Clinical genetics and genetic counseling in the era of disease-modifying therapies for dementia: lessons from Japan

Abstract Recent advances in hereditary dementia research have clarified its molecular pathogenesis and clinical applications, with several advances already reaching implementation. The late 2023 introduction of anti-amyloid β therapies for Alzheimer’s disease (AD) in Japan marked the beginning of a transformative era, though amyloid-related imaging abnormalities (ARIA) remain a notable adverse effect. Because APOE genotype, and ε4 dose in particular, is a major determinant of ARIA, genotyping is now embedded in pretreatment assessment. This review examines how one national health system has incorporated these advances and distinguishes between two frequently conflated domains: real-world clinical practice and clinical research. Practically, we describe the Guidelines for the Appropriate Use of APOE Genetic Testing in Dementia, established in 2025 and revised in 2026 following national health insurance approval, which position APOE testing as a pharmacogenetic tool governing monitoring intensity rather than treatment eligibility. We consider what the lower ε4 allele frequency in Japan implies, now that per-genotype effect estimates have been revised to values comparable to those in European-ancestry populations, and we set out the counseling required when a pharmacogenetic result carries risk information for untested relatives. On the research side, we describe the Hereditary Dementia Trial Ready Cohort, a national registry spanning 21 causative genes, and explain why its scope diverges from that of autosomal dominant AD-focused international initiatives such as DIAN. We conclude that features of the Japanese experience are most likely to be transferred to other healthcare systems.