The huge annual Alzheimer’s meeting
starts tomorrow in Chicago, and it comes at an interesting time for the
field. I mean “interesting” in, of course, the sense of the old curse,
“may you live in interesting times.” The last couple of weeks brought shocks from two different
directions. One was the devastating failure of two drugs based on the
leading theory of the disease: that Alzheimer’s is caused by an
accumulation of sticky brain plaques made of the peptide (a part of a
protein) called amyloid-beta, and that if you induce the body to make
antibodies against this protein and/or administer a drug to dissolve the
plaques, you will be well on your way to treating the disease. The
other shock was the surprising success of an antihistamine drug (!) that
came out of left field, by which I mean Russia. Let’s start with the seemingly good news. A drug called dimebon,
which years ago was sold in Russia as an antihistamine (manufacturers
stopped selling it when a new generation of antihistamines became
available) was given to 183 patients there with mild to moderate
Alzheimer’s three times a day for six months, followed by another six
months of getting the drug or a placebo. As scientists led by Rachelle Doody of Baylor College of Medicine reported in a special edition of The Lancet,
the dimebon group showed significant improvements in ability to track
dates, understand instructions, follow commands, memorize a list of
words, and perform simple tasks such as copying drawings or addressing
an envelope. The placebo group declined on these measures. As the authors write, “patients given dimebon were significantly
improved compared with baseline, and compared with those taking
placebo.” Considering that there are currently “no approved therapies
for mild-to-moderate Alzheimer’s disease [that] have shown increasing
improvement over 12 months,” they write, that is no small feat. In the same issue, scientists reported that although immunizing 80
Alzheimer’s patients against the amyloid-β peptide can clear amyloid
plaques in their brains, it does not keep them from getting worse. Hopes
that that approach would work were based on positive findings in mice
(immunizing them with full-length amyloid-β both reduced plaques and
improved brain function), but it doesn’t work in people, Clive Holmes
and colleagues at Moorgreen Hospital, in Southampton, England, reported.
“There is little evidence to suggest that there is any major effect on
cognitive function,” they reported. “All but one of the individuals who
died during the follow-up phase had clear end-stage dementia before
death, including the two individuals with . . . almost complete
elimination of plaques. These findings imply that progressive
neurodegeneration can occur in Alzheimer’s disease despite removal of
plaques.” What’s going on? One scientist told me that dissolving plaques may be
completely the wrong way to go: you melt these suckers and the gunk
they’re made of is free to wash around the brain, somehow exerting
mind-killing effects. But the larger point is that we are more than 20 years into
gene-based, rigorous basic research on this horrific disease. And pet
hypotheses keep falling, while the totally unexpected keeps happening. That's worth keeping in mind when the parade of announcements start
coming out of the annual Alzheimer’s meeting this weekend and next week.
You will be hearing lots of claims for successful therapies, some
targeting amyloid-beta and others taking aim at tangles inside brain
neurons made of a different protein, called tau. Just remember, we have
been down this road before. Some questions to keep in mind:
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