Journal
NATURE AGING
Volume 2, Issue 11, Pages 1040-+Publisher
SPRINGERNATURE
DOI: 10.1038/s43587-022-00300-1
Keywords
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Categories
Funding
- Alzheimer Nederland [WE.03-2018-05]
- attraction talent fellowship of Comunidad de Madrid [2018-T2/BMD-11885]
- San Pablo CEU University
- Institute of Health Carlos III [PI18/00435, INT19/00016]
- Department of Health Generalitat de Catalunya PERIS program [SLT006/17/125]
- Penn University
- National Institute on Aging [NINDS R01-NS109260-01A1, P01-AG066597, P30-AG072979, U19-AG062418-03, NINDSP50-NS053488-09]
- Alzheimer Center Amsterdam
- Stichting Alzheimer Nederland
- Selfridges Group Foundation
- Stichting VUmc fonds
- Pasman stichting
- Stichting Dioraphte - ZonMW, NWO
- EU-FP7
- Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte
- stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation
- Biogen MA
- Roche BV
- Fujifilm
- ZonMW [3305095007, LSHM20106]
- Health~Holland, Topsector Life Sciences Health [LSHM20106]
- European Commission (Marie Curie International Training Network) [860197, 831434]
- EPND (IMI 2 Joint Undertaking (JU)) [101034344]
- JPND (bPRIDE)
- National MS Society
- Dutch Research Council (ZonMW)
- Alzheimer Drug Discovery Foundation
- Alzheimer Netherlands
- Alzheimer Association
- Edwin Bouw Fonds
- [NR170065]
- Marie Curie Actions (MSCA) [860197] Funding Source: Marie Curie Actions (MSCA)
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This study identifies specific dysregulated CSF proteins along the AD continuum, reflecting the multifactorial nature of disease progression. Some of these dysregulated proteins can be used as biomarkers for the diagnosis and clinical trials of AD.
Development of disease-modifying therapies against Alzheimer's disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(A beta+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity ligation-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(A beta+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(A beta+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85-0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8-0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials. This study identifies CSF proteins specifically dysregulated along the AD continuum that reflect the multifactorial nature of disease progression. Some of these CSF proteins were used to build biomarker panels with high diagnostic accuracies.
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