Aims

To compare cerebrospinal fluid (CSF) levels of the synaptic protein, VAMP-2, in Lewy body dementia (LBD) and Alzheimer’s disease (AD) patients.

Methods

We quantified VAMP-2 using a Single Molecular Array (ADx NeuroSciences) in aged cognitively normal controls (n=68) and patients from the Sant Pau Initiative for Neurodegeneration cohort clinically diagnosed with mild cognitive impairment/dementia due to LBD (n=47) or AD (n=119). LBD with AD co-pathology (LBD+AD n=28) was distinguished from pure LBD (n=19) using our validated CSF p-tau/Aβ₄₂ cut-off. Regression analyses were controlled for age and APOE E4 status.

Results

Compared to controls, mean CSF VAMP-2 levels were lower in pure LBD (0.86-fold, p=.005) but elevated in LBD+AD (1.58-fold, p=.009) and AD (1.25-fold, p=.04).The CSF p-tau/Aβ₄₂ ratio*LBD diagnosis interaction term contributed more to VAMP-2 levels (t=7.0, p<.0001) than either variable alone (t=5.6, p<.0001 and t=-4.4, p<.0001, respectively).

In ROC analyses, VAMP-2 showed good accuracy (area under the curve) to discriminate LBD+AD (.796, 95%CI .67-.90) and AD (.715, 95%CI .64-.79) from controls but poor accuracy to discriminate pure LBD (.579, 95%CI .42-.74) from controls.

VAMP-2 was associated with CSF Aβ₄₂/Aβ₄₀ in LBD+AD (r²=.40, p=.0002) and AD (r²=.17, p<.0001), with CSF tau markers in all groups (r²=.42 to .67, all p<.002) and with CSF Nf-L in controls (r²=.25, p=.01).

Conclusions

CSF VAMP-2 is not a surrogate marker of neurodegeneration. Low CSF VAMP-2 levels may reflect reduced synapse density in LBD patients, an effect that may be masked by AD pathology. Synuclein and AD pathologies may have a synergistic effect on CSF VAMP-2 levels.