After the Elan-Wyeth phase 2a trial on the AN1792 Aβ vaccine had to be halted because some patients developed meningeal encephalitis, scientists have redoubled their efforts to come up with safer vaccines for Alzheimer disease (AD). One theoretical solution to the inflammatory problem is to use genomic or proteomic profiling to identify, in advance, patients who would appropriately respond to therapy. A paper in the October Archives of Neurology adds substance to that theory. Margot O’Toole, Andrew Dorner, and colleagues from Wyeth Research Labs, Cambridge, Massachusetts, report the proteomic profiling of over 150 U.S. patients who had been enrolled in the Elan trial. From this they obtained a list of potential biomarkers that might identify those most at risk for meningoencephalitis.

O’Toole and colleagues had access to blood samples drawn from the American enrollees in the Elan trial prior to vaccination. The authors obtained mononuclear blood cells from these samples and subjected them to transcriptional profiling. When they compared the profiles obtained from five patients who developed encephalitis with those from 118 other patients who received the vaccine, the authors found more than 650 gene sequences that were associated with the inflammatory response. Not surprisingly, sequences most tightly associated were those involved in propagating proinflammatory signals, such as the transcriptional activator STAT1. O’Toole and colleagues found that high levels of STAT1 in peripheral mononuclear cells prior to vaccination increased the risk for meningoencephalitis by over 230-fold (odds ratio for association). For another 363 genes, the odds ratio for elevated risk for encephalitis exceeded 10.

The authors also correlated gene expression with antibody (IgG) synthesis. An immunoglobulin rather than a T cell response has become the sine qua non for any AD vaccine since the trial ended prematurely (see ARF related news story) and T cells were subsequently blamed for the side effect. Any biomarkers that could potentially be used to predict or monitor patient Ig responses would therefore be useful. O’Toole and colleagues found that transcripts that correlated with the up-regulated IgG responses were those involved in general, not immune-specific, functions, such as those regulating protein synthesis and trafficking, RNA processing, and cellular assembly. This led the authors to posit that some general decline might explain why some patients failed to mount any IgG response. This possibility is echoed by Roger Rosenberg, University of Texas Southwestern Medical Center in Dallas, who writes in an accompanying Archives of Neurology editorial that the failure of some of the trial patients to mount an immunoglobulin response might well be due to age-related reduced responsiveness to immunization.

Curiously, Jeffrey Keller and colleagues at the University of Kentucky, Lexington, reported in the October 5 Journal of Neuroscience that the capacity for protein synthesis is reduced early in the progression of AD.

First author Qunxing Ding and colleagues compared brain autopsy samples from ten controls, eight AD patients, and eight patients diagnosed with mild cognitive impairment (MCI). The authors found that though there was no difference in the number of polyribosomes (these are the ribosomes that are actively synthesizing proteins) found in the samples, the fitness of the ribosomes was another matter. Polyribosomes isolated from cortical regions of both MCI and AD patients were about 40 and 70 percent, respectively, poorer at synthesizing protein than polyribosomes from control samples or from the cerebellum. While these findings do not reflect directly on the robustness of AD patients’ immune systems, they do suggest that protein synthesis problems are an early facet of the disease, at least in the cortex.

There are many reasons why protein synthesis might be compromised. Ding and colleagues found, for example, that levels of specific tRNAs were lower in the MCI and AD samples, while oxidation of ribosomal RNA was higher. The latter observation fits in with theories that increased levels of reactive oxygen species might be a key factor in the etiology of AD and may even be exacerbated by Aβ (see, e.g., ARF related news story).

Aβ, of course, has been found to be toxic to neurons, affecting synaptic transmission and compromising long-term potentiation (see ARF related news story and ARF news story), which brings the story back to immunotherapy. Because synaptic dysfunction is thought to be one of the earliest manifestations of AD, the ability of a vaccine to protect synapses is one way to test the value of this therapeutic approach. Also reporting in the October 5 Journal of Neuroscience, Dora Games and colleagues from Elan, San Francisco, working with Eliezer Masliah at University of California, San Diego, add to the evidence that Aβ vaccines may pass this test (see ARF related news story on the ability of antibodies to protect synapses from Aβ). First author Manuel Buttini and colleagues used the well-characterized PDAPP transgenic mouse, which expressed mutant human AβPP, to test the effects of active or passive immunization on brain synapses. The authors found that in addition to reducing the amount of amyloid plaques in the brain, either strategy protected mice from the loss of synaptophysin, a synapse-specific marker, in the hippocampus or the frontal cortex. There may well be reason to be optimistic that Aβ immunotherapy will work out. As Rosenberg points out in his editorial, “gene vaccination with the Aβ(1-42) complimentary [sic] DNA in a plasmid vector has been shown to generate high titers of anti-Aβ(1-42) in the AD transgenic mouse model without the activation of cytotoxic T cells (see Qu et al., 2004).—Tom Fagan


  1. The protection of synapses is, indeed, a vital component in the early treatment of AD. However, evidence suggests that the presence or absence of synapses is far from the whole synaptic story. We have shown that reduced expression of selected transcripts and proteins involved in trafficking of synaptic vesicles is found in postmortem AD brain even when other markers of synaptic structure may be unaffected (Yao et al., 2003). One of the gene products we found to be most reduced in AD was dynamin 1, a molecule critical in synaptic vesicle trafficking. More recently, Adriana Ferreira and her co-workers demonstrated that Aβ reduced the expression of dynamin 1 in hippocampal neurons (Kelly et al., 2005). These two papers suggest that markers of synaptic function would be a more sensitive marker of early synaptic deficits than markers related to only the presence or absence of synapses.


    . Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease. Neurobiol Dis. 2003 Mar;12(2):97-109. PubMed.

    . Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J Biol Chem. 2005 Sep 9;280(36):31746-53. PubMed.

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News Citations

  1. Sorrento: Immunotherapy Update Hot Off Lectern of AD/PD Conference
  2. Aβ Production Linked to Oxidative Stress
  3. Earliest Amyloid Aggregates Fingered As Culprits, Disrupt Synapse Function in Rats
  4. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  5. Immunotherapy Protects against Synaptic Effects of Soluble Amyloid-β Oligomers

Paper Citations

  1. . Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch Neurol. 2004 Dec;61(12):1859-64. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Risk factors associated with beta-amyloid(1-42) immunotherapy in preimmunization gene expression patterns of blood cells. Arch Neurol. 2005 Oct;62(10):1531-6. PubMed.
  2. . Immunotherapy for Alzheimer disease: the promise and the problem. Arch Neurol. 2005 Oct;62(10):1506-7. PubMed.
  3. . Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci. 2005 Oct 5;25(40):9171-5. PubMed.
  4. . Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease. J Neurosci. 2005 Oct 5;25(40):9096-101. PubMed.