The definitive diagnosis of Alzheimer disease or VCI is based on histopathology. Theories surrounding the onset of Alzheimer disease describe either a pathological deposition of amyloid protein resulting in neuronal damage and Alzheimer disease  or chronic vascular damage leading to cerebral hypoperfusion, a neuroglial energy crisis, and neuronal damage ultimately leading to Alzheimer disease . The pathological changes seen in Alzheimer disease and VCI are quite specific, however. Alzheimer disease is characterized by the deposition of extraneuronal neuritic plaques and development of intracellular neurofibrillary tangles. Neuritic plaques are structurally based on amyloid-beta (β) fibrils that are a product of amyloid precursor protein cleavage by β and gamma (γ) secretases such as the presenilins. This proteolytic action generates highly hydrophobic amyloid-β fibrils that are prone to aggregation and thus deposition in the extracellular matrix. On the other hand, neurofibrillary tangles are intraneuronal protein aggregates of tau proteins that are thought to be the toxic effects of amyloid plaques on surrounding neurons. Separately, tau protein mutations are also associated with other neurodegenerative disorders described as ‘tauopathies’ [frontotemporal dementia (FTD), corticobasal degeneration, and progressive supranuclear palsy]. The pathological characteristics of VCI are more diverse and include discrete infarction, hemorrhage, and white matter lesions. Pathological studies have demonstrated an overlap of histopathological findings between Alzheimer disease and VCI and the prevalence of both conditions in patients that undergo autopsy ranges from 25 to 50% [21,22]. Increasing evidence suggests the relationship between amyloid and ischemia is bidirectional, with amyloid deposition causing vascular damage and ischemia causing an increase in amyloid deposition .
Vascular risk factors have been associated with the onset of cognitive impairment. As with most vascular and neurocognitive disorders, VCI is more common in older patients. The presence of atheromatous formations in the extracranial and intracranial vessels predisposes the patient to ischemic events, both subclinical brain infarction (SBI) and stroke, and small vessel disease as well as amyloid angiopathy cause white matter damage and the latter causes hemorrhage as well. The presence of SBI, white matter lesions, hemorrhage, and brain atrophy seen on brain imaging in large population-based studies has been linked with the vascular risk factors in vivo and vascular pathology on autopsy [24,25]. Further, vascular damage has been linked to loss of brain microstructural integrity (as measured by diffusion tensor imaging – DTI) in normal appearing white matter, but few population-based studies exist . In turn, subclinical cerebrovascular damage increases the risk of stroke and predicts VCI [14,15,27–35]. The number and volume of lesions is also a predictor of dementia. Clinical–pathological correlations have suggested that larger volumes and greater numbers of lesions are associated with a greater risk of VaD [7,36]. Increasing evidence suggests that exposure to risk factors in midlife is associated with VCI later on, making the length of exposure a key factor.
Several studies have examined the association between hypertension and cognitive impairment. High blood pressure in midlife has been shown to be associated with cognitive impairment 14, 25, and 30 years later, and high diastolic blood pressure at age 50 has been found to predict poor cognitive outcomes at age 70 [37–39]. High blood pressure has also been associated with impairment on tests of executive function . In addition, control of blood pressure decreased the incidence of dementia in a controlled trial . High blood pressure may damage small blood vessels and affect cognition by disrupting subcortical circuits. This is supported by the finding that white matter hyperintensity (WMH) and subclinical infarcts are associated with elevated blood pressure [32,42]. But the relationship between blood pressure and VCI is likely age-dependent as low blood pressure has been associated with a greater risk of dementia in the oldest old, underscoring the importance of midlife exposure [43,44]. Longstanding hypertension impairs vasomotor reactivity and shifts the cerebral autoregulation curve such that reducing blood pressure later on may result in an increased risk of stroke because of an increase in the minimum blood pressure required for adequate cerebral perfusion . This argues in favor of hypoperfusion as a possible cause of VCI but requires further study. Conversely, VCI may lead to damage of autonomic systems that regulate blood pressure and this could cause further worsening of cognition in a feed forward manner.
There is some evidence suggesting that treating hypertension to prevent heart disease and stroke decreases the risk of cognitive impairment. In the Heart Outcomes Prevention Evaluation (HOPE) study, the effect of the angiotensin-converting enzyme inhibitor (ACE-I) ramipril was compared against placebo in 1013 high-risk patients with a history of stroke or transient ischemic attack (TIA). Beyond the 24% relative risk reduction in stroke, myocardial infarction, and vascular death among patients treated with ramipril, the study showed a 59% relative risk reduction of cognitive decline [46,47]. Similarly, in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) , 6105 patients with stroke or TIA within 5 years were randomized to the ACE-Inhibitor Perindopril versus the combination of perindopril plus the diuretic indapamide. The combination resulted in a 43% relative reduction of risk of recurrent stroke, a 40% relative reduction in vascular events, and a 23% risk reduction of VCI , without a significant difference for the ACE-I group alone. Finally, the European Systolic Hypertension (SYST-EUR) trial, which randomized patients to receive the calcium channel blocker (CCB) enalapril or placebo, showed a 42% relative reduction in the incidence of stroke in the treatment group  and a 55% relative reduction in the risk of dementia .
The ongoing Systolic Pressure Intervention Trial Memory and cognition IN Decreased hypertension (SPRINT-MIND) study is designed to determine if a systolic blood pressure goal of less than 120 mmHg compared to 140 mmHg will decrease the rate of incident dementia and MCI, global and domain-specific cognitive function, and small vessel ischemic disease .
The abnormalities of serum lipids (dyslipidemia) have been found to be a risk factor for coronary artery disease (CAD) but less so for cerebrovascular disease. Dyslipidemia has been found to be an important risk factor for dementia and Alzheimer disease, especially in those who are Apoε4 negative [65▪]. However, data from long-term population-based studies suggest that elevated total cholesterol in midlife increases the risk of both Alzheimer disease and VCI later in life [66–69]. Similarly, data from the Rotterdam Study suggests that treatment with statins, but not other lipid-lowering agents, was associated with a lower risk of dementia . However, the association between statins and dementia is unclear and a recent meta-analysis showed no net effect of statins on the risk of dementia .
There is increasing evidence that those with the metabolic syndrome, a composite of several risk factors including abdominal obesity, elevated triglycerides and LDL-cholesterol, low HDL-cholesterol, raised blood pressure, insulin resistance, and prothrombotic and proinflammatory states, have a greater incidence of vascular outcomes, and this may place these people at greater risk of cognitive dysfunction through VCI. For example, in the Honolulu–Asia Aging study of Japanese–American men, the metabolic syndrome predicted VaD but not Alzheimer disease . Few studies have been done on VCI, but waist circumference has been associated with worse executive function in one study . Race–ethnic disparities in the association between the metabolic syndrome and VCI are understudied, and many of the components are highly prevalent in Hispanic and black individuals. For example, the population-based Northern Manhattan Study found the metabolic syndrome to be associated with worse cognitive performance [74▪▪].
Consumption of alcohol is also a potential mediator of the effects of vascular disease on cognition. Moderate consumption has been associated with better cognitive function or a lower risk of dementia compared to abstainers in some studies [80–83], but other studies have shown a U-shaped relationship with heavy drinkers having decreased cognitive function or an increased risk of dementia [82–84]. The connection between alcohol and VCI is suggested by the data showing that moderate alcohol consumption is related to a lower burden of WMH and subclinical infarcts, supporting the idea that it may diminish vascular damage to the brain [82,85]. However, study results have varied in relation to the amount of alcohol associated with a positive effect on the development of VCI.
Atrial fibrillation is present in approximately 1% of the U.S. population and the incidence increases with age, with a prevalence of 6% in individuals older than 65 and of 10% in those older than 75 years . Both persistent and paroxysmal atrial fibrillation are potent predictors of first and recurrent stroke, and the annual risk of stroke in untreated individuals with nonvalvular atrial fibrillation is about 5% per year . Atrial fibrillation-related stroke is associated with greater severity, disability, and mortality than stroke because of other causes , and the risk of stroke is even greater in patients with concomitant hypertension, diabetes, prior stroke or TIA, CAD, or CHF . Several studies show that atrial fibrillation is more common among patients with cognitive impairment, and the Rotterdam Study found atrial fibrillation was an independent predictor for the development of Alzheimer disease and VCI [96–98]. Moreover, even in the absence of manifest stroke, atrial fibrillation is a risk factor for cognitive impairment and hippocampal atrophy . The causal mechanisms by which atrial fibrillation may predispose to dementia in those without stroke need clarification, but subclinical embolic infarction is a likely cause.
These glycoproteins are responsible for lipid transport in the central nervous system and other organs. Three main isoforms (ε2, ε3, and ε4) are encoded in chromosome 19. The ε4 allele is a well-known genetic factor associated with the onset of Alzheimer disease  and cardiovascular disease . Though it is known that Apoε4 increases the risk of Alzheimer disease, the mechanisms are unclear and the presence of this genotype does not imply that the carrier will develop Alzheimer disease, and, moreover, some Alzheimer disease patients are not carriers of the Apoε4 genotype. In relation to VaD, several studies report no association with Apoε4 genotype [102,103].
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 104).
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