Although hypertension is well known as a cause of vascular dementia (VaD), recent findings highlight the role of hypertension in the pathogenesis of Alzheimer's disease (AD) as well as mild cognitive impairment (MCI).

Recent studies have shown that disruption of diurnal blood pressure (BP) variation is closely associated with cognitive impairment via injury of the small cerebral arteries indicating that long-standing hypertension constitutes a risk of brain matter atrophy or white matter lesions (WMLs).

In several clinical trials, BP-lowering with antihypertensive agents was suggested to reduce the risk of dementia or cognitive decline.

This review paper focuses on the role of hypertension as a risk factor for cognitive impairment, and summarizes current knowledge on the relationships between ambulatory BP monitoring (ABPM) and cognitive impairment.

Finally, an overview of the impact of antihypertensive therapy on dementia prevention is provided.

American Journal of Hypertension 2010; doi:10.1038/ajh.2009.212

Although hypertension is well known as a cause of vascular dementia (VaD),¹ recent findings highlight the role of hypertension in the pathogenesis of Alzheimer's disease (AD).

Mild cognitive impairment (MCI) is regarded as a risk for dementia, and its identification is thought to lead to secondary prevention by controlling the risks for cardiovascular diseases.

Recent studies have shown that disruption of diurnal blood pressure (BP) variation was closely associated with cognitive impairment.^2,3

In several clinical trials, BP-lowering with antihypertensive agents was shown to substantially reduce the risk of dementia or cognitive decline.

This review paper focuses on the role of hypertension as a risk factor for cognitive impairment, and summarizes current knowledge on the relationships between ambulatory BP monitoring (ABPM) and cognitive impairment. Finally, an overview of the impact of antihypertensive therapy on dementia prevention is provided.

Dementia was subdivided into AD, VaD, or mixed variants. In spite of the literature on the dichotomy between AD and VaD, new concepts highlight the role of cardiovascular risks in the pathogenesis of AD.

VaD can arise from stroke involving brain areas critical for memory processing.^6,7 In the elderly, subcortical small vessel disease is known to be associated with VaD.

Exposure of the small brain vessels to higher BP, pulsatile pressure and flow leads to microvascular damage⁸ that results in white matter damage, silent lacunae, and cortical disconnection.⁹

Multiple infarction dementia exhibits a stepwise but unpredictable course, depending on the size, localization, and number of ischemic insults.⁷

In a case–control study nested within the Framingham cohort, stroke survivors showed a 2.0–2.8-fold greater risk of dementia than controls.⁹

The extraneuronal and intraneuronal accumulation of amyloid β-peptide (Aβ) starts a pathogenetic cascade that results in neurotoxicity among AD patients.¹¹

Aβ toxicity starts in the entorhinal cortex, and then involves neurons of other areas. The second histopathological hallmark of AD is neurofibrillary tangles that consist of hyperphosphorylated microtubule-associated protein Tau.¹¹

These tangles aggregate as pairs of filaments, so-called paired helical filaments, that affect the nutrition of axon terminals and dendrites.

Neuroimaging¹² and postmortem histopathological¹³ studies indicate that up to one-third of AD patients have some degree of vascular pathology, and whereas AD lesions are also present in a similar proportion of VaD.

Cholinesterase inhibitors treatments stimulate regional cerebral blood flow (CBF) in patients with AD or VaD.¹⁴ Aβ constricts human cerebral arteries.¹⁵

Aβ attenuates endothelium-mediated dilatation in the cerebral arteries by production of reactive oxygen radicals and impairs the increase in neocortical CBF in response to somatosensory activation.¹⁶

Transgenic mice overexpressing mutated forms of amyloid precursor protein, from which misfolded Aβ originates, show a reduction in CBF^15,16 and an impaired autoregulation of the cerebral circulation.¹⁷

The APOEε4 allele plays a critical role in plaque formation.¹⁸ Staessen et al. summed up these pathophysiological overlaps and interactions between AD and VaD.⁵

In the present review, we focus on the relationship between hypertension and components of AD, and consider the factors shared in common by AD and VaD (Figure 1).

Common pathophysiology for VaD and AD.

Each of vascular and cholinergic factor is associated with reduced cerebral blood flow. This would be act as a common factor for silent brain injury such as leukoaraiosis or brain atrophy. AD, Alzheimer's disease; VaD, vascular dementia.

Michiaki Nagai^1,2, Satoshi Hoshide¹ and Kazuomi Kario¹

• ¹Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
• ²Department of Internal Medicine, Shobara City Soryo Clinic, Shobara, Japan

Correspondence: Kazuomi Kario, (kkario@jichi.ac.jp)

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