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Cited by 57Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

High Soluble Amyloid‐β42 Predicts Normal Cognition in Amyloid‐Positive Individuals With Alzheimer's Disease‐Causing Mutations

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Sturchio, Andrea, the Dominantly Inherited Alzheimer Consortia (DIAN), Dwivedi, Alok K., Malm, Tarja, Wood, Matthew J.A., Cilia, Roberto, Sharma, Jennifer S., Hill, Emily J. +8 more·2022·Journal of Alzheimer's Disease
DOI 10.3233/jad-220808PMC PMC9661329
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Abstract

BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. OBJECTIVE: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. CONCLUSION: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

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Cited by

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Authors
Sturchio, A., (DIAN), T. D. I. A. C., Dwivedi, A. K., Malm, T., Wood, M. J. A., Cilia, R., Sharma, J. S., Hill, E. J., Schneider, L. S., Graff-Radford, N. R., Mori, H., Nübling, G., El Andaloussi, S., Svenningsson, P., Ezzat, K., & Espay, A. J.
Affiliations
  • Karolinska Institutet (SE)
  • Texas Tech University Health Sciences Center (US)
  • University of Eastern Finland (FI)
  • University of Oxford (GB)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • University of Cincinnati (US)
  • University of Southern California (US)
  • Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
  • German Center for Neurodegenerative Diseases (DE)
  • Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Stockholm, Sweden
Corresponding author
  • Sturchio, Andrea
  • Espay, Alberto J.
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2022-10-25
Volume
90
Issue
1
Pages
333-348
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-220808
PMC
PMC9661329
OpenAlex
W4296328734
Cited by
57
References
4
Citations by year
2026: 9 · 2025: 9 · 2024: 18 · 2023: 17 · 2022: 4
FWCI
7.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion, other-oa)
Funders
  • Alzheimer's Association (SG-20-690363-DIAN)
  • Fondation Brain Canada
  • Japan Agency for Medical Research and Development
  • Korea Health Industry Development Institute
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Fleni
  • Canadian Institutes of Health Research
  • Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
  • Instituto de Salud Carlos III
  • National Institute on Aging (U19AG032438, P30AG066530)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
amyloid-beta 42, Alzheimer's disease
MeSH terms
Alzheimer Disease, Amyloidosis, Cognition, Dementia, Humans, Mutation, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Cognitive Dysfunction

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