryman, D. C., Acosta-Baena, N., Aisen, P. S., Bird, T., Danek, A., Fox, N. C., Goate, A., Frommelt, P., Ghetti, B., Langbaum, J. B. S., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000596 · Cited by 502
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Dominantly Inherited Alzheimer Network, Preische, O., Schultz, S. A., Apel, A., Kuhle, J., Kaeser, S. A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0304-3 · Cited by 927
Self-citationA critical appraisal of amyloid-β-targeting therapies for Alzheimer disease
Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0116-6 · Cited by 965
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988
“A change in CSF Aβ levels can be detected even up to 25 years before a patient begins to show symptoms.(478) Thus, the current application of Aβ therapies may be too late for symptomatic patients, whose therapeutic window has already closed.”
Backgroundthe Dominantly Inherited Alzheimer Network, Barthélemy, N. R., Li, Y., Joseph-Mathurin, N., Gordon, B. A., Hassenstab, J., Benzinger, T. L. S., Buckles, V., Fagan, A. M., Perrin, R. J., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0781-z · Cited by 651
Self-citationAlzheimer’s disease: Recent treatment strategies
Vaz, M., & Silvestre, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173554 · Cited by 547
Metadata
- Authors
- McDade, E., Wang, G., Gordon, B. A., Hassenstab, J., Benzinger, T. L. S., Buckles, V., Fagan, A. M., Holtzman, D. M., Cairns, N. J., Goate, A. M., Marcus, D. S., Morris, J. C., Paumier, K., Xiong, C., Allegri, R., Berman, S. B., Klunk, W., Noble, J., Ringman, J., Ghetti, B., Farlow, M., Sperling, R. A., Chhatwal, J., Salloway, S., Graff-Radford, N. R., Schofield, P. R., Masters, C., Rossor, M. N., Fox, N. C., Levin, J., Jucker, M., Bateman, R. J., for the Dominantly Inherited Alzheimer Network, Dominantly Inherited Alzheimer Network, Fague, M. S., Jack, C., & Koeppe, R.
- Affiliations
- University of Southern California (US)
- Washington University in St. Louis (US)
- From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones...
- ORCID
- McDade, Eric
- Wang, Guoqiao
- Gordon, Brian A.
- Hassenstab, Jason
- Benzinger, Tammie L.S.
- Fagan, Anne M.
- Holtzman, David M.
- Goate, Alison M.
- Marcus, Daniel S.
- Morris, John C.
- Paumier, Katrina
- Xiong, Chengjie
- Allegri, Ricardo
- Berman, Sarah B.
- Klunk, William
- Noble, James
- Ringman, John
- Ghetti, Bernardino
- Farlow, Martin
- Sperling, Reisa A.
- Chhatwal, Jasmeer
- Salloway, Stephen
- Schofield, Peter R.
- Masters, Colin
- Rossor, Martin N.
- Fox, Nick C.
- Levin, Johannes
- Jucker, Mathias
- Bateman, Randall J.
- Jack, Clifford
- Koeppe, Robert
- Venue
- Neurology
- Published
- 2018-10-02
- Volume
- 91
- Issue
- 14
- Pages
- e1295-e1306
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC6177272
- OpenAlex
- W2892024211
- Cited by
- 314
- References
- 35
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 48 · 2023: 28 · 2022: 47 · 2021: 52 · 2020: 46 · 2019: 24 · 2018: 3
- FWCI
- 24.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10033, NF-SI-0513-10134, NF-SI-0508-10123)
- Rosetrees Trust (M668-CD1)
- Medical Research Council (MR/L023784/2, MR/M009106/1, MR/L023784/1)
- National Institute on Aging (K23AG049087, UF1AG032438, K23AG046363, U19AG032438, U01AG032438, U24AG021886, K01AG053474)
- 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 › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- autosomal dominant Alzheimer's disease, disease progression, biomarkers, amyloid-beta, phosphorylated tau, cerebrospinal fluid biomarkers, cortical metabolism, hippocampal atrophy, mutation carriers, symptom onset, longitudinal change
- MeSH terms
- Adult, Alzheimer Disease, Brain, Cognition, Cross-Sectional Studies, Female, Follow-Up Studies, Genes, Dominant, Heterozygote, Humans, Longitudinal Studies, Male, Middle Aged, Mutation, Peptide Fragments, Phosphorylation, Biomarkers, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Presenilin-1, Presenilin-2
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