VAMP2 Expression and Genotype Are Possible Discriminators in Different Forms of Dementia.

Andrea Saul Costa,Beatrice Arosio,Mario Clerici,Evelyn Ferri,Paolo Dionigi Rossi,Franca Rosa Guerini

doi:10.3389/fnagi.2022.858162

Abstract

Vascular alterations often overlap with neurodegeneration, resulting in mixed forms of dementia (MD) that are hard to differentiate from Alzheimer’s Disease (AD). The 26 bp intergenic polymorphism of VAMP2, a key component of SNARE complex, as well as its mRNA and protein levels are associated with neurological diseases. We evaluated ApoE4 and VAMP2 26 bp Ins/Del genotype distribution in 177 AD, 132 MD, 115 Mild Cognitive Impairment (MCI) and 250 individuals without cognitive decline (CT), as well as VAMP2 gene expression in a subset of 73 AD, 122 MD, 103 MCI and 140 CT. Forty-two MCI evolved to AD (22 MCI-AD) or MD (20 MCI-MD) over time. VAMP2 mRNA was higher in MD compared to AD (p = 0.0013) and CT (p = 0.0017), and in MCI-MD compared to MCI-AD (p < 0.001) after correcting for age, gender, MMSE and ApoE4 +/− covariates (pc = 0.004). A higher VAMP2 expression was observed in subjects carrying the minor allele Del compared to those carrying the Ins/Ins genotype (p = 0.012). Finally, Del/Del genotype was more frequently carried by MD/MCI-MD compared to CT (pc = 0.036). These results suggest that VAMP2 mRNA expression can discriminate mixed form of dementia from AD, possibly being a biomarker of AD evolution in MCI patients.

Highlights

Dementia is a common condition of the elderly characterized by multiple cognitive impairments leading to high disability
The MMSE score was different among the four groups (p < 0.001) with Alzheimer’s Disease (AD) and mixed forms of dementia (MD) patients having a significant lower MMSE score compared to cognitive decline (CT) and Mild Cognitive Impairment (MCI) (p < 0.001 for all the comparisons), as well as for the MCI compared to CT (p < 0.001)
The distribution of the ApoE4 variant showed a significant difference among the four groups (p < 0.001), with the ApoE4 allele being more frequent in AD compared to CT, MCI and MD patients (AD vs. CT: p < 0.001; OR: 3.76; 95% CI: 2.43–5.89; AD vs. MCI: p < 0.001; OR: 2.57; 95% CI: 1.54–4.33; AD vs. MD: p < 0.001; OR: 2.20; 95% CI: 1.34–3.64)

Summary

Introduction

Dementia is a common condition of the elderly characterized by multiple cognitive impairments leading to high disability. This clinical condition results from heterogeneous neurodegenerative and/or cerebrovascular diseases characterized by selective neuronal loss and by intra- or extracellular deposition of proteins (Prusiner, 2001) and/or by blood vessel blockage leading to dead tissue or bleeding area in the brain (Alzheimer’s Association, 2021). Neuropathological studies showed that synaptic loss is already evident in MCI. VAMP2: A Possible Mixed-Dementia Discriminator (Counts et al, 2014) and MCI subjects exhibit loss of pre- and postsynaptic proteins (Pham et al, 2010). MCI is often the initial step toward development of different kinds of dementia, including Alzheimer’s Disease (AD), Vascular dementia (VAD), Dementia with Lewy Body (DLB) and Frontotemporal Dementia (FTD) (Alzheimer’s Association, 2021)

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Results

Conclusion