2025 Volume 11 Pages 6-9
According to the estimation of Japan’s population composition, the number of individuals over 65 years is expected to rise significantly, with one in four predicted to be 75 years or older by 2070. This demographic trend has increased the focus on dementia prevention. Fourteen modifiable risk factors, including hypertension, diabetes, smoking, and obesity are linked to dementia. Cerebral small-vessel disease (SVD), associated with vascular risk factors, plays a critical role in dementia progression. SVD, which affects small blood vessels in the brain, leads to brain damage including white matter lesions and microbleeds, detectable through magnetic resonance imaging. Recent research demonstrates that SVD progression contributes to cognitive decline and dementia, particularly in individuals with Alzheimer’s disease (AD), as both often coexist and impact cognitive function. Although the effect of SVD on AD progression remains debatable, managing vascular risk factors is crucial for preventing both SVD and dementia. Early detection and management of SVD may delay the onset of dementia and slow cognitive decline, emphasizing the need for preventive healthcare strategies for aging populations.
Japan is facing a population aging, and the 2024 edition of the White Paper on Aging, published by the Cabinet Office, reports that 36.23 million people are aged 65 years or older, accounting for 29.1% of the total population1). By 2070, it is estimated that one in 2.6 people will be 65 years old or older, and one in four will be 75 years old or older. In response to this aging society, various measures are being implemented to address mild cognitive impairment (MCI) and dementia, and measures to prevent dementia are beginning to show partial effects. In a 2022 regional survey on dementia prevalence, the reported rates were lower than those published from the 2012 Ministry of Health, Labor and Welfare report2). This decline may reflect a decreased progression from MCI to dementia and the importance of dementia prevention.
In 2020, Livingston et al. identified 12 modifiable risk factors for dementia prevention3). In 2024, they added high low-density lipoprotein cholesterol and visual loss, thereby increasing the total of 14 factors4). The proportion of potentially modifiable risk factors of dementia was estimated at 40% in the 2020 report and 45% in the 2024 report. These 14 risk factors include vascular factors such as hypertension, diabetes, smoking, and obesity, which highlight their importance in dementia prevention.
Recent studies have highlighted the significant role of small vessel disease (SVD) for the onset and progression of dementia. This review summarizes the current findings on the impact of SVD on dementia, including its pathophysiology, diagnostic methods, and future issues and prospects.
Cerebral SVD refers to lesions that occur in the small blood vessels (arteries and veins with a diameter of 0.1 to 0.3 mm) that perfuse white matter tracts, basal ganglia, thalamus, and pons5). In the brain, small blood vessels mainly supply blood to the deep gray matter and subcortical white matter and, to a lesser degree to the cortical gray matter, juxtacortical white matter, and leptomeninges6,7). Small cerebral blood vessels branch directly from the main cerebral blood vessels, and microvascular studies have demonstrated that each small blood vessel perfuses a different area with almost no overlap or anastomosis with neighboring vessels8). Due to these characteristics, the small cerebral blood vessels are close to the large arteries and are therefore at high risk of being affected by hypertension, because there is no overlap in perfusion, the blockage of small blood vessels is likely to lead to infarction downstream9).
Small-vessel disease is strongly associated with arteriosclerotic risk factors, such as hypertension, diabetes, and hyperlipidemia. The incidence of the disease increases with age, and approximately 5% of people aged 50 years and approximately 100% of those older than 90 years are affected6). The prevalence of SVD increases with age, but there are no significant sex differences, and there are currently no known differences across racial and ethnic groups or geography6). A study conducted in 1999 reported that the incidence of lacunar infarction was high among African Americans; however, this has not been replicated10).
The most common pathologies associated with SVD are cerebral amyloid angiopathy (CAA) and hypertension-related SVD5). Pathological findings of SVD include atherosclerosis, cortical and subcortical microinfarcts, white matter lesions, and microhemorrhages11). These pathological changes cause regional cerebral hypoperfusion, tissue ischemia, neuronal cell death, gliosis, brain atrophy, and accumulation of amyloid-β (Aβ) and phosphorylated tau proteins12). In addition to a cause of direct blood flow disorders, SVD also involves degeneration of the walls of blood vessels and inflammatory reactions and has a wide-ranging impact on brain function.
Cerebral white matter lesions (WML) can be easily identified using cerebral magnetic resonance imaging (MRI), and can be used as imaging biomarkers for SVD13,14). The severity of WML has been reported to correlate with the presence or absence of vascular risk factors (VRFs)15). WMLs are often categorized into deep white matter hyperintensity (DWMH) and periventricular hyperintensity (PVH). DWMH and PVH are caused by ischemic damage to the brain13). DWMH is closely related to SVD, as it is accompanied by neuropathological changes due to damage to nerve fibers caused by ischemic changes16), while PVH is caused by blood-brain barrier dysfunction or disruption of the ventricular ependymal lining, and as a result, it may cause cerebrospinal fluid to leak into the periventricular white matter17).
Cerebral microbleeds (CMBs) are imaging biomarkers of SVD and are strongly associated with aging9). The CMBs distribution is associated with two different pathologies. CMB in the lobar region is thought to be associated with CAA, whereas CMB in the deep or subcortical regions suggests hypertensive microangiopathy18).
A meta-analysis conducted in 2021 showed that hypertension, diabetes, hyperlipidemia, and smoking were significantly associated with the risk of lacunar infarction and WML19). This study suggests that measures for controlling these risk factors are necessary to prevent SVD.
In 2024, the results of a study on the relationship between the incidence of MRI markers of SVD, such as WML and CMBs, in the community-dwelling older adults, and the prevalence of modifiable lifestyle factors were reported5). In this study, 241 community-dwelling older adults underwent two cerebral MRIs with a mean interval of 5.9 years, and the incidence of WMH, lacunar infarction, medial temporal lobe atrophy, and CMBs were evaluated, and the relationship with modifiable lifestyle factors was analyzed using multivariate regression analysis. The results showed that smoking was related to the incidence of CMBs, and moderate-to-high alcohol intake was related to medial temporal lobe atrophy. It was concluded that interventions for these modifiable lifestyle factors could prevent SVD.
We investigated the relationship between VRFs such as hypertension, dyslipidemia, and diabetes, and cerebral MRI findings in 49 patients with MCI and mild dementia with mini-mental state examination (MMSE) scores of 20 or more and clinical dementia rating scores of 0.5 or 1. The percentage of the WML area relative to the brain parenchymal area was defined as the percentage of WML. The results showed that the percentage of WML was significantly higher in the group with hypertension (mean percentage (SD) = 8.7 (4.9)) than in the group without hypertension (mean percentage (SD) = 4.3 (3.0)) (p = 0.002). When CMBs were evaluated separately as lobar or deep, no significant differences were observed; however, the number of CMBs tended to be higher in the group with hypertension than in the group without hypertension.
Not all infarctions lead to acute symptomatic stroke. However, when asymptomatic cerebral ischemia progresses over a long period, it can have a devastating toll. The burden of SVD accumulates over time, leading to cognitive impairment and eventually dementia. Vascular disease is thought to be involved in approximately 50% of all-cause dementia9).
Mina et al. conducted a 14-year follow-up study of patients with sporadic SVD to investigate the relationship between baseline SVD severity, progression of SVD as measured using cerebral MRI, and the onset of dementia20). Higher baseline WMH volume was independently associated with all-cause dementia and vascular dementia. WML progression predicts the onset of all-cause dementia. Both baseline severity and progression of SVD were independently associated with an increased risk of all-cause dementia over 14 years of follow-up. These results suggest that SVD progression may precede dementia and contribute to its development. Slowing SVD progression may delay the onset of dementia.
In our case studies, we examined the relationship between the results of neuropsychological testing and WML in 49 patients with MCI and mild dementia. Although there were no statistical significance between the WML area and neuropsychological test scores (MMSE (rs = –0.051, p = 0.770), Frontal Assessment Battery (rs = –0.289, p = 0.093), and Japanese version of Montreal Cognitive Assessment (rs = –0.261, p = 0.129)), there was a tendency that the larger percentage of WML showed the lower score of the neuropsychological test (Fig. 1).
We examined the relationship between neuropsychological testing results and percentage of WML in 49 patients with MCI and mild dementia. Statistical analyses were performed using IBM SPSS Statistics version 28 (IBM Japan, Tokyo, Japan). The association between the percentage of WML and neuropsychological test scores was evaluated using Spearman’s rank correlation coefficient. There was no statistical significance of association between the percentage of WML and the scores of the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), or Japanese version of the Montreal Cognitive Assessment (MoCA-J), but there was a trend that the larger percentage of WML showed the lower score of the neuropsychological test.
As coexistence of pathological indicators of AD and SVD is often observed in older brains, there has been considerable interest in understanding their relationship. A previous autopsy study of patients with AD has shown that the presence of cerebrovascular disease can reduce the cognitive function of patients with AD in the early stages of Braak neurofibrillary tangle pathology21). In our previous study on the association between cerebral Aβ accumulation and SVD in patients with AD, we found that more severe ischemic MRI findings are associated with milder Aβ accumulation22). We conclude that SVD may hasten the onset of cognitive decline and promote the early detection of dementia in AD.
While cerebral WMLs are caused by chronic hypoperfusion and ischemic damage to the brain, parietal WML seen in AD brains are considered to result from Wallerian degeneration as a consequence of AD pathology23). Based on our previous studies, WML in patients with AD is thought to reflect both the pathophysiology of AD and the consequences of SVD22). Vascular risk factors are closely associated with cerebrovascular disease and the development of AD24,25). Given that up to 90% of patients with AD have cerebral hypoperfusion and pathological features of amyloid angiopathy26), early intervention to prevent ischemia is crucial27).
However, some studies reported that the effect of SVD on progressive cognitive decline in AD is mild. Littau et al. used platelet-derived growth factor receptor beta as a marker to assess arteriolar pericyte coverage in post-mortem brains of familial AD patients with presenilin-1 mutations, and compared it with the progression of cognitive decline28). They found a significant negative correlation between pericyte coverage and MMSE decline, suggesting that severer pathological cerebrovascular damage is associated with slower progression of cognitive decline. Moonen et al. investigated whether SVC affects cognitive decline in non-demented individuals with Aβ-positive findings on cerebrospinal fluid or amyloid-PET. The results showed that in non-demented individuals with Aβ-positive biomarkers, the presence or absence of SVD did not affect the progression of cognitive decline29). These conflicting results may be derived from differences in hereditary or sporadic AD, disease stage, or other factors. To our knowledge, no large study has directly compared WML and Aβ burden regarding cognitive decline over time, highlighting the need for further research.
We explored the relationship between SVD and cognitive decline, highlighting the importance of managing VRFs to prevent SVD. Early assessment and management of SVD and its risk factors are crucial for preventing dementia and slowing its progression.
Conflict of interest: The authors have no potential conflicts of interest to declare.
Funding: This study was supported, in part, by a Health and Labor Sciences Research Grant for Research on Intractable Diseases from The Ministry of Health, Labour and Welfare of Japan (23FC2001).
