To date, the concept of VaDep is still not widely accepted; there are no formal agreed definitions or diagnostic criteria, the pathomechanisms are not fully understood, the natural history is unknown, and no specific therapy has been confirmed. It is acknowledged that old age depression is a heterogeneous illness with high treatment resistance associated with a number of contributing neurobiological factors, including CVD, neurodegeneration, inflammation, and others, all of which also contribute to its longitudinal prognosis and course [
32,
166]. Elderly people are probably vulnerable to depression, and cardiovascular disease, diabetes mellitus, high cholesterol levels, and other such diseases increase the risk for LLD [
32,
46,
61,
86,
224]. Drugs used for cardiovascular disease, such as beta blockers, may also potentially cause depression. Thus, if a stroke victim develops depression, this by itself does not prove a causal relationship. VaDep is frequently presumed to be associated with cognitive decline and an increased risk of subsequent dementia [
30]. CVD, deep white matter changes, and other (neurodegenerative) lesions have been hypothesized to contribute to increased risk of dementia in the aged, and a host of neuroimaging and clinicopathological studies have examined the interplay between brain pathologies and LLD. This has resulted in new concepts such as the VaDep hypothesis, but despite multiple studies, the relationship between microstructural and related (biochemical) changes in human brain and LLD remains controversial. Recent studies suggested a relationship between brain levels of high-energy phosphate metabolites and executive function in geriatric depression, which is consistent with predictions of the VaDep hypothesis, but further work is necessary to clarify these effects [
225]. Unlike VaDep, the hyperfacilitation of the motor cortex found at baseline in vascular MCI-no dementia patients suggested enhanced glutamatergic neurotransmission that might contribute to the preservation of cognitive functioning in these patients [
226]. It seems that diagnosing an elderly person as having VaDep just because imaging studies demonstrate WMHs might be debatable, since the latter are quite common in the elderly anyway, particularly in those with cardiovascular disease. Thus, although there is considerable empiric support for the validity of a VaDep subtype of LLD, fundamental questions remain open, including how the illness is defined, how vascular disease and depression influence each other, why VaDep is not a progressive disorder despite the possible related brain lesions tending to accumulate, and whether executive dysfunction or WMHs and global vascular risk are responsible for poor response to anti-depressive treatment [
28,
227]. While postmortem findings in some elderly suicided persons revealed lacunes, CSVD, WMHs, and AD-related and other pathologies [
228], recent autopsy findings in patients fulfilling the diagnostic criteria of VaDep challenged the role of cerebrovascular pathologies as major morphological substrates of depressive symptoms or poorer executive function and memory in the aged. Similarly, neuropathological data suggested that EOD is not associated with an acceleration of age-related cerebral lesions [
31]. Of note, selective serotonin reuptake inhibitor treatment is associated with more neurogenesis and angiogenesis in the human hippocampus [
229], whereas in the dentate gyrus, there is less neurogenesis and angiogenesis in MDD patients than in controls. Nevertheless, this trend is reversed by selective serotonin reuptake inhibitor treatment [
230], suggesting that one of the mechanisms of action of antidepressants could be through re-establishment of the angiogenesis/neurogenesis niche in this region, which is crucial for memory and emotional regulation. In the case of VaDep drugs, sustaining the vasculature could be essential for cell survival, assuming that vascular changes are the first mediators of cellular changes. There is a need for genetic studies related to cerebral pathologies in LLD in order to better grasp its neuronal basis [
231]. Such work may benefit not only from examining genetic markers of neurotransmitter or neuronal activity, but also markers related to vascular disease risk [
232].