RESUMEN
Alzheimer's disease (AD) is the most common cause of dementia, which is characterized by a progressive neurodegenerative disorder that is extremely difficult to treat and severely reduces quality of life. Amyloid beta (Aß) has been the primary target of experimental therapies owing to the neurotoxicity of Aß and the brain Aß load detected in humans by amyloid positron emission tomography (PET) imaging. Recently completed phase 2 and 3 trials of third-generation anti-amyloid immunotherapies indicated clinical efficacy in significantly reducing brain Aß load and inhibiting the progression of cognitive decline. Anti-amyloid immunotherapies are the first effective disease-modifying therapies for AD, and aducanumab and lecanemab were recently approved through the US Food and Drug Administration's accelerated approval pathway. However, these therapies still exhibit insufficient clinical efficacy and are associated with amyloid-related imaging abnormalities. Further advances in the field of AD therapeutics are required to revolutionize clinical AD treatment, dementia care, and preventive cognitive healthcare.
RESUMEN
Anti-amyloid immunotherapies have recently emerged as treatments for Alzheimer's disease. While these therapies have demonstrated efficacy in clearing amyloid-ß and slowing cognitive decline, they have also been associated with amyloid-related imaging abnormalities (ARIA) which include both edema (ARIA-E) and hemorrhage (ARIA-H). Given that ARIA have been associated with significant morbidity in cases of antithrombotic or thrombolytic therapy, an understanding of mechanisms of and risk factors for ARIA is of critical importance for stroke care. We discuss the latest data regarding mechanisms of ARIA, including the role of underlying cerebral amyloid angiopathy, and implications for ischemic stroke prevention and management.
RESUMEN
Aß immunization of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aß removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aß immunization, we have assessed the impact of previous Aß immunization on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunized with AN1792 (iAD) and from 27 nonimmunized AD (cAD) cases was immunolabeled for proapoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3ß on tyrosine 216 (GSK3ßtyr216 ), p53 and Cdk5/p35. Expression of these proteins was analyzed in relation to immunization status and other clinical data. The antigen load of all of these proapoptotic proteins was significantly lower in iAD than cAD (P < 0.0001). In cAD, significant correlations (P < 0.001) were observed between: Cdk5/p35 and GSK3ßtyr216 ; a-casp3 and Aß42 ; p53 and age at death. In iAD, significant correlations were found between GSK3ßtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aß42 ; and Cdk5/p35 and Aß-antibody level. Although neuronal loss was increased by immunization with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.