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Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease
Open accessAbstract
OBJECTIVE: To identify a novel biochemical marker that precedes clinical symptoms in Alzheimer disease (AD). METHODS: Using quantitative polymerase chain reaction techniques, we measured circulating cell-free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) from study participants, selected from a cohort of 282 subjects, who were classified according to their concentrations of amyloid β1-42, total tau, and phosphorylated tau and by the presence or absence of dementia, into asymptomatic subjects at risk of AD, symptomatic patients diagnosed with sporadic AD, presymptomatic subjects carrying pathogenic PSEN1 mutations, and patients diagnosed with frontotemporal lobar degeneration (FTLD). We performed equivalent studies in a separate validation cohort of sporadic AD and FTLD patients. In addition, we measured mtDNA copy number in cultured cortical neurons from mutant amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice. RESULTS: Asymptomatic patients at risk of AD and symptomatic AD patients, but not FTLD patients, exhibit a significant decrease in circulating cell-free mtDNA in the CSF. These observations were confirmed in the validation cohort. In addition, presymptomatic subjects carrying pathogenic PSEN1 gene mutations show low mtDNA content in CSF before the appearance of AD-related biomarkers in CSF. Moreover, mtDNA content in CSF discriminates with high sensitivity and specificity AD patients from either controls or patients with FTLD. Furthermore, cultured cortical neurons from APP/PS1 transgenic mice have fewer mtDNA copies before the appearance of altered synaptic markers. INTERPRETATION: Low content of mtDNA in CSF may be a novel biomarker for the early detection of preclinical AD. These findings support the hypothesis that mtDNA depletion is a characteristic pathophysiological factor of neurodegeneration in AD.
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“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [213]
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The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786
Mitochondrial DNA copy number in human disease: the more the better?
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Biological aging processes underlying cognitive decline and neurodegenerative disease
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A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease
Area-Gomez, E., de Groof, A., Bonilla, E., Montesinos, J., Tanji, K., Boldogh, I., Pon, L., & Schon, E. A. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0215-0 · Cited by 235
Metadata
- Authors
- Podlesniy, P., Figueiro‐Silva, J., Llado, A., Antonell, A., Sanchez‐Valle, R., Alcolea, D., Lleo, A., Molinuevo, J. L., Serra, N., & Trullas, R.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Neurology Service Hospital Clinic de Barcelona Barcelona Spain
- Hospital Clínic de Barcelona (ES)
- Hospital de Sant Pau (ES)
- Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED Madrid Spain
- Neurobiology Unit Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, CSIC Barcelona Spain
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2013-09-04
- Volume
- 74
- Issue
- 5
- Pages
- 655-668
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W1778065122
- Cited by
- 219
- References
- 24
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 13 · 2023: 18 · 2022: 21 · 2021: 21 · 2020: 17 · 2019: 12 · 2018: 20 · 2017: 11 · 2016: 21 · 2015: 16 · 2014: 15 · 2013: 4
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
- Funders
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Alzheimer's disease, preclinical Alzheimer's disease, mitochondrial DNA, cerebrospinal fluid biomarkers, PSEN1 mutations, frontotemporal lobar degeneration, APP/PS1 mice, cortical neurons, mtDNA depletion, neurodegeneration, early detection
- MeSH terms
- Alzheimer Disease, Animals, DNA, Mitochondrial, Female, Humans, Male, Mice, Transgenic, Peptide Fragments, Phosphorylation, Biomarkers, Amyloid beta-Protein Precursor, tau Proteins, Mice, Presenilin-1, Cognitive Dysfunction, Prodromal Symptoms
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