• Alzheimer's disease
• blood biomarkers
• dementia with Lewy bodies
• Parkinson's dementia

Alzheimer’s Disease (AD), Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) are the most frequent neurodegenerative diseases (NDDs). AD pathological hallmarks are extracellular neuritic plaques, primarily represented by accumulations of amyloid beta peptide (Aß) and intraneuronal neurofibrillary tangles (NFT), mainly composed of abnormally phosphorilated tau protein. PDD and DLB are characterized by the presence of Lewy bodies, that is abnormal intraneuronal aggregates consisting of protein alpha-synuclein (α-syn). Nevertheless, several recent studies report that almost 40% of PDD and DLB subjects show pathological Aβ deposition and that 1/3 of AD subjects show α-syn accumulations. These findings suggest a consistent overlap in the pathophysiological processes underpinning those NDDs.
The blood-based detection of biomarkers could be an ideal tool to identify pathogenic mechanisms underlying NDDs since it is non-invasive, repeatable and relatively cheap.
In the present cross-sectional study we aimed to 1) evaluate differences in the levels of biomarkers Aβ1-42 (amyloid-ß peptide containing 42 amino acids), t-tau (total tau protein), α-syn, α-syn-Aβ (heterodimer alpha-synuclein/amyloid-ß peptide) and α-syn-tau (heterodimer alpha-synuclein/tau protein) detected in red blood cells (RBCs) between a group of subjects diagnosed with mild AD dementia or Mild Cognitive Impairment (MCI) due to AD (AD group), a group of subjects diagnosed with Lewy Body Disease (LBD) including PDD and DLB patients (LBD group), and a group of cognitively healthy subjects or CHS (CHS group); 2) assess the diagnostic accuracy of RBC biomarkers in discriminating AD, LBD and CHS groups.
AD group consists of 51 subjects diagnosed with AD at the Center for Cognitive Disorders whereas LBD group consists of 27 subjects diagnosed with LBD at the Center for Movement Disorders. In parallel, 60 CHS have been recruited (CHS group).
A blood sample was taken from all subjects and every sample underwent the same processing. Subsequently, RBCs were isolated from blood samples and subjected to different immunoenzymatic essays in order to detect the concentrations of Aβ1-42, t-tau, α-syn and heterodimers α-syn-Aβ and α-syn-tau.
The ANOVA test showed statistically significant differences between the groups for all the biomarkers with the exception of Aβ1-42. In particular, mean levels of t-tau, α-syn and heterodimer α-syn/tau were found to be higher in CHS group compared to both AD and LBD groups whereas mean levels of heterodimer α-syn-Aβ turned out to be higher in CHS group than in AD group.
Interestingly, ROC curve analysis highlighted the role of heterodimer α-syn-tau in differentiating CHS group from both LBD and AD groups with a good (0.81) and a fair (0.76) accuracy, respectively. Heterodimer α-syn-Aβ showed a fair accuracy (0.72) in discriminating CHS group from AD group, whereas t-tau similarly turned out to be fairly accurate (0.73) in the discrimination between CHS and LBD groups.
Our results show that concentrations of all biomarkers except Aβ1-42 are higher in CHS compared to demented patients, but they do not significantly differ between AD and LBD groups. In light of the frequent concomitance of proteinopathies, we suggest that these NDDs show similar concentrations of RBC biomarkers on account of some common pathophysiological pathways. Indeed, recent post-mortem studies report several cases of copathologies of different misfolded proteins (Aβ, α-syn, tau abnormal depositions) in patients with AD or LBD clinical pictures.
Aberrant proteins related to NDDs are in a constant dynamic balance among central nervous system (CNS) and peripherical tissues by means of cerebrospinal fluid (CSF), plasma and blood cells. Diffusion processes and blood-brain barrier damage seem to be the mechanisms that are most likely involved.
Additionally, blood is a highly complex system as it contains a range of different molecules which could interact with each other in different ways depending on several variables (e.g. kidney or liver metabolism).
It may be noted that some limitations, such as the relatively small sample size, hindered further stratification (concerning PDD and DLB patients). The non-homogeneity of the groups in regard to age, sex and disease stages should be likewise considered. Moreover, given the cross-sectional nature of our study and the lack of adequate follow-up, we are unable to explore the prognostic value of these RBC biomarkers.
Finally, a comparison of biomarker concentrations in RBCs with those in plasma and CSF will be necessary in future investigations.
Thus, in order to expand these results, additional studies including larger cohorts of patients need to be carried out, taking into account different phenotypes in different stages of disease and evaluating changes in the levels of RBC biomarkers over a longer term. These investigations might be useful in the diagnostic work-up providing additional information on the complex pathogenic mechanisms underpinning AD, PDD, DLB and NDDs on a much wider scale.