Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.

Glioblastoma is a lethal brain tumour for which current multimodal treatment rarely prevents recurrence. Therapeutic failure is driven by extensive intratumoural cellular heterogeneity with a microenvironment dominated by tumour-associated macrophages that sustain tumour growth and immunosuppression. Although chimeric antigen receptor (CAR)-T cell therapies are being developed for glioblastoma, sustained response has been undermined by non-uniform antigen expression, antigen loss and microenvironmental barriers that are not directly engaged by tumour-targeting designs. These limitations motivate new strategies that address the disease as a coupled tumour-immune system rather than a single malignant compartment. Here we use a multi-omic target discovery platform to identify GPNMB as a dual-compartment antigen in glioblastoma. Anti-GPNMB CAR-T cells showed potent anti-tumour activity, with long-term disease control in orthotopic patient-derived xenografts and syngeneic glioma models through concomitant depletion of GPNMB+ tumour and immunosuppressive myeloid populations. By collapsing tumour control and microenvironmental reprogramming, these findings provide a new strategy for antigen selection and targeting in heterogeneous, myeloid-rich solid cancers.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.