Recent advances in dementia research have substantially improved our understanding of its pathogenesis, prevention, and treatment. While disease-modifying therapies, such as anti-amyloid-β monoclonal antibodies, have ushered in a new era in Alzheimer’s disease management, increasing attention has been directed toward dementia prevention strategies. Accumulating evidence suggests that lifestyle-related diseases, particularly vascular risk factors, play a critical role in cognitive decline and dementia development. This review discusses the relationship between vascular health and dementia prevention, with a focus on nutritional interventions and brain-targeted supplements, especially omega-3 polyunsaturated fatty acids, as adjunctive strategies for neuroprotection.

Background: Chronic cerebral hypoperfusion is among the main causes of white matter hyperintensities and lobar cerebral microbleeds (CMBs). Long-term resveratrol intake is associated with improvement in cerebral blood flow. However, it remains unclear whether long-term resveratrol therapy could contribute to the amelioration of cerebral small vessel disease.

Methods and Results: This retrospective study enrolled patients with asymptomatic carotid artery stenosis of ≥50% or occlusion who underwent two brain MRI at an interval of 6–13 months. Patients who were administered 30 mg/day of resveratrol after the first MRI were compared to those who were not. We included 39 patients who received resveratrol and 237 who did not. Over a mean follow-up duration of 290.4 and 310.6 days (p = 0.11), the resveratrol group showed significantly lower prevalence of exacerbated lobar CMBs than the non-resveratrol group (5.1% vs. 14.1%; p = 0.046). Furthermore, the long-term intake of resveratrol showed a trend toward being an independent protective factor against lobar CMB exacerbation (adjusted odds ratio, 0.24; 95% confidence interval [CI], 0.054–1.10; p = 0.065) and was independently associated with fewer increases in the number of lobar CMBs (count ratio, 0.23; 95%CI, 0.05–0.97; p = 0.045).

Conclusion: Long-term resveratrol therapy may be associated with attenuation of lobar CMB progression; however, these findings are exploratory and require confirmation in randomized controlled trials.

Background: Diabetes mellitus (DM) has been suggested to increase the risk of developing Alzheimer’s disease (AD). We have previously demonstrated that DM induces a unique phosphorylation pattern in AD-associated tau protein, which correlates with its accumulation in the brain. However, the effect of DM on tau seeding activity was not fully explored. In this study, we quantified tau seeding activity in the brains of diabetic AD mice with a highly sensitive in vitro assay using tau-biosensor cells and investigated its correlation with site-specific tau phosphorylation.

Method and Results: We extracted tau from the brains of AD mice fed with a high-fat diet (TauTg-HFD mice) and quantitatively assessed its seeding activity using tau-biosensor cells. The phosphorylation levels of each phospho-site on tau were quantified by phosphoproteomic analyses using brain extracts derived from TauTg-HFD mice. There was a significant variation in the number of intracellular tau aggregates induced by TauTg-HFD mice-derived brain tau, which was not associated with the amount of total tau. We found that phosphorylation levels at seven phospho-sites were positively correlated with the number of intracellular tau aggregates (p < 0.05).

Conclusions: The increase in tau aggregation induced by DM might depend on the degree of phosphorylation at specific sites. Seven phospho-sites associated with tau seed activity induced by DM may contribute to the increased risk of AD.

Background: Endovascular therapy (EVT) for large-vessel occlusion stroke involves mechanical manipulation and reperfusion, both of which may stress the neurovascular unit. However, their potential impact on post-stroke cognitive trajectory remains unknown.

Method and Results: Patients with supratentorial acute ischemic stroke were included. Pre-existing diagnoses of dementia or aphasia as symptoms of stroke, transient ischemic attack, or lacunar infarction were excluded. The baseline was defined as 3 months after stroke onset, with MMSE ≥21 and mRS 0–3 (expanded to MMSE ≥18 and mRS 0–4 from December 13, 2021, due to slow recruitment). Patients were divided into the medical management only (MED) group and the EVT group. Of 454 patients, 20 in MED and 11 in EVT were included in the final analysis. The primary outcome was a change in MMSE from the baseline to 12 months. MMSE change did not differ between groups. In within-group analyses, MMSE improved in the MED group, whereas no significant improvement was observed in the EVT group. In multiple linear regression models, NIHSS at discharge was negatively associated with the change in MMSE.

Conclusions: This exploratory study observed no significant difference in cognitive change between EVT and medically managed patients; however, these findings should be interpreted with caution given the limited sample size and baseline differences between groups.

Toward the early intervention for dementia, there is a growing demand for methods to screen efficiently for cognitive decline. Neuropsychological tests based on interviews and paper-and-pencil tasks are widely used; however, challenges remain regarding the test-related burdens and the objectivity of assessments. In recent years, entirely new cognitive assessment methods using digital technology have been developed, and some have already reached the stage of clinical application. Specifically, this review outlines main digital modalities, including touchscreen-based testing, natural language processing-driven speech analysis, and eye-tracking-based assessments. These methods are expected to be applied as dementia screening tools that are marked by both convenience and objectivity. Particularly in the cases of vascular dementia or vascular cognitive impairment, frontal lobe dysfunction and attention deficits are observed in most cases, in which long-duration neuropsychological testing can impose a significant burden. Therefore, concise and objective assessments utilizing these specific digital modalities are highly relevant to clinical practice, as they alleviate the testing burden and are exceptionally well-suited for the early screening and longitudinal monitoring of vascular dementia. Finally, key challenges in artificial intelligence (AI)-based cognitive assessment, particularly the “black box” nature of AI and the critical need for diagnostic explainability, are discussed, along with future directions toward implementing cost-efficient, scalable screening methods.

Adrenomedullin (AM) is a vasoactive peptide with pleiotropic vascular actions beyond vasodilation, including endothelial protection, anti-oxidative and anti-inflammatory effects, and pro-angiogenic/arteriogenic activities mediated by VEGF/bFGF induction and PI3K/Akt activation. In mice subjected to chronic cerebral hypoperfusion, AM administration or genetic strategies that raise circulating AM levels promote collateral artery growth and capillary angiogenesis, leading to earlier recovery of cerebral blood flow, attenuation of white-matter injury, and improved cognitive performance—providing a rationale for clinical translation. In the AMFIS (AM For Ischemic Stroke) phase II trial in acute ischemic stroke, the safety of intravenous AM was confirmed. Subsequently, the AMCAD (AM for CADASIL) trial targeting the rare hereditary small-vessel disease CADASIL is underway, using arterial spin labeling (perfusion MRI)–derived changes in frontal cortical cerebral blood flow as the primary endpoint. For efficacy assessment in vascular cognitive impairment, it is crucial to visualize pharmacological effects using objective intermediate markers derived from perfusion imaging, diffusion tensor imaging of white matter, and blood biomarkers, in addition to clinical symptoms. Optimization of target populations by integrating perfusion/white-matter imaging with biomarkers may establish AM as a disease-modifying therapy for cerebral small-vessel disease and vascular cognitive impairment.

Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by the accumulation of amyloid beta (Aβ) in the walls of small blood vessels. CAA’s progression is divided into four stages: (1) cerebrovascular amyloid deposition, (2) alteration of cerebrovascular function, (3) non-hemorrhagic brain damage, and (4) hemorrhagic brain lesions. Amyloid depositions in cerebral vessels are estimated to occur approximately 30 years before symptomatic hemorrhagic lesions appear. The early diagnosis of CAA is crucial for determining treatment strategies; however, current diagnostic criteria depend on the presence of hemorrhagic lesions on brain images, which occurs in the late stage of CAA, necessitating markers with higher sensitivity. Recently, the Boston criteria version 2.0 was published, featuring improved sensitivity for CAA compared to previous versions. Cerebrospinal fluid levels of Aβ40 and Aβ42 have been reported to decrease in patients with CAA, although conflicting reports exist. Understanding the molecular basis of CAA is needed to explore novel fluid biomarkers.