[Insulin signaling and neuropathological changes in Alzheimer's disease]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Its pathological features include abnormal aggregation of amyloid-β (Aβ) and tau proteins, neuronal loss, and brain atrophy. The "amyloid hypothesis" suggests that Aβ accumulation triggers disease progression, leading to the development of anti-Aβ antibody therapies. However, their effectiveness is limited once dementia has developed, highlighting the need for early intervention in the preclinical stage. This review focuses on type 2 diabetes (T2D) and insulin resistance as acquired risk factors for AD, summarizing epidemiological and experimental evidence on their impact on AD neuropathology. While early postmortem studies produced inconsistent results regarding the association between T2D, insulin resistance, and Aβ deposition, recent amyloid PET imaging studies have clarified this relationship in the human brain. Additionally, animal studies suggest that diet-induced insulin resistance promotes Aβ accumulation. Conversely, genetic disruption of insulin signaling molecules significantly suppresses Aβ pathology. These seemingly contradictory findings suggest that while reduced brain insulin signaling may inhibit Aβ pathology, peripheral metabolic disturbances associated with worsening insulin resistance may accelerate Aβ deposition. Understanding the multifaceted roles of insulin signaling and the molecular basis of these complex interactions is crucial for identifying new preventive and disease-modifying therapeutic targets. Advancing this knowledge is essential for developing innovative AD treatments.