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Cited by 531Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCancer-related cognitive impairment studies

Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease

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Jack, C. R., Wiste, H. J., Vemuri, P., Weigand, S. D., Senjem, M. L., Zeng, G., Bernstein, M. A., Gunter, J. L. +8 more·2010·Brain
DOI 10.1093/brain/awq277PMC PMC2965425
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Abstract

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer's disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer's disease co-existent with other pathologies.

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  • The risk of short-term cognitive decline increases continuously with worsening (N) biomarkers.

    “the risk of short-term cognitive decline increases continuously with worsening (N) biomarkers, and this may be true of T biomarkers as well [108,109].”

    From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [109]

  • The risk of short-term cognitive decline may also increase continuously with worsening T biomarkers.

    “the risk of short-term cognitive decline increases continuously with worsening (N) biomarkers, and this may be true of T biomarkers as well [108,109].”

    From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [109]

    The Statistical methods section identifies hippocampal volume and Aβ load as the primary predictors; the Discussion reports a continuous risk relationship for hippocampal atrophy, an (N) biomarker. The paper does not report whether risk increases continuously with worsening tau (T) biomarkers (searched: tau, phosphorylated tau, and the predictors analysed). (LLM, conf=0.77)

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Authors
Jack, C. R., Wiste, H. J., Vemuri, P., Weigand, S. D., Senjem, M. L., Zeng, G., Bernstein, M. A., Gunter, J. L., Pankratz, V. S., Aisen, P. S., Weiner, M. W., Petersen, R. C., Shaw, L. M., Trojanowski, J. Q., Knopman, D. S., & Initiative, T. A. D. N.
Affiliations
  • Mayo Clinic (US)
  • University of California San Diego (US)
  • University of California, San Francisco (US)
  • University of Pennsylvania (US)
Corresponding author
Jack, C. R.
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2010-10-08
Volume
133
Issue
11
Pages
3336-3348
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awq277
PMC
PMC2965425
OpenAlex
W2168283959
Cited by
531
References
29
Citations by year
2026: 21 · 2025: 20 · 2024: 35 · 2023: 18 · 2022: 31 · 2021: 27 · 2020: 32 · 2019: 29 · 2018: 40 · 2017: 35 · 2016: 29 · 2015: 34 · 2014: 41 · 2013: 48 · 2012: 48
FWCI
30.17
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Mayo Foundation for Medical Education and Research (AG16574)
  • National Institutes of Health (AG11378, AG06786, AG024904, R01 AG11378, AG16574)
  • National Institute on Aging (R01AG11378, P50‐AG16574, U01AG06786, AG 024904, U01AG006786, R01AG011378, U19AG010483, P50AG016574)
  • National Center for Research Resources (C06RR018898)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
Keywords
Alzheimer's disease, mild cognitive impairment, time to progression, amyloid-beta, Pittsburgh compound B PET, hippocampal atrophy, neurodegeneration, biomarkers, Alzheimer's Disease Neuroimaging Initiative, amyloid deposition, dementia risk prediction, multiple imputation, hippocampal volume
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Cognition Disorders, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Time Factors, Amyloid beta-Peptides, Disease Progression

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