In Alois Alzheimer’s time (1900s), dementia was thought to be caused predominantly by “hardening of the arteries” (arteriosclerotic dementia) (Bowler, 2007 and Jellinger, 2006). Vascular factors were considered a major player in dementia well into the 20th century, until, in the 1980s, the Aβ peptide was identified as the

main component of parenchymal (amyloid plaque) and vascular (amyloid angiopathy) amyloid deposits, pathological hallmarks of AD (Glenner and Wong, 1984 and Kang et al., 1987). Shortly after, mutations in the amyloid precursor protein (APP) gene were identified in familial forms of AD (Bertram and Tanzi, 2008). Since then, the emphasis shifted from vascular dementia to AD, a process defined as the “Alzheimerization of dementia” (Figure 1) (Bowler, Abiraterone chemical structure 2007). However, an increasing appreciation of the impact of cerebrovascular lesions on AD brought to the forefront the importance of cerebrovascular health in cognitive function (Esiri et al., 1999, Gold et al., 2007 and Snowdon et al., 1997).

Furthermore, community-based clinical-pathological studies revealed that the largest proportion of dementia cases have mixed pathology, comprising features of AD (amyloid plaques and neurofibrillary tangles) as well as ischemic lesions (Launer et al., 2008 and Schneider et al., 2009). These developments have promoted an interest to gain a better understanding of how vascular brain lesions affect cognition and how vascular pathology and neurodegeneration interact to amplify their respective pathogenic contribution. The concept of dementia caused by cerebrovascular click here pathology has evolved considerably over the years (Figure 2). For many decades vascular dementia was attributed to sclerosis of cerebral arteries leading to diffuse ischemic injury and brain atrophy (Jellinger, 2006). The first significant departure from this concept, inspired by the work of Tomlinson and colleagues (Tomlinson et al., 1970), was proposed by Hachinski Adenylyl cyclase and colleagues (Hachinski et al., 1974), who suggested that dementia on vascular bases was caused by multiple

and discrete ischemic lesions in patients with vascular risk factors, such as hypertension (multi-infarct dementia) (Figures 2 and 3). The construct of multi-infarct dementia, by attributing cognitive impairment to multiple strokes, raised the possibility that preventing cerebrovascular diseases could also prevent dementia (Hachinski et al., 1974). The introduction of brain imaging led to the realization that diffuse white matter lesions, termed leukoaraiosis (Hachinski et al., 1987), were a frequent correlate of cognitive impairment, much more common than multiple infarcts, which turned out to be a rare cause of dementia (Hulette et al., 1997) (Figures 2 and 3). Genetic causes of white matter lesions were discovered, the prototypical one being the Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) (Chabriat et al., 2009).