Potential Diagnostic Value of Red Blood Cells α-Synuclein Heteroaggregates in Alzheimer’s Disease

A plethora of complex misfolded protein combinations have been found in Alzheimer disease (AD) brains besides the classical pathological hallmarks. Recently, α-synuclein (α-syn) and its heterocomplexes with amyloid-β (Aβ) and tau have been suggested to be involved in the pathophysiological processes of neurodegenerative diseases. These pathological features are not limited to the brain, but can be also found in peripheral fluids. In this respect, red blood cells (RBCs) have been suggested as a good model to investigate the biochemical alterations of neurodegeneration. Our aim is to find whether RBC concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) were different in AD patients compared with healthy controls (HC). The levels of homo- and heteroaggregates of α-syn, Aβ and tau, were analyzed in a cohort of AD patients at early stage either with dementia or prodromal symptoms (N = 39) and age-matched healthy controls (N = 39). All AD patients received a biomarker-based diagnosis (low cerebrospinal fluid levels of Aβ peptide combined with high cerebrospinal fluid concentrations of total tau and/or phospho-tau proteins; alternatively, a positivity to cerebral amyloid-PET scan). Our results showed lower concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) in RBCs of AD patients with respect to HC. RBC α-syn/Aβ as well as RBC α-syn/tau heterodimers discriminated AD participants from HC with fair accuracy, whereas RBC α-syn concentrations differentiated poorly the two groups. Although additional investigations are required, these data suggest α-syn heteroaggregates in RBCs as potential tool in the diagnostic work-up of early AD diagnosis.