In the brain, arteries and veins do not run in parallel, and its perfusion system has characteristics not found in other organs. The presence of a tight blood-brain barrier and lack of authentic lymphatic vessels in the parenchyma means clearance of some waste products, such as β-amyloid (Aβ), is impeded. Aβ is thus cleared from the brain via at least four clearance pathways including 1) transcytotic delivery, 2) intramural periarterial drainage, 3) glymphatic drainage and 4) enzymatic or glial degradation. Failure in any four such pathways has been implicated in the pathophysiological processes behind Alzheimer’s disease. In clinical trials of Aβ vaccination therapy, vascular Aβ deposition was paradoxically enhanced, with encephalitis subsequently occurring in a fraction of patients. This serious side effect may be associated with insufficient clearance of solubilized Aβ through clearance systems in response to immunotherapy. Transcytotic delivery, intramural periarterial drainage, and glymphatic drainage clearance pathways depend on vascular integrity and are partly driven by vascular wall motion; therefore arteriosclerosis or perfusion pressure reduction is assumed to increase Aβ accumulation. Strategies activating clearance systems may be helpful in the treatment of intractable disease through reduction of brain Aβ, therefore aiding development of neurovascular prevention strategies for Alzheimer’s disease.

Lifestyle-related diseases, such as diabetes mellitus, hypertension, and dyslipidemia, are known to promote arteriosclerosis and increase the risk of vascular dementia. Recent epidemiological studies have revealed that these lifestyle-related diseases are risk factors not only for vascular dementia but also for Alzheimer’s disease. Such findings suggest a common molecular pathology between vascular dementia and Alzheimer’s disease, which is mediated by biological pathways associated with lifestyle-related diseases, including the renin-angiotensin system and insulin signaling. There is a complicated interplay in mutual modifications among lifestyle-related diseases, vascular dementia, and Alzheimer’s disease. It is important to take the complex and multifactorial nature of the disease into account when considering the underlying disease mechanisms of individual patients with dementia. It is also becoming evident that the molecules related to the pathogenesis of Alzheimer’s disease, such as β-amyloid, have a direct impact on cerebrovascular damages, which could also be important for understanding the link between vascular dementia and Alzheimer’s disease, and how it is influenced by lifestyle-related diseases. Given the rapid growth of the aging population, the treatment strategy for dementia is necessarily shifting to earlier-stage interventions and prevention. Understanding how lifestyle-related diseases contribute to the pathogenesis of both vascular dementia and Alzheimer’s disease could be a key in tackling dementia.

Homozygous mutations of high temperature requirement A serine peptidase 1 (HTRA1) gene cause an autosomal recessive cerebral small vessel disease, namely cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Meanwhile, heterozygous mutations of the HTRA1 can also cause an autosomal dominant small vessel disease with a milder clinical phenotype. Here we described 2 patients in a Japanese family with the same heterozygous HTRA1 mutation (c.496 C>T, p.R166C), showing a unique clinical history of traumatic subarachnoid hemorrhage (SAH), no alopecia or spondylosis, in addition to previously similar clinical phenotypes such as cognitive impairment, gait disturbance, and hyperreflexia. The present cases suggest that traumatic SAH may be an important risk of the heterozygous HTRA1 mutation (c.496 C>T, p.R166C), especially in Asia.