Immunization against the major suspect in Alzheimer’s disease is possible confirms a report published in the September, 2000 Annals of Neurology. Indeed, the study holds out the possibility that the devastating brain damage of Alzheimer’s could one day be slowed or prevented with a painless immunization by nasal spray.
Researchers in Boston found that they could reduce many of the brain changes in a mouse model of Alzheimer’s by nasal administration of the protein amyloid-beta (A-beta), the prime suspect in the disease. Scientists theorize that this “vaccination” with A-beta drives the body’s immune system to increase its natural mechanisms for clearing the body of the toxic molecule.
The next step, say the study’s authors, is a clinical trial in humans. “Phase I clinical trials in humans of nasally administered A-beta peptide are being planned to begin in 2001,” said lead author Howard L. Weiner, MD, a neurologist at Harvard University and Brigham and Women’s Hospital. The mouse study was a collaboration of Weiner’s laboratory and that of Dennis J. Selkoe, MD, a neurologist at the same institutions.
Allan I. Levey, MD, PhD, of Emory University in Atlanta, Georgia, who comments on the study in an accompanying editorial, said, “If, and that is a big “if,” a vaccine is found to be effective in patients with Alzheimer’s disease, this would have tremendous implications for clinical practice, since it would be a major step towards an effective way to slow down the progression of this devastating disease, and potentially, a step towards cure.”
Levey’s qualification reflects the fact that scientists have still not conclusively determined whether A-beta is truly responsible for the mental deterioration of Alzheimer’s disease, and whether elimination of A-beta by itself will be sufficient to prevent the symptoms. A human immunization trial may well answer that question.
The present study confirms data from a report last year by Elan Corporation of San Francisco in which mice injected with A-beta had fewer A-beta aggregations, or “senile plaques,” that accumulate in the brains of humans who have died of the disease.
Through genetic engineering, these mice carry a human gene that predisposes human carriers to get the disease. As the mouse ages, it develops many of the pathological features that Alzheimer’s patients show at autopsy, such as senile plaques and damaged nerve endings.
Weiner and his colleagues employed the same mice (provided for the study by Elan), but took a different tack, based on the observation that the immune system can be spurred into action by administering proteins via the mucous membranes of the gastrointestinal tract and nose.
The authors report that mice treated via the nasal membranes with A-beta had 60% fewer A-beta plaques than did control mice. Other indicators–such as the levels of non-plaque A-beta in the brain and evidence of damage to brain cells–were also reduced significantly in the mice treated with nasal A-beta.
When the researchers administered A-beta via the oral route, there was no evidence that brain A-beta levels were lowered or that damage to brain cells was lessened.
“The most important results are that nasal administration of amyloid peptide may be an effective way to develop an immunologic approach for treatment of AD,” said Weiner. “This may be more well tolerated by patients and may be a less invasive way of vaccination.”
Levey acknowledges the novelty of the intranasal administration. “More importantly, they were able to confirm the earlier study. This now makes it more believable that an immunization strategy might be effective in reducing amyloid burden.”
Levey believes that any A-beta immunization in humans will ultimately be given by injection. He notes that in the earlier study by Elan researchers, injection of A-beta almost completely reduced plaques and damage to brain cells, whereas the nasal administration in the present study was only partially successful.
Weiner and his coauthors acknowledge this difference, and both they and Levey suggest that variations in method–for example, the Elan study mice were vaccinated at a much earlier age and in the presence of an adjuvant (a booster of the immune system)–may account for it.
Noting that the two forms of administration both appear to have activated the immune system, Wiener and Selkoe suggest that a combination of nasal and injectable A-beta might be even more effective than either one alone.
[Disclosure: Howard Weiner is a consultant to and stockholder in Autoimmune, Inc, which develops nasally administered drugs, and which has sold the rights to develop nasally administered A-beta to Elan Corporation. Dennis Selkoe is a consultant to and stockholder in Elan Corporation, Inc.]