The relevance of cerebrospinal fluid [alpha]-synuclein levels to sporadic and familial Alzheimer's disease

Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) [alpha]-synuclein ([alpha]Syn) levels and [alpha]Syn pathology in the brains of Alzheimer's disease (AD) patients suggests that [alpha]Syn is involved in the pathophysiology of AD. To investigate whether [alpha]Syn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of [alpha]Syn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members. Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline [alpha]Syn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF [alpha]Syn and the APOE[epsilon]4 allele. Further, CSF [alpha]Syn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF [alpha]Syn was positively correlated to .sup.11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOE[epsilon]4-positive ADAD mutation carriers exhibited an association between CSF [alpha]Syn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of [alpha]Syn, tau and amyloid-[beta].sub.1-40. Our results suggest that higher CSF [alpha]Syn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOE[epsilon]4 may promote the processes driven by [alpha]Syn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD de