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Amyloid-β, Anxiety, and Cognitive Decline in Preclinical Alzheimer Disease: A Multicenter, Prospective Cohort Study
Open accessAbstract
IMPORTANCE: Alzheimer disease (AD) is now known to have a long preclinical phase in which pathophysiologic processes develop many years, even decades, before the onset of clinical symptoms. Although the presence of abnormal levels of amyloid-β (Aβ) is associated with higher rates of progression to clinically classified mild cognitive impairment or dementia, little research has evaluated potentially modifiable moderators of Aβ-related cognitive decline, such as anxiety and depressive symptoms. OBJECTIVE: To evaluate the association between Aβ status and cognitive changes, and the role of anxiety and depressive symptoms in moderating Aβ-related cognitive changes in the preclinical phase of AD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments, we studied 333 healthy, older adults at hospital-based research clinics. MAIN OUTCOMES AND MEASURES: Carbon 11-labeled Pittsburgh Compound B (PiB)-, florbetapir F 18-, or flutemetamol F 18-derived measures of Aβ, Hospital Anxiety and Depression Scale scores, and comprehensive neuropsychological evaluation that yielded measures of global cognition, verbal memory, visual memory, attention, language, executive function, and visuospatial ability. RESULTS: A positive Aβ (Aβ+) status at baseline was associated with a significant decline in global cognition, verbal memory, language, and executive function, and elevated anxiety symptoms moderated these associations. Compared with the Aβ+, low-anxiety group, slopes of cognitive decline were significantly more pronounced in the Aβ+, high-anxiety group, with Cohen d values of 0.78 (95% CI, 0.33-1.23) for global cognition, 0.54 (95% CI, 0.10-0.98) for verbal memory, 0.51 (95% CI, 0.07-0.96) for language, and 0.39 (95% CI, 0.05-0.83) for executive function. These effects were independent of age, educational level, IQ, APOE genotype, subjective memory complaints, vascular risk factors, and depressive symptoms; furthermore, depressive symptoms and subjective memory complaints did not moderate the association between Aβ and cognitive decline. CONCLUSIONS AND RELEVANCE: These results provide additional support for the deleterious effect of elevated Aβ levels on cognitive function in preclinical AD. They further suggest that elevated anxiety symptoms moderate the effect of Aβ on cognitive decline in preclinical AD, resulting in more rapid decline in several cognitive domains. Given that there is currently no standard antiamyloid therapy and that anxiety symptoms are amenable to treatment, these findings may help inform risk stratification and management of the preclinical phase of AD.
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Metadata
- Authors
- Pietrzak, R. H., Lim, Y. Y., Neumeister, A., Ames, D., Ellis, K. A., Harrington, K., Lautenschlager, N. T., Restrepo, C., Martins, R. N., Masters, C. L., Villemagne, V. L., Rowe, C. C., & Maruff, P.
- Affiliations
- United States Department of Veterans Affairs (US)
- The University of Melbourne (AU)
- New York University (US)
- Edith Cowan University (AU)
- Corresponding author
- Pietrzak, Robert H.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2015-03-01
- Volume
- 72
- Issue
- 3
- Pages
- 284
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2049932209
- Cited by
- 214
- References
- 51
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 24 · 2023: 17 · 2022: 22 · 2021: 27 · 2020: 19 · 2019: 15 · 2018: 15 · 2017: 20 · 2016: 15 · 2015: 10
- FWCI
- 16.22
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- JAMA Psychiatry (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Australasian Journal of Paramedicine (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- 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
- amyloid-beta, preclinical Alzheimer's disease, anxiety, cognitive decline, depressive symptoms, moderating effect, amyloid PET, Pittsburgh compound B, florbetapir, verbal memory, executive function, language, global cognition, older adults, subjective memory complaints, APOE genotype, mild cognitive impairment, dementia risk
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Anxiety, Depression, Female, Genotype, Humans, Male, Middle Aged, Neuropsychological Tests, Prospective Studies, Amyloid beta-Peptides, Disease Progression, Positron-Emission Tomography, Prodromal Symptoms
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