Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer’s Disease
Abstract
Background: The earliest stage of preclinical Alzheimer’s disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ 42 ). However, covariance in longitudinal dynamic change of Aβ 42 and tau in incipient preclinical AD is poorly understood. Objective: To examine dynamic interrelationships between Aβ 42 and tau in preclinical AD. Methods: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ 42 levels in CSF, CI were classified into three groups: 1) Aβ 42 stable with normal levels of Aβ 42 over time ( n = 15); 2) Aβ 42 declining with normal Aβ 42 levels at baseline but showing decline over time ( n = 14); and 3) Aβ 42 levels consistently abnormal ( n = 18). Results: In the Aβ 42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time ( p = 0.0001). Correlation between longitudinal slopes of Aβ 42 and p-tau confirmed that both trajectories were anti-correlated (rho = –0.60; p = 0.02). Regression analysis showed that Aβ 42 slope (decreasing Aβ 42 ) predicted p-tau slope (increasing p-tau) (R 2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ 42 and p-tau slopes ( p < 0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. Conclusions: The evolution of Aβ 42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ 42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ 42 and p-tau thus may be evident in very early stages of preclinical AD.
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In individuals with low baseline WMH, the strong correlation between Aβ accumulation and p-Tau217 change suggests a rapid pathogenetic cross-talk and a temporal sequence of successive amyloid and tau phosphorylation in early pre-clinical stage.
“Individuals with low baseline WMH exhibited a strong correlation between Aβ accumulation and p‐Tau217 change, consistent with previous findings, 33 , 36 , 37 suggesting a rapid pathogenetic cross‐talk and a temporal sequence of successive amyloid and tau phosphorylation in this early pre‐clinical stage.”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [37]
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- Authors
- Gomar, J. J., Conejero-Goldberg, C., Davies, P., Goldberg, T. E., & Initiative, F. T. A. D. N.
- Affiliations
- The Litwin-Zucker Research Center, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
- Northwell Health (US)
- Corresponding author
- Goldberg, Terry E.
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2016-02-26
- Volume
- 51
- Issue
- 4
- Pages
- 1085-1097
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2291588658
- Cited by
- 13
- References
- 46
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 2
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- BioClinica
- Eisai
- National Institute on Aging (R01AG038734)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- preclinical Alzheimer's disease, cerebrospinal fluid biomarkers
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Peptide Fragments, Regression Analysis, Amyloid beta-Peptides, tau Proteins, Disease Progression, Statistics, Nonparametric, Prodromal Symptoms
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