An introduction to therapeutic challenges of vascular cognitive impairment

Neurodegenerative disorders (NDD) are classified based on subtypes of aggregated proteins, regional brain degeneration and associated clinical syndromes. The designation of vascular cognitive impairment, or rather vascular neurodegenerative disorders (VNDD) can apply to any degenerative brain disease where vascular pathologies are considered as drivers of the dysfunction and degeneration. While pathologies can be quantified at autopsy, the diagnosis of VNDD can be made pre‐mortem based on existing vascular risk factors, biomarker abnormalities and presence of neuropsychiatric symptoms. The differences in classification and approach to diagnosis of NDD versus VNDD, however, and the perceived prevalence of none vascular NDD over VNDD pose barriers to therapeutic developments for VNDD. Often, based on A/T/N biomarkers, the pre‐mortem diagnosis of an individual with biomarker abnormalities and cognitive impairment would be AD, even in presence of significant vascular risk factors and imaging biomarker abnormalities.The first question we need to ask is how can we make the diagnosis of VNDD more accurately and more often? The second would be what are the therapeutically targetable cellular and molecular pathologies in VNDD and how diverse is the vascular pathology underpinning neurodegeneration in VNDD? Finally, if we posit that the most therapeutically targetable phase of VNDD is preclinical, prior to clear cognitive deficits, how do we gauge therapeutic efficacy of interventions?