Alzheimer's disease is the most common form of dementia. This illness has been shown to be associated with the aggregation and accumulation of certain proteins that cause neuronal death. These causative proteins have been a promising target of therapy. Dr. Iwatsubo's group has elucidated the aggregation mechanism of amyloid β and other causative proteins, including the influence of apolipoprotein E and other key disease-modifying molecules. Several antibody therapies have been approved or are under regulatory review. Clinical collaborations will help establish a more effective therapy from Japan.

The onset of dementia is believed to be associated with the accumulation of pathogenic proteins in the brain, resulting from a decline in the mechanisms that clear pathogenic molecules produced in the brain. In this study, we aim to elucidate the molecular mechanisms involved in the disruption of clearance that occurs during disease progression and to identify the mechanisms responsible for the elimination of dementia-causing molecules. Based on the mechanisms identified in this research, we aim to discover novel therapeutic targets that have not been explored before.

Dementia is characterized by brain dysfunction resulting from neuronal network injury. Regenerating these neuronal networks could aid in restoring impaired brain functions. However, the molecular mechanisms underlying neuronal network regeneration remain incompletely understood. In this study, we aim to develop a novel culture system to evaluate neuronal network regeneration. The findings from this subproject may help identify potential targets for enhancing cognitive function recovery.

Different types of dementia are characterized by different patterns of aggregation of amyloid β, tau, α synuclein, and other abnormal proteins in the brain. Highly sensitive positron emission tomography (PET) modalities will be developed using agents (probes) that bind specifically to these proteins. These new techniques will be used to scan brain lesions and circuit injuries to evaluate their relationships. Based on these findings, the new PET techniques will be evaluated for clinical utility and performance. Moreover, potential therapeutics will be proposed in light of the findings regarding the protein-binding probes. Theranostics is an emerging field of medicine in which diagnostic findings inform tailored therapy. This approach will open new doors to dementia therapy.

The stages of Parkinson's disease have long been determined based on clinical observation. Dr. Hattori and colleagues have performed blood examinations showing precursors of α-synuclein, a key protein involved in the disease pathology. A quick and easy method to quantitatively identify these molecules will be established. Moreover, new techniques to detect aberrant bloodborne molecules that play a key role in other neurodegenerative diseases will be developed.

Genetic biomarkers for neuropsychiatric and neurocognitive disorders will be discovered by analyzing a large genomic sequence dataset collected from patients and controls. The analysis will cover the types of variants that have not been fully investigated in previous studies. Based on the results of the large-scale genomic analysis, integrative bioinformatics analyses will be conducted to advance knowledge on disease pathology and therapeutic targets.