Alzheimer Immunotherapy Can Alter Vascular Amyloid
Alzheimer Immunotherapy Can Alter Vascular Amyloid
Abstract & Commentary
By Norman R. Relkin, MD, PhD, Director, Memory Disorders Program, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Relkin reports that he receives grant/research support from Baxter Bioscience, and is a consultant to Eisai, Pfizer, Myriad, and Smart Genetics.
Synopsis: Although the active immunization trial was stopped because of severe side effects, autopsy studies revealed that soluble plaque amyloid moves to the perivascular spaces as an initial step before it is cleared from the brain.
Source: Boche D, Zotova E, Weller RO, et al, Consequence of Ab immunization on the vasculature of human Alzheimer's disease brain. Brain 2008;131:3299-3310
Brain autopsies from participants in the ill-fated AN-1792 Alzheimer's disease (AD) vaccine trial indicate that immunotherapy against beta amyloid (Ab) can alter vascular amyloid deposits and potentially impact on congophilic amyloid angiopathy (CAA). AD patients in the Elan-sponsored AN-1792 trial were vaccinated with fibrillar Ab-42 plus an immune adjuvant in a novel Phase II immunotherapy trial. The trial ended prematurely in 2002 when 6% of subjects developed meningo-encephalitis. Delphine Boche and colleagues from the University of Southampton studied the brains of nine patients who received AN-1792 and died between four months and five years after their first immunization. They also examined the brains of 11 AD patients who died at comparable stages of the disease but were unimmunized.
Previous studies of the brains from the AN-1792 trial demonstrated removal of some or all of the plaque-associated amyloid deposits in cerebral cortex. The investigators hypothesized that after vaccination with AN-1792, soluble Ab from brain plaques might drain into the brain's perivascular spaces and promote vascular amyloid deposition. To test this hypothesis, they paid particular attention in this study to amyloid in blood vessels. They found that AD patients immunized with AN-1792 had about 14 times as many blood vessels containing the 42-amino-acid form of Ab (Ab-42) in the cerebral cortex as unimmunized controls, and seven times more Ab-42 in the leptomeninges. Levels of the 40-amino-acid form of beta amyloid (Ab-40), more commonly associated with CAA, were also significantly increased. Patients who received AN-1792 had more cortical microhemorrhages and microvascular lesions than the unimmunized controls. However, none of the nine subjects studied had major CAA-related intracerebral hemorrhages. They did not find evidence that this form of immunotherapy otherwise altered structural proteins in the walls of cerebral blood vessels.
There was some indication that changes in vascular amyloid following AN-1792 immunization were time dependent. Most of the patients who died in the first three years after immunization had high levels of vascular amyloid compared to controls. However, two patients who survived four to five years after vaccination showed nearly complete clearance of brain plaques as well as vascular amyloid. The authors suggested that immunotherapy may initially deliver solubilized plaque amyloid to the vascular compartment resulting in an increase in vascular amyloid deposits. However, once the majority of amyloid in the brain substance is removed, the continued effect of antibodies against amyloid may reduce vascular amyloid burden, resulting in a long-term reduction.
This study by Boche and colleagues provides intriguing evidence that movement of amyloid from the brain parenchyma to the perivascular spaces may be a first step in the clearance of Ab from the brain of AD patients who had active vaccination. It does not necessarily follow that all vaccines or other approaches to anti-amyloid therapy will lead to comparable changes in vascular amyloid. However, side effects relating to the brain vasculature, such as microhemorrhages, microvascular ischemic changes, and vasogenic brain edema, have now been reported following active vaccination and passive immunotherapy against Ab. This study suggests why these side effects may occur, but also provides the interesting observation that sustained antibody exposure can actually reduce vascular amyloid deposits once the pool of parenchymal brain amyloid is sufficiently small. This raises the possibility that CAA itself could be a target for future immunotherapy interventions, perhaps using antibodies that more specifically target the vascular amyloid pool.Although the active immunization trial was stopped because of severe side effects, autopsy studies revealed that soluble plaque amyloid moves to the perivascular spaces as an initial step before it is cleared from the brain.
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