Synucleinopathy in Alzheimer’s disease: role of the alpha‐synuclein seed amplification assays

Background Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most frequent proteinopathies of the central nervous system. Alpha‐synuclein seed amplification assays (αS‐SAA) are the most promising techniques for the in vivo detection of synucleinopathies, ie, PD and DLB. In neuropathological studies, Lewy Bodies (LBs) have been found in 50‐60% of AD patients. In AD, concomitant LB pathology could lead to parkinsonism and to a more aggressive course of the disease. Whether concomitant LBs could be related to some clinical aspects of AD, i.e., clinical variants or clinical progression, remains to be assessed. In our work, we applied αS‐SAA to determine whether the rate of assay positivity differs in AD vs controls (CTRL), and among AD clinical variants. Method We used αS‐SAA to test 457 CSF samples from a cohort of AD, CTRL, and patients with PD and DLB. Classical AD CSF biomarkers were used to select CTRL and AD patients according to the A/T/(N) system. All CTRL showed a CSF A‐/T‐/N‐ profile while all AD patients were A+T+. Details of the subjects included are reported in Table 1. Fisher’s Exact test for count data and logistic regression (by assuming age and gender as covariates) were used to evaluate the significance of the different prevalences observed. Result We observed significantly higher αS‐SAA positivity in PD/DLB (86%) and AD patients (30%) with respect to CTRL subjects (13%, 7% in CTRL CN and 16% in CTRL MCI subjects) (Fig‐1A). Among the AD clinical variants, patients with posterior variant exhibited significantly higher αS‐SAA positivity (Fig‐1C). Interestingly, αS‐SAA positivity increased in the diagnostic groups as they progressed to later stages of AD, with the highest percentage in the AD at dementia phase (AD‐dem) group (36%) (Fig‐1B). Conclusion Our results show that a large portion of AD cases have concomitant synucleinopathy and αS‐SAA could allow stratification of AD cases, as assay positivity was associated with AD subtypes and progression. Further evaluation of cross‐sectional and longitudinal clinical data is needed to determine potential prognostic value of αS‐SAA in AD. Early detection of synucleinopathy in AD patients will be increasingly important for design of personalized disease‐modifying therapies.