S. M. Greenberg, B. J. Bacskai & B. T. Hyman
 
 

Neurology Service Massachusetts General Hospital Charlestown, Massachusetts, USA
Correspondence should be addressed to B T Hyman. e-mail: b_hyman@helix.mgh.harvard.edu
 

The first examination of a brain from a patient enrolled in a halted clinical trial for an Alzheimer disease (AD) vaccine reveals striking—and potentially dangerous—effects.

Amyloid- (A), a peptide of 39–43 amino acids, accumulates in the brains of patients with AD and is thought to be the cause of cognitive decline. A can also incite inflammatory responses, but whether this inflammation promotes or counterbalances neurological damage is unclear. Many pathological and epidemiological studies have suggested that inflammation is a key step in the pathogenesis of Alzheimer disease (AD)¹. In contrast, more recent investigations, have raised the possibility that inflammation serves to clear A. In these investigations, immunization with A or treatment with anti-A antibodies cleared or prevented A-containing plaque deposits in the brains of transgenic AD mouse models^2-4.

In this issue, Nicoll et al.⁵ describe the first autopsy of a brain from an AD patient treated with an experimental A vaccine. The results provide support for the notion that inflammation against A can be both harmful and helpful.

The neuropathological examination of the brain by Nicoll et al. uncovered intriguing evidence of an effective immune response against A. Whole areas of cerebral cortex, in a patchy, uneven distribution, were rendered nearly devoid of A deposits to an extent not observed in brains of unvaccinated AD patients. The only detectable A in these regions was associated with activated microglial cells, which are presumably the rearguard of the inflammatory response against A.

These data suggest an astonishingly powerful effect of the vaccination—clearance of A from much of the cerebral cortex—and provide the strongest evidence to date that an induced immune response can affect A pathology in human AD.

What these data do not do is prove the effectiveness of the vaccine against AD. It is still not known whether symptoms improve after clearance of A, and data concerning cognitive testing during the trial are not yet available. Indeed, whereas the treatment seemed to clear plaque deposits and some surrounding abnormal neurites, other neuronal abnormalities, presumably not targeted by the vaccine, seemed unaffected in these regions (Fig. 1). The unaffected lesions included numerous neurofibrillary tangles and neuropil threads, both representing intracellular accumulations of the microtubule-associated tau protein normally found in AD brains.

The results of this striking case should guide future approaches to immunotherapy. Because neurofibrillary tangles and neuropil threads are closely associated with cognitive impairments in AD, their continued presence even after apparent large-scale A removal suggests that A-specfic therapy may not clear up much of the damage that already exists. Should therapy be aimed even earlier, at presymptomatic individuals? Recent advances in neuroimaging of A in humans have brought this once far-fetched possibility within our grasp⁸.

If T-cell-mediated inflammation is the cause of severe side effects, then methods to minimize this inflammation could be effective. Should researchers consider using passive immunization (direct infusion of antibodies) or epitopes designed to minimize the cellular response? Recent data have highlighted the plausibility of such approaches. (Fab')₂ fragments of A-specific antibodies that do not interact with Fc receptors, and so fail to activate the cellular immune response, can clear A in a mouse model⁹. In another mouse model, passive immunization with A-specific antibodies seemed to cause CAA-related hemorrhages¹⁰, but hemorrhagic strokes did not occur in the (Fab')₂-treated mice⁹ and were not a prominent feature in the Elan human vaccine study⁶.

In trying to reformulate an immune-based therapy for AD, researchers have focused on methods that might elicit an immune response without leading to the types of complications encountered by this patient. Although it is impossible to draw firm conclusions from a single case, the data presented here suggest that the cellular immune response to any candidate therapy must be weighed heavily. The current case highlights not only the risks awaiting future attempts at AD immunotherapy, but also the considerable promise for the potential effectiveness of this approach.