LAUSR

BACKGROUND AND OBJECTIVES Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer's disease (AD) pathology. Cerebrospinal fluid (CSF) biomarkers allow the detection in vivo of AD-related pathological hallmarks included in the AT(N) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuro-axonal damage are correlated with the presence of AD co-pathology in LBD and can be useful to differentiate LBD patients with different AT(N) profiles. METHODS We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, p-tau, t-tau) and of synaptic (β-synuclein, α-synuclein, SNAP-25, neurogranin) and neuro-axonal proteins (NfL) in 28 cognitively unimpaired participants with non-degenerative neurological conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups. RESULTS CSF β-synuclein, α-synuclein, SNAP-25, neurogranin and NfL levels did not differ between LBD (n = 101, age = 67.2 ± 7.8 years, 27.7% females) and controls (age = 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI n = 30, AD-dem n = 30, age = 72.3 ± 6.0 years, 63.3% females) compared to both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuro-axonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and β-synuclein showed the highest discriminative accuracy between the two groups (AUC = 0.938, 95%CI = 0.884 - 0.991). CSF β-synuclein (p = 0.0021), α-synuclein (p = 0.0099) and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarkers levels within the normal range. CSF α-synuclein was significantly decreased only in LBD patients with T- profiles compared to controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level. DISCUSSION LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuro-axonal biomarkers compared to LBD/A-T- and control subjects. LBD patients with AD co-pathology might, thus, experience similar degrees of synaptic dysfunction than pure AD cases. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that CSF levels of β-synuclein, α-synuclein, SNAP-25, neurogranin and NfL are higher in patients with AD than in patients with LBD.