Magnetic resonance–guided focused ultrasound (MRgFUS) is a minimally invasive surgical technique proven effective for treating drug–resistant essential tremor and Parkinson disease. Several factors influence the effectiveness of MRgFUS. Skull characteristics, including thickness and the skull density ratio, can affect the temperature rise during treatment. Since the actual power and exposure time are related and crucial for the thermal effects of ultrasound, it is necessary to carefully monitor these parameters to prevent unintended cavitation. Achieving a temperature increase enlarges the coagulation nest, enhancing treatment effectiveness but also raising the risk of complications. Given the multifactorial nature of the treatment, prioritizing safety while maximizing temperature efficiency and ensuring adequate sonication at the target area is essential. In summary, it is crucial to recognize the complexity of MRgFUS treatment, ensuring safety, optimizing temperature efficiency, and providing sufficient sonication at the target site to achieve the best outcomes.

Significant neuropathological hallmarks of Alzheimer disease (AD) include amyloid–β (Aβ) deposition and the formation of associated senile plaques (SPs), concurrent with the appearance of neurofibrillary tangles (NFTs). Both SPs and NFTs are recognized more abundantly in AD brains than in the physiological range of normal aging. SPs are the extracellular deposits of Aβ, particularly abundant in the cerebral cortex. Based on the presence or absence of a dense Aβ core, plaques are morphologically classified as neuritic or diffuse, respectively. Composed of intraneuronal aggregates of hyperphosphorylated tau protein, NFTs are primarily formed in pyramidal cell neurons in the cerebral cortex. NFTs have a flame–like shape. Following the cell death, tangle–bearing neurons become extraneuronal “ghost” tangles. NFTs consist of abnormal 20 nm helical filaments with an 80 nm half–periodicity, termed paired helical filaments. The spatiotemporal progression of NFTs correlate with the severity of cognitive decline. The predictable progression of Aβ plaque pathology from the neocortex, over limbic structures, and basal ganglia to the brainstem and cerebellum is captured in phases described by Thal et al. Similarly, the progression of NFT pathology from the transentorhinal region to the limbic system and ultimately the neocortex has been described in stages proposed by Braak et al. Braak stages V and VI (isocortical stages) showed the strongest association with clinically observed dementia, while stages III and IV (limbic stages) were associated with mild cognitive impairment. Stages I and II (transentorhinal stages) were observed in asymptomatic individuals. The density of neuritic plaques was determined using the criteria defined by the Consortium to Establish a Registry for AD (CERAD). These staging systems are used internationally for the pathological diagnosis of AD according to the National Institute on Aging–Alzheimer's Association (NIA–AA) guidelines for the neuropathological assessment of AD. In these guidelines, each pathological hallmark is scored individually using a three–tiered scoring system, and these scores are used to assign the likelihood of AD pathology. In future aging and dementia studies, the significance of the neuropathological diagnosis of AD is expected to remain prominent.

Alzheimer disease (AD) is the most common age–related neurodegenerative disorder and is characterized by major pathological hallmarks in the brain, including senile plaques composed of amyloid β–protein (Aβ), neurofibrillary tangles of tau protein, and neuronal death.

In the pathophysiology of AD, the “amyloid hypothesis” has been proposed that abnormal aggregation of amyloid β protein (Aβ) causes damage to nerve cells. It was originally thought that the accumulation of insoluble amyloid fibrils in the brain leads to neurotoxicity that causes AD, but in recent years, the position of early and intermediate aggregates such as oligomers and protofibrils have also been emphasized (oligomer hypothesis). In particular, the pathogenesis of Aβ protofibrils, which are the target molecules of lecanemab, is attracting attention following the positive results of its phase 3 clinical trials in early AD patients and its approval in the United States. Using mainly high–speed atomic force microscopy (HS–AFM) mainly, we revealed that there is a possibility that protofibrils may be located in a pathway (off–pathway) different from the pathway (on–pathway) in which monomers aggregate to form the final aggregates, mature fibrils. Next, we reported that protofibrils of Aβ disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Recently, we showed that lecanemab not only binds and surrounds protofibrils with high affinity, but also inhibits further aggregation processes of Aβ by binding globular oligomers, resulting in the reduction of neuronal toxicity by HS–AFM and cellular experiments. In conclusion, protofibrils may be important pathogenic molecules for disease–modifying therapy in AD.

With the approval of lecanemab, a disease–modifying drug for Alzheimer disease, in Japan in 2023, amyloid PET has also been clinically implemented. Does this mean that clinicians will be freed from spending time interpreting MRI and brain perfusion SPECT, by ordering only amyloid PET? Of course, this is not the case, and in reality, solid knowledge of various imaging biomarkers is more crucial than ever before. Behind the recent development of disease–modifying drugs for dementia is the fact that brain pathophysiology assessment technologies such as amyloid PET and tau PET have served as foundational technologies. These technologies have reduced misdiagnosis in patient inclusion in clinical trials, enabled monitoring of treatment efficacy, and allowed stratification of patients based on pathological severity. In clinical practice, one of the most important roles of imaging biomarkers for dementia is to avoid missing potentially treatable conditions, such as cerebrovascular disease, chronic subdural hematoma, brain tumors, and normal pressure hydrocephalus. A physician familiar with brain imaging will be able to characterize morphological changes and use a variety of nuclear medicine techniques to help differentiate brain pathologies. However, it should always be noted that there are various pitfalls in doing so. It is hoped that future interventions in patients in preclinical stages will delay or prevent the onset of dementia ; however, there are various issues to be resolved, including the development of affordable and less invasive screening methods. This paper focuses on brain imaging in relation to the recent progress of research on the pathophysiology of dementia and outlines the role of brain imaging in the development of disease–modifying drugs for dementia, including the results of clinical trials. In addition, the application of imaging biomarkers in clinical practice and the challenges and prospects in realizing precision medicine in the future will also be discussed.

Lecanemab, an anti–amyloid–β (Aβ) antibody, has been shown to remove Aβ plaques substantially from the brain of Alzheimer disease (AD) patients in a phase 3 clinical trial. Based on its clinical benefit, Lecanemab was approved for treatment of AD in Japan. The role of biomarkers in clinical practice has been dramatically changed by the introduction of disease–modifying therapy such as Lecanemab. In order to identify appropriate patients for the use of Lecanemab, “amyloid–β test” is required to confirm Aβ pathology in the brain either by cerebrospinal fluid (CSF) testing or amyloid PET scan. Early stage of AD including mild cognitive impairment (MCI) and mild dementia is a target of Lecanemab treatment. Biomarker tests for those population have become more important. Specialists for dementia practice are expected to play a major role for establishing amyloid–β testing system throughout Japan, which facilitates an efficient diagnostic pathway for the use of lecanemab. With the advent of disease–modifying therapy, the clinical significance of APOE testing should be reconsidered. The incidence of amyloid–related imaging abnormalities (ARIA), which may occur as an adverse event of anti–amyloid–β antibody therapy, is largely influenced by APOE genotypes. Symptomatic ARIA is most frequently observed in patients with APOE ε4 homozygotes, followed by ε4 heterozygotes and ε4 non–carriers. The U.S. FDA has issued a warning about ARIA in the label of lecanemab, and announced that APOE testing should be performed in prior to the use of lecanemab. The clinical significance of APOE testing and its appropriate use in the era of disease–modifying therapy are discussed.

With the rapid increase in the number of dementia cases worldwide and the development of disease–modifying therapy with anti–amyloid antibodies for Alzheimer disease, the demand for a more concise and precise method for diagnosing dementia at earlier stages has risen. The use of artificial intelligence (AI) has been gaining ground in medicine, particularly in dementia research―it has become an important tool for analyzing patient–derived data. AI–driven analyses of brain images, biofluid biomarkers, and genetic information could increase the accuracy of dementia diagnosis. For example, a machine learning model applied to magnetic resonance imaging to diagnose early–stage dementia reportedly achieves high accuracy with over 80% sensitivity and specificity. Furthermore, AI–driven analysis can reveal information on patient–derived data that may not be accessible via conventional approaches. Thus, AI–powered analysis could lead to a deeper understanding of the pathogenesis of dementia and the development of new targets for dementia therapies. AI–assisted methods for dementia screening have been proposed and tested in real–world settings in combination with cutting–edge sensing techniques. Low explainability has been a major bottleneck in utilizing AI in medical diagnosis ; however, new techniques, such as Shapley Additive exPlanations (SHAP), which are used to explain the individual predictions made by the AI model, could help in overcoming issue. In this review article, recent progress in AI–related research in the dementia field is discussed along with the challenges and benefits of AI use in this field.

The amyloid hypothesis, in which β–amyloid is considered to be the pathogenic protein of AD, has been widely supported by genetic and pathological evidence, and progress has been made in disease–modifying therapy (DMT) targeting the pathological mechanism of the disease. Passive immunization with humanized anti–Aβ antibodies has been pursued, and in 2023, lecanemab raised against protofibrillar form of Aβ achieved ∼27.1% reduction in the speed of clinical progression in early AD (mild cognitive impairment [MCI] to mild AD dementia), in an 18–month Phase III clinical trial, and was approved in the U.S. and Japan for clinical use. Problems in the practical use of lecanemab and anti–Aβ antibody drugs, as well as future perspectives in disease–modifying therapies, will be discussed.

The therapeutic effects of disease–modifying drugs have demonstrated that reversing the symptoms of dementia after its onset is difficult. The FINGER study published in 2015 revealed that multifactorial interventions, such as diet, exercise, and lifestyle, can preserve and enhance cognitive function in elderly individuals who are at risk of developing dementia. In Japan, a similar study has started in 2019, and we conducted a multifactorial intervention in Tamba citizens, in which the intervention group showed significantly improved cognitive function compared to the control group. Kobe University is developing activities called ‘CogniCare’ to implement the results in society. This paper discusses the challenges of social implementation preventing dementia, as well as the current status of evidence for its prevention.

現在，認知症は世界規模の問題になっている．Alzheimer病（Alzheimer disease：AD）では，臨床・病理像の解明は進み，優れた診断技術も数多く開発されている．治療に関して歴史的には神経伝達物質に注目した疾患修飾薬開発に端を発し，2000年前半のアミロイドワクチン療法開発を経て，現在は様々なアミロイドβ蛋白（amyloid beta–proteins：Aβ）の分画に対するモノクローナル抗体の研究が主流になっている．近年はAβ凝集の中間産物であるAβ protofibrilをターゲットにしたlecanemabが臨床の場に登場している．本稿では，Aβの分子挙動や凝集反応に関する最新の知見を概説する．