Current Topics - Frontiers in Alzheimer's and Dementia Research
Foreword
2024 Volume 72 Issue 7 Pages 600-601
Details
2024 Volume 72 Issue 7 Pages 600-601
Japan precedes other countries in embracing population aging that is unprecedented in the world. Dementia is prevalent across the world, affecting 55 million people in 2019 and an estimated 139 million in 2050.1) As the strongest risk factor for dementia is aging, Japan is also experiencing an increase in the patient population with 9.53 million people being affected (8% of the Japanese population); one in four elderly people is suffering from dementia.2) The most common form of dementia is Alzheimer’s disease (AD), followed by vascular dementia and dementia with Lewy bodies. Significant progress has been made in the field, culminating in the approval of lecanemab, a disease-modifying agent for early AD, in Japan and the U.S.3) Japan is also planning a new national project to strengthen efforts in dementia research.4) Thus, this is the right time to summarize recent progress in the field. This issue of Chemical and Pharmaceutical Bulletin includes four Reviews and a Regular Article that pertain to disease-modifying therapies on amyloid and tau, symptomatic agents for behavioral and psychiatric symptoms of dementia (BPSD), neuroinflammation, and epigenetic approaches and protein degradation.
There has been a substantial need to develop drugs having disease-modifying effects. Building on the significant progress in biomarker research on AD, many academic institutes and pharmaceutical industries have pursued therapeutics that can clear or inhibit amyloid and tau aggregations. Suzuki et al. summarize recent findings on major anti-amyloid antibodies and advanced tau therapies. They also discuss future directions and perspectives, which I believe include attractive insights and therefore could facilitate ongoing research.
The approved amyloid antibody of lecanemab has the potential to slow disease progression of AD but cannot halt it.5) Progress in the field of dementia other than AD has not been rapid. Thus, symptomatic agents are still required as people living with dementia suffer from symptoms related to it. In particular, BPSD places a significant burden on families and caregivers, affecting their quality of life, labor productivity, and social costs. In 2023, the U.S. Food and Drug Administration granted approval of brexpiprazole for agitation, a major symptom in BPSD, which is associated with dementia due to AD.6) In this issue, Oguma and Jino update recent progress on clinical trials for treating BPSD including their future considerations.
Although amyloid accumulation is likely to be the primary initiating event of AD, this alone cannot explain the pathogenesis. Genome-wide association studies for sporadic AD patients have suggested that neuroinflammation could play a key role in the pathogenesis and act as a bridge between amyloid and tau pathologies.7) Shimo and colleagues assemble key findings on genetics, imaging and biofluid biomarkers, and clinical pipelines and present their perspectives.
Cognitive impairment featuring memory loss is the key symptom of AD. Synaptic dysfunction is correlated with cognitive deficits, with the epigenetics mechanism capable of modulating protein expression without changing genotype shape synaptic alternations.8) Therefore, epigenetic regulation, such as histone modifications, has the potential to improve cognitive function and thereby leads to cognitive enhancers. Yamashita et al. review small molecule inhibitors of histone deacetylase (HDAC), lysine-specific demethylase 1 (LSD1) and bromodomains and extra-terminal domain (BET) protein, along with their future directions for these epigenetic inhibitors.
Targeted protein degradation, such as a proteolysis targeting chimeras (PROTAC) approach, is often leveraged in drug discovery. PROTAC to degrade pathological proteins for dementia is a promising modality for disease intervention.9) Lysine demethylase 5 (KDM5) is an epigenetic target involved in learning and memory formation.10) Iida et al. report KDM5 targeted PROTAC that promote neurite outgrowth, a process in learning and memory formation related to synaptic alternations. Further characterization, such as brain penetration or selectivity over close subtypes, could provide an alternative approach for epigenetic modulation.
The Alzheimer’s disease research field has reached a pivotal moment with the clinical development of disease-modifying therapies of several antibodies, which are based on understanding of pathophysiology and the development of biomarkers for diagnosis. Finally, the Editor is grateful to the authors for contributing to this issue, which should help readers understand the current status of this field and gain insights for future research.
