Abstract
Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1–42 (Aβ), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low Aβ in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by Aβ and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with Aβ and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, Aβ and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low Aβ and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that exhibits marked heterogeneity regarding its etiology and age of clinical onset
Whether these differences result in a unique biomarker profile that distinguishes slow progression AD (spAD) from rapid progressive AD (rpAD) at the early stages of cognitive decline has not been explored in detail
We previously found that patients with spAD, and no other dementias, which have the two core AD related biomarkers low Aβ and high t-tau in cerebrospinal fluid (CSF), exhibited low CSF content of cell-free mitochondrial DNA compared to control subjects without any AD-related biomarker or known genetic AD risk factor such as ApoE4 [20,21]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that exhibits marked heterogeneity regarding its etiology and age of clinical onset. The diagnosis of possible or probable AD utilizes clinical criteria with increasing support from neuroimaging and cerebrospinal fluid (CSF) core AD related biomarkers such as total-tau (t-tau), phospho-tau (p-tau) and beta-amyloid 1-42 (Aβ). These CSF biomarkers are able to predict the rate of cognitive decline in AD [12,13,14]. Despite the limited information about the molecular basis of rpAD, the rate of cognitive decline has been associated with the presence of diverse structural assemblies of Aβ [17,18] and with a proteomic content in amyloid plaques different that found in spAD [19]. Whether these differences result in a unique biomarker profile that distinguishes spAD from rpAD at the early stages of cognitive decline has not been explored in detail
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
