۱- Background

۲- Methodological considerations

۳- Historical context and origins of the terminology

۴- Controversies on MxD clinicopathological significance

۵- Vascular contribution to AD: shared risk factors and mixed pathological burden

۶- The inner relation between AD and VaD. Is there a mechanistic link?

۷- Towards new ways of conceptualizing MxD

۸- Conclusive remarks

References

Abstract

Clinical and pathological data show that Alzheimer’s disease (AD) and vascular dementia (VaD) are the most prevalent types of dementia in the elderly. Medically speaking, mixed dementia (MxD) is a heterogenous disorder mostly referred to the coexistence of AD and VaD. The weight of vascular contribution to AD phenotype is nowadays matter of debate. Despite great efforts in the field of neurodegeneration and cerebrovascular disease, controversy over the exact nature of their relation still remains, hampering progress in the specialty and raising doubts about the MxD concept validity. Is MxD a neglected clinical entity or a nosographic artifice? Starting from the assumption that recent advances in dementia classification and diagnostic criteria make this a propitious time to set up preventive and therapeutic strategies, this narrative review and opinion paper summarizes the literature concerning the questioned etiopathogenic overlap between AD and VaD and challenges the traditional view of MxD as the mere co-occurrence of different pure forms of dementia.

Background

The term mixed dementia (MxD) literally refers to the combination of more than one possible cause of dementia, of whatever type. In medical practice, it is mostly applied to those cases wherein there is clinical and/or pathological evidence of both dementia of Alzheimer type and cerebrovascular disease. While in vivo criteria likely underestimate MxD frequency, data from neuroimaging and autopsy-based studies suggest that mixed pathology accounts for the majority of dementia cases among very old individuals [1]. Signs of cerebral microangiopathy and large infarcts are of frequent occurrence in patients otherwise diagnosed as suffering from Alzheimer’s disease (AD), as well as hippocampal atrophy and hyperphosphorylated tau-protein aggregates, both typically deemed as markers of neurodegeneration, can be found among patients affected by vascular dementia (VaD) [2,3]. The role of vascular pathology as critical contributor to AD is a topic of current interest. Experimental and clinical evidence seems to challenge the traditional view that AD and VaD are distinct conditions and supports the notion of converging pathogenic mechanisms, thus making dementing disorders liable to preventive approaches [4]. On the other hand, the concept of MxD solely understood as the coexistence of different pure forms of dementia is still far from being abandoned. After a brief excursus on the evolution of MxD concept over time, this paper updates current opinion on AD and VaD and their inner relation, paying attention to shared risk factors and pathophysiology.