Sato, Naoyuki

AbstractObjectiveAlzheimer's disease (AD) often coexists with cerebrovascular diseases. However, the impact of cerebrovascular diseases such as stroke on AD pathology remains poorly understood.MethodsThis study examines the correlation between cerebrovascular diseases and AD pathology. The research was carried out using clinical and neuropathological data collected from the National Alzheimer's Coordinating Center (NACC) database and an animal model in which bilateral common carotid artery stenosis surgery was performed, following the injection of tau seeds into the brains of wild‐type mice.ResultsAnalysis of the NACC database suggests that clinical stroke history and lacunar infarcts are associated with lower neurofibrillary tangle pathology. An animal model demonstrates that chronic cerebral hypoperfusion reduces tau pathology, which was observed in not only neurons but also astrocytes, microglia, and oligodendrocytes. Furthermore, we found that astrocytes and microglia were activated in response to tau pathology and chronic cerebral hypoperfusion. Additionally, cerebral hypoperfusion increased a lysosomal enzyme, cathepsin D.InterpretationThese data together indicate that cerebral hypoperfusion reduces tau accumulation likely through an increase in microglial phagocytic activity towards tau and an elevation in degradation through cathepsin D. This study contributes to understanding the relationship between tau pathology and cerebrovascular diseases in older people with multimorbidity.

Background: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer’s disease, their relationship remains to be elucidated. Objective: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. Methods: We reviewed the National Alzheimer’s Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Results: Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17–1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10–1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99–1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. Conclusion: The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.