Associations Between Alzheimer Disease Biomarkers, Neurodegeneration, and Cognition in Cognitively Normal Older People
Open accessAbstract
IMPORTANCE: Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort. INTERVENTION: Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning. MAIN OUTCOMES AND MEASURES: For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography). RESULTS: Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention. CONCLUSIONS AND RELEVANCE: Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.
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The rate of cognitive decline is significantly greater for cognitively impaired and CU individuals who have abnormalities in both an amyloid biomarker and a second biomarker type (CSF T-tau or P-tau, atrophy, or hypometabolism) in comparison to individuals who have neither or only one of these biomarker abnormalities.
“The rate of cognitive decline is significantly greater for cognitively impaired and CU individuals who have abnormalities in both an amyloid biomarker and a second biomarker type (which could be CSF T-tau or P-tau, atrophy, or hypometabolism) in comparison to individuals who have neither or only one of these biomarker abnormalities [30–35,39,40,42–45].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [42]
The Discussion (page unavailable) says amyloid burden and neural injury can interact to lower cognition, which supports the general relevance of both biomarker types. But the study is cross-sectional: it does not establish a significantly greater rate of cognitive decline for people with both abnormalities than for those with one or neither, or establish that comparison across cognitively impaired and cognitively unimpaired people. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe combination of an abnormal MRI, CSF T-tau, or FDG PET study with an abnormal amyloid biomarker provides much more powerful prediction of future cognitive decline than an abnormal amyloid study alone.
“However, the combination of an abnormal MRI, CSF T-tau, or FDG PET study with an abnormal amyloid biomarker provides much more powerful prediction of future cognitive decline [30–35,39,40,42–45] than an abnormal amyloid study alone.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [42]
The Discussion (page unavailable) says neural injury and amyloid burden can interact to lower cognition, and suggests that accumulating neurodegenerative abnormalities could increase the risk of future decline. But the Methods describe cross-sectional analyses, and this paper does not show that combining MRI, CSF T-tau, or FDG-PET with an amyloid biomarker predicts future decline more powerfully than an abnormal amyloid study alone. (LLM, conf=0.85)
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- Authors
- Wirth, M., Villeneuve, S., Haase, C. M., Madison, C. M., Oh, H., Landau, S. M., Rabinovici, G. D., & Jagust, W. J.
- Affiliations
- University of California, Berkeley (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Wirth, Miranka
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2013-10-28
- Volume
- 70
- Issue
- 12
- Pages
- 1512-9
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4962545
- OpenAlex
- W2074980270
- Cited by
- 171
- References
- 9
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 8 · 2023: 6 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 17 · 2018: 14 · 2017: 16 · 2016: 16 · 2015: 21 · 2014: 26 · 2013: 1
- FWCI
- 15.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (131515)
- National Institute on Aging (P30AG010129, P01 AG1972403, K01AG030514, AG034570, K23AG031861, R01AG034570, P50AG023501)
- 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, preclinical Alzheimer's disease, neurodegeneration, amyloid-beta, Pittsburgh compound B, white matter lesions, hippocampal volume, glucose metabolism, cortical thickness, cognitive function, memory, executive function, cerebrovascular disease, cognitively normal older adults, neurodegeneration biomarkers, carbon-11
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Aniline Compounds, Cognition Disorders, Cross-Sectional Studies, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Neuropsychological Tests, Psychiatric Status Rating Scales, Thiazoles, Cohort Studies, Biomarkers, Neurodegenerative Diseases, Fluorodeoxyglucose F18, Positron-Emission Tomography, Community-Based Participatory Research
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