Alzheimer’s Disease : Novel Biomarker for Early Detection

Dr. Ramon Trullas Research Professor CSIC Institute of Biomedical Research of Barcelona

Dr. Ramon Trullas
(left rear) Interview with:
Dr. Ramon Trullas
Research Professor
CSIC Institute of Biomedical Research of Barcelona What are the main findings of the study?

Answer: The findings reported in this manuscript that we consider can be underscored are:

1) Asymptomatic subjects at risk of developing sporadic Alzheimer’s disease (AD), as well as symptomatic patients diagnosed with probable sporadic AD show a low concentration of circulating cell free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF).

2) Pre-symptomatic subjects carrying pathogenic PSEN1 gene mutations which cause early onset familial AD, also exhibit low mtDNA content in CSF.

3) Reduced mtDNA content in CSF occurs in preclinical PSEN1 mutation carriers at least one decade before patients are expected to manifest clinical signs of dementia and well before any alteration in currently known AD biomarkers.

4)  Low mtDNA content in CSF distinguishes patients diagnosed with AD from either controls or patients with fronto-temporal lobar degeneration.

These findings indicate that the amount of circulating cell-free mtDNA content in CSF may be a novel biomarker for the early detection of AD in the preclinical stage of AD. Moreover, the observation that low mtDNA content in the CSF is associated with both sporadic and familial forms of AD suggests that, independently of the etiology, regulation of mtDNA content is a converging factor in the pathophysiology of AD. What should clinicians and patients take away from your report?

Answer: Diagnosis and treatment of dementias are currently faced with two major problems:

1) Uncertain diagnosis and

2) Lack of therapeutic treatments. Both problems are likely due to the lack of knowledge on what causes dementia. Another difficulty for diagnosis is that neurodegenerative disorders, including dementia, rarely appear as a single disorder.

In all cases, it is extremely important to identify these neurodegenerative disorders at the earliest stage of the disease, before the appearance of irreversible clinical symptoms. This is now difficult because we still do not have the knowledge of which are the biochemical processes that cause dementia.

Moreover, without the availability of efficient therapies, some people believe it is not useful to have a diagnosis. However, I think that the finding that low mtDNA precedes the appearance of dementia may help to advance in the knowledge of what causes dementia as well as help in both diagnosis and development of new therapies. Thus, a decrease in the content of mtDNA in CSF may help to diagnose AD before the appearance of irreversible clinical symptoms such as cognitive decline.

Although, in my opinion, the most important contribution of this finding is that when validated may help to identify new therapeutic treatments. What recommendations do you have for future research as a result of this study?

Answer: The next step is to make sure that this finding is reproduced in other hospitals and with other patient cohorts. This is not trivial. The uncertainty we have now in knowing that control subjects do not have the disease because we do not have precise diagnostic means is likely to have influenced recently failed clinical assays to develop new therapeutic treatments. Thus the difficulty in diagnosis may influence the results and we will not be confident that the finding is validated until other hospitals with different cohorts of patients reproduce our results. Once validated, future research will be devoted in identifying mechanisms that regulate mtDNA copy number in neurons.


Low CSF concentration of mitochondrial DNA in preclinical Alzheimer’s diseaseAccepted manuscript online: 22 JUN 2013, Petar Podlesniy, Joana Figueiro-Silva, Albert Llado, Anna Antonell, Raquel Sanchez-Valle, Daniel Alcolea, Alberto Lleo,
Jose Luis Molinuevo, Nuria Serra and Ramon Trullas

Annals of Neurology online: 22 JUN 2013
DOI: 10.1002/ana.23955

Last Updated on August 16, 2013 by Marie Benz MD FAAD