Published online: 17 March 2003
Alzheimer disease's double-edged vaccine
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-beta (Abeta), 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. Abeta 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 Abeta. In these investigations, immunization with Abeta or treatment with anti-Abeta antibodies
cleared or prevented Abeta-containing plaque deposits in the brains of transgenic AD mouse models2-4.
In this issue, Nicoll et al.5 describe the first autopsy of a brain from an AD patient treated with an
experimental Abeta vaccine. The results provide support for the notion that inflammation against Abeta can
be both harmful and helpful.
The brain was obtained from one of approximately 360 AD patients enrolled in the trial of the Elan
Pharmaceutical AN-1792 vaccine. Patients with mild to moderate AD were vaccinated with a 42-amino
acid form of Abeta. The trial was discontinued in January, 2002 after several patients experienced clinical
signs consistent with inflammation in the central nervous system described as meningoencephalitis6.
The patient described by Nicoll et al. was 1 of the 15 who eventually developed meningoencephalitis. The
description of the patient's clinical course leaves little doubt about the potential severity of this adverse
response to vaccination. Over a 2-week period that followed 42 relatively stable weeks of repeated
vaccination, the patient rapidly worsened, progressing through a downhill course of dizzy spells,
drowsiness, unstable gait and fever that ultimately left her cognitively untestable and fully dependent on
nursing care. Neuroimaging revealed extensive abnormalities of the white matter. The patient made no
substantial recovery during the year that she survived.
The neuropathological examination of the brain by Nicoll et al. uncovered intriguing evidence of an
effective immune response against Abeta. Whole areas of cerebral cortex, in a patchy, uneven distribution,
were rendered nearly devoid of Abeta deposits to an extent not observed in brains of unvaccinated AD
patients. The only detectable Abeta in these regions was associated with activated microglial cells, which
are presumably the rearguard of the inflammatory response against Abeta.
These data suggest an astonishingly powerful effect of the vaccination—clearance of Abeta from much of
the cerebral cortex—and provide the strongest evidence to date that an induced immune response can affect
Abeta 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 Abeta, 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.
Harder to interpret are the accumulations of inflammatory cells in the leptomeninges, cerebral cortex and
white matter, which are presumably related to the patient's precipitous clinical decline. Much of the
inflammatory activity seemed to surround Abeta-containing blood vessels, raising the possibility of
inflammation-induced abnormalities in blood vessel function. Indeed, such Abeta deposits within vessel
walls occur in most AD patients and are known as cerebral amyloid angiopathy (CAA).
There are striking parallels between the rare syndrome of spontaneous CAA-related inflammation and the
vaccine-associated meningoencephalitis; both result in subacute cognitive decline, extensive white matter
changes on neuroimaging, abnormal cerebrospinal fluid and a T-cell and microglial response surrounding
amyloid-laden vessel segments7. Thus, one interpretation of the patient's pathology is that the vaccination
triggered an inflammatory response not only against Abeta-containing plaques within the brain, but also
against vascular amyloid (present extensively in this patient), resulting in the abnormalities of cerebral
blood flow that were responsible for her clinical decline. These observations suggest that advanced CAA
might complicate immunotherapy in some patients, particularly if the therapy induces pronounced T-cell
and microglial responses.
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 Abeta removal suggests that Abeta-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 Abeta 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 Abeta-specific antibodies that do not interact with Fc
receptors, and so fail to activate the cellular immune response, can clear Abeta in a mouse model9. In
another mouse model, passive immunization with Abeta-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.
Published online 17 March 2003.
Nature Medicine
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