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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 26, 2012

An Alzheimer's Update: Amyloid Lives?

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Posted by Derek

There's a good state-of-the-field post over at Chemiotics on Alzheimer's, in the wake of the bapineuzumab news the other day.

Of particular interest is the recent finding by deCODE and Genentech researchers that there's a mutation in the Alzheimer's precursor protein (APP) that actually seems to be protective against the disease. There are several APP mutations that are known to bring on amyloid-driven Alzheimer's at much earlier ages, but seeing one that goes the other way does lend more support to the idea that amyloid really is a causative agent:

The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without suffering major cognitive decline, such as memory loss. They also perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.

For Stefánsson, this suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. “Pathologists have always suspected that there was a substantial overlap between Alzheimer’s disease and normal age-related changes,” says Stefánsson. A drug that mimics the effects of the mutation, he says, would have the potential both to slow cognitive decline and to prevent Alzheimer’s.

Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks — and the alteration is enough to reduce the enzyme’s efficiency.

The flip side of this news is that targeting beta-secretase has already been the subject of a huge amount of work in the drug industry. That's good, in that we're not exactly starting from scratch, but that's bad, since the lack of success so far shows you that it's not exactly an easy thing to do. But there are still plenty of people taking cracks at it - CoMentis and Astellas have a compound in development, as do Merck, Lilly, Takeda, and others. Here's hoping that something from this class finally works out, and that this latest result isn't a red herring from a small mutation population.

Comments (9) + TrackBacks (0) | Category: Alzheimer's Disease


1. johnfg on July 26, 2012 1:36 PM writes...

So when I read these types of things, where we have some solid research on both sides pushing the issue, I always have to wonder if what we think of as alzheimers is really a spectrum of disorders that present similar symptoms.

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2. Curious Wavefunction on July 26, 2012 2:02 PM writes...

"CoMentis and Astellas have a compound in development, as do Merck, Lilly, Takeda, and others"

Aren't most of these and other companies gutting their CNS departments though? These days it seems like the urgency of finding a cure for a disease is inversely proportional to the amount of resources a major company is willing to put into it.

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3. Rick Wobbe on July 26, 2012 2:50 PM writes...

It seems like the most significant lesson from Alzheimer's research so far is the limits of what genetics can do to differentiate cause from effect from correlation from coincidence. If ever there were a disease tailor-made for genetic target validation and target-based drug screening, it's AD, but the repeated and utter failures of every drug aimed at amyloid precursor protein/b-amyloid suggest that, for reasons we haven't figured out yet, the genetics has led us to targets too far downstream of the key, pathology-triggering event. Unfortunately, the research keeps taking us back to the same starting point(s) that have proven ineffective so far, rather than revealing new paths forward. What're we doing wrong?

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4. Jon on July 26, 2012 2:52 PM writes...

Except that he makes the jump from APP variation to amyloid beta buildup. The huge gaping question that remains is "what is the physiological function of APP?" Therein lies the answer to why variations in APP lead to difference in cognitive ability with aging and possibly a targetable mechanism for therapeutic intervention.

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5. CR on July 26, 2012 2:59 PM writes...

@2, CW:

Generally speaking, when companies have cut their CNS departments they are cutting the psychiatry aspect, but keeping neurodegeneration. That being said, most will still entertain offers for psychiatry drugs (i.e., in-licensing, etc.).

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6. NoDrugsNoJobs on July 26, 2012 4:55 PM writes...

The genetic allele you refer to lasts the persons entire life....we are trying to treat people who already have plaques. It might be like treating people after they've had a stroke as compared to preventing a stroke. The brain has many adaptive mechanisms and by the time a person is manifesting signs of cognitive decline, the implication is that they've already exhausted their own work arounds. Ripping up plaques after the damage is done might be equivalent to ripping a scab off an old injury. The scab is not the injury but a response to it. The plaque is more like that - a post-apocalyptic artifact that symbolizes more what has already happened than what is happening. A very well-tolerated bace-inhibitor in a prophylatic mode starting at age 30 might due the trick. The drug needs to be damn safe!

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7. RD on July 26, 2012 11:55 PM writes...

Has there been any news on the CoMentis BACE inhibitor since 2008?

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8. Jesse on July 27, 2012 9:30 AM writes...

One the professors here at my medical school (Dr. Robert Nagele) has an interesting take on Alzheimer's. He is of the opinion that amyloid plaques do not form extra-cellularly (or at least, not some sub-set of plaques that matter to disease progression), but actually result from endocytosis and intra-cellular accumulation; each plaque is actually the tombstone of a deceased cell.

As such, antibodies against aggregated amyloid would not be effective, as the aggregation occurs intra-cellularly, with antibody-mediated clearance only removing plaque left-over after a cell has lysed. If anything, anti-amyloid antibodies may simply add to the burden of junk getting dumped into a cell's lysosomes.

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9. Anonymous on July 29, 2012 11:34 PM writes...

APP genetics are the best argument for the amyloid hypothesis, and this is a nice study that strengthens the association. However, it still seems quite possible that the abeta accumulation is a downstream effect from processes leading to, rather than the primary cause of, neuronal death. (In low concentrations abeta can actually have a growth effect in cellular assays, and you have to go to some lengths to make it toxic.) The field tends to skip over looking at biological effects of APP/intermediate APP cleavage products (the biology is poorly understood and seemingly rather complex) in favor of simply measuring levels of abeta, though the latter hasn't really produced much of benefit so far.

I sincerely hope that BACE inhibition is more successful than the previous treatments, but I won't be holding my breath. Honestly I still don't think we have useful targets, and my #1 wish would be that we understood APP/abeta biology better.

#1: That's actually a somewhat common, though usually kept reasonably quiet, thought of people in the field.

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