A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment
Open accessAbstract
Alzheimer’s disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson’s disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ 42 ), tau, and phosphorylated tau (p-tau 181 )] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer’s Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ 42 , tau, and p-tau 181 . pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ 42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)–(0.005)]). CSF α-synuclein predicted Alzheimer’s Disease Assessment Scale-Cognitive (β= –0.59, p = 0.0015, 95% CI [(–0.96)–(–0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)–(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)–(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)–(0.20)]). pS129 was associated with executive function (β= –2.55, p = 0.0085, 95% CI [(–4.45)–(–0.66)]). Lower values in the mismatch between α-synuclein and p-tau 181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)–(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau 181 -Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.
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There is a strong correlation between cerebrospinal fluid levels of αSyn and both total tau and phosphorylated tau.
“The same study further confirmed the by us and others previously reported strong correlation between CSF levels of αSyn and both t-tau and p-tau [19, 81, 98].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [98]
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- Authors
- Wang, H., Stewart, T., Toledo, J. B., Ginghina, C., Tang, L., Atik, A., Aro, P., Shaw, L. M., Trojanowski, J. Q., Galasko, D. R., Edland, S., Jensen, P. H., Shi, M., Zhang, J., & Initiative, F. T. A. D. N.
- Affiliations
- University of Washington (US)
- University of Pennsylvania (US)
- Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA
- University of California San Diego (US)
- Aarhus University (DK)
- Corresponding author
- Zhang, Jing
- ORCID
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2018-01-23
- Volume
- 61
- Issue
- 4
- Pages
- 1541-1553
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC5828159
- OpenAlex
- W2791984994
- Cited by
- 33
- References
- 51
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 4 · 2018: 4
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Scopus (Elsevier) (submittedVersion)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Alzheimer's Association (U01 AG024904, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (W81XWH-12-2-0012, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
- Lundbeckfonden (R223‐2015‐4222)
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, AG024904)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
- National Institute on Aging (U01-AG-024904, R01AG056711, P50AG005131, P30AG010124, P30AG062429, U19AG024904)
- National Institute of Neurological Disorders and Stroke (U01NS082137, U01NS091272)
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- alpha-synuclein, phosphorylated alpha-synuclein
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Male, Memory Disorders, Neuropsychological Tests, Phosphorylation, Biomarkers, Multivariate Analysis, Linear Models, tau Proteins, Disease Progression, alpha-Synuclein, Executive Function, Cognitive Dysfunction
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