Collectively, these observations highlight the importance of neurovascular factors in maintaining white matter health. The realization that most cases of dementia have mixed pathological features has raised the intriguing possibility that vascular factors play role in AD and other neurodegenerative diseases. As discussed in the section on “Mixed lesions,” AD brains have a wide variety of vascular lesions, suggesting

a potential pathogenic interaction between vascular factors and AD. However, since cerebrovascular diseases and AD are common in the aged, the coexistence of the two pathologies could simply be coincidental (Hachinski, 2011). The overall effect on cognition would results from the combined burden of vascular and neurodegenerative pathology, according to an additive model. Alternatively, vascular disease could promote AD and vice-versa, PI3K Inhibitor Library resulting in a reciprocal interaction amplifying their pathogenic effects. The DNA Damage inhibitor cognitive impact of vascular and AD neuropathology depends on the severity of the AD pathology and location of the vascular lesions (Gold et al., 2007). In advanced cases of AD, vascular lesions do not seem to have a major influence on the progression of the cognitive deficits, suggesting the AD pathology is the major driver of the cognitive dysfunction (Chui et al., 2006 and Jellinger,

2001). On the other hand, in older individuals with moderate AD pathology subcortical too vascular lesions are a major determinant of the expression of the dementia (Esiri et al., 1999, Schneider et al.,

2007b and Snowdon et al., 1997). Cerebrovascular function is reduced in patients with early AD or at risk for AD (Claassen et al., 2009, Gao et al., 2013, Luckhaus et al., 2008, Mentis et al., 1996, Niedermeyer, 2006, Ruitenberg et al., 2005, Sabayan et al., 2012 and Tanaka et al., 2002), implicating reduced cerebral perfusion in the pathobiology of the disease (Iadecola, 2004). Conversely, some studies (Jendroska et al., 1995 and Ly et al., 2012), but not others (Aho et al., 2006 and Mastaglia et al., 2003), have reported increased amyloid deposition in stroke patients, implicating that ischemia promotes AD pathology. Furthermore, AD and cerebrovascular diseases may have common risk factors, such as hypertension, insulin resistance, diabetes, obesity, hyperhomocystinemia, hyperlipidemia, etc. (Craft, 2009, Fillit et al., 2008, Honjo et al., 2012 and Purnell et al., 2009). However, the correlation was most evident when the risk factors were considered together and not individually (Chui et al., 2012). Furthermore, the correlation was strongest for vascular dementia and weakest for AD, suggesting that vascular risk factors may independently increase the likelihood of dementia without exacerbating AD pathology (Chui et al., 2012).