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DBL%20Hendrix%20small.png College chemistry, 1983

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: derekb.lowe@gmail.com Twitter: Dereklowe

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May 6, 2008

Alzheimer's: A Report From the Front

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Posted by Derek

Several recent papers in Neurology offer some interesting ideas on Alzheimer's disease. The one that's getting some headlines today suggests that long-term use of ibuprofen has a protective effect against the disease. Actually, the authors looked at all sorts of non-steroidal antiinflammatory drugs, but the correlation was strongest for ibuprofen. (That may be just because it's used so much, however, and not some intrinsic property of that specific drug). Interestingly, although some NSAIDs have been shown to inhibit formation of beta-amyloid (the protein fragment implicated for many years in Alzheimer's), no particular effect was seen for that class of drugs versus the other NSAIDs.

There's long been a suspicion that a lot of Alzheimer's pathology is driven by inflammation cascades, and although evidence has been mixed to date, this would seem to be good evidence for that idea. (More on this in another post). This wasn't a prospective study - they didn't enroll people just to test this idea - but a huge number of VA patients were studied retrospectively, and the authors appear to have done as much as possible to control for other variables. Of course, in an observational study like this one, you can't control for the biggest possible confounding factor: what if there's something about patients who end up taking NSAIDs more often that also keeps them from developing Alzheimer's? That certainly can't be ruled out, but I don't think there's room for that in most of the headlines. It's going to be tempting for worried patients to start taking ibuprofen to prevent dementia - and that just might work, still - but we really can't be sure without plenty of prospective trial data.

Of course, not everything is good for preventing Alzheimer's. You can apparently add statins to that list. An examination of aging Catholic clergy (mostly nuns) showed no correlation at all between statin use and the development of the disease. This is one of those long-running studies that ends with death and subsequent brain histopathology, too, so it's pretty hard to argue with. Intellectually demanding work, though, does perhaps show a protective effect. Interestingly, this effect was even stronger in the cohort of patients that scored lower in assessment of overall intelligence, which makes sense in a way. (Cue the arguments about whether general intelligence exists, whether it can be measured, and if so, whether it's being measured in the correct way).

On the ever-profitable herbal front, you see all sorts of claims made for Gingko biloba extract and cognitive function, and there are a lot of contradictory studies (many of which, unfortunately, aren't worth much). This latest one won't help much - in the intent-to-treat analysis, no effect was seen. When they controlled for how well patients stuck to the treatment, then some correlations emerged between taking the extract and slower rates of memory loss. Unfortunately, a correlation (at the same level of significance) emerged with stroke and associated TIAs. My prediction: the ginkgo biloba sellers will trumpet the first set of statistics, assuming they need recourse to any data at all, and ignore the second one completely.

Such is the current state of Alzheimer's. To be honest, none of these studies (or most of the others in the same issue) would have been out of place back when I was working in the field in the early 1990s. The field awaits its breakthrough, and has been waiting for a long time. . .

Comments (13) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. Wavefunction on May 6, 2008 11:59 AM writes...

Curcumin

Permalink to Comment

2. Retread on May 6, 2008 5:15 PM writes...

"Of course, in an observational study like this one, you can't control for the biggest possible confounding factor: what if there's something about patients who end up taking NSAIDs more often that also keeps them from developing Alzheimer's?"

Bravo

Science vol. 297 p. 325 -326 '02 -- There were OVER FIFTY observational studies showing health benefits for hormone replacement in menopausal or pre-menopausal women, before the PremPro study (giving menopausal women premarin (an estrogen) and progesterone) was done. During the planning study for the Women's Health Initiative, some argued that it was uneithical to deny some women hormones and give them a placebo.

The Women's Health Initiative trial in 16,608 women actually showed INCREASED risk of stroke, dementia, and global cognitive decline with hormone replacement. In addition there was no benefit for mild cognitive impairment. Subsequent work extended the initial early findings to a followup to 5.6 years. The rate of stroke was 31% higher. 80% of the strokes were ischemic. The increased risk was seen in all categories of baseline stroke risk. 40/61 women diagnosed with dementia were in the hormone (prempro) group. The followup was in a subgroup of 4,532 of the original 16,608 women in the study. Some references are JAMA (Journal of the American Medical Association) vol. 289 pp. 2663 - 2672, 2651 - 2662, 2673 - 2684, 2717 - 2719 '03.

Why? The women taking hormones in the 50 observational studies were (1) thinner (2) better educated (3) concerned enough about their health and vigor to take hormones -- it isn't well known (but it should be) that people who actually take the mediation -- even those who take placebo medication -- have a better outcome than people who don't -- just the fact that one group in the observational studies took hormones, made then different (4) smoked less.

Similarly, noises had been made about female hormones preventing and or treating Alzheimer's disease since the 70s (again based on retrospective studies). It wasn't until 2000 that the number of women in a proper trial (double blind and placebo controlled) of estrogen as a treatment for Alzheimer's disease passed 200 -- Neurol. vol. 54 pp. 2035 - 2037 '00 -- there was no benefit. Pathetic. What was academic neurology doing all this time? This was not a high-tech study using the latest in NMR or femtosecond spectroscopy -- it could have been done at any time (but wasn't).

Buy a large box of salt, to be taken with observational studies like the ones cited. It's good to see you express the proper skepticism about these results. Do not hold your breath until a prospective randomized placebo controlled double blind trial is done.

Retread

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3. 3+speckled on May 6, 2008 11:19 PM writes...

"It's going to be tempting for worried patients to start taking ibuprofen to prevent dementia"

No kidding, and that's why there should be some kind of advisory in the Academy of Neurology press release about possible consequences of doing so. They make no mention of any problems more serious than diarrhea and nausea. They did the same thing for their release concerning ibuprofen and Parkinson's in Dec 07.

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4. Morten on May 7, 2008 1:16 AM writes...

Was it ibuprofen that increased muscle growth (in a group of 60-65 year old men) ?
Ibuprofen doesn't have BBB penetration does it?

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5. Peter Ellis on May 7, 2008 2:05 AM writes...

When they controlled for how well patients stuck to the treatment, then some correlations emerged between taking the extract and slower rates of memory loss.

You mean... patients that remembered to take their ginkgo had better memories than the ones that forgot their pills? Astounding! What will they discover next?

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6. Retread on May 7, 2008 6:23 AM writes...

To Peter Ellis

The business about patients remembering to take their gingko is just another example of how different 'compliers' are from noncompliers. The same effects are seen with placebo -- see post #2.

On a more scientific note, I've got another post up on "The Skeptical Chymist" this morning and would be happy to hear any comments, particularly since rational drug design is about altering protein conformation and structure.

Retread

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7. eugene on May 7, 2008 9:37 AM writes...

What do they mean by 'intellectually demanding work'? From what I've read about Alzheimer's, it sounds like learning languages does the trick, so I've been doing that diligently since it's fun and matters in the real world, but does playing an intellectually demanding video game count? I suppose I should pick up the old Calculus textbook once in a while (even though it won't matter in the real world)...

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8. retread on May 7, 2008 12:20 PM writes...

The idea that intellectual activity prevents Alzheimer's disease is a classic case of post hoc propter hoc. It is worthwhile considering (and reading for yourself) the following study.

Here is the reference [ J. Am. Med. Assoc. vol. 275 pp. 528 - 532 '96 ]

Here are my notes taken on the paper at the time. 93 Nuns ages 75 - 95 were studied. All had written an autobiographical essay at age 22 to get into the order. 14 died and some had Alzheimer's disease. Those with low idea density and low grammatical complexity in their autobiographies had the neuropathology of Alzheimer's disease, while those with high idea density and grammatical complexity were free of Alzheimer's disease. Of the living 79 patients the smart ones at age 22 remained smart (for the most part) at 75+, while the less intellectually gifted ones stayed the same. All of these women were college educated and were teachers for most of their lives. Thus this wasn't confounded by education or occupation. The sociology of the sisters was the same.

Not that supreme intellectual ability guarantees freedom from the disease -- Claude Shannon died of it, and I saw many formerly highly intelligent people with the disorder as a neurologist.

Retread

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9. Anonymous BMS Researcher on May 7, 2008 12:59 PM writes...

retread on May 7, 2008 12:20 PM wrote:
> Not that supreme intellectual ability guarantees freedom from the disease -- Claude Shannon
> died of it, and I saw many formerly highly intelligent people with the disorder as a neurologist.

A prominent member of my church and brilliant Yale mathematician died of AD a few years ago. It's an awful disease for anybody but it was particularly sad for all of us to watch a mind like his being slowly destroyed. Extremely hard for his wife and family. Like most of the industry BMS has programs in AD, with a lot of good people working on them (very good people, I know a number of them) -- but as Derek has noted many times this is NOT an easy area for drug discovery.

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10. Jumbo on May 7, 2008 4:09 PM writes...

Derek - wrt statins, be careful not to get caught in the PK trap. The brain (as you well know) is a notoriously difficult organ to target, and I am pretty sure that both pro- and retrospective studies with statins so far have not looked at drugs that are particularly good at partitioning into the brain. Not that I am arguing that statins will be helpful for AD, just cautioning that a CNS-specific statin-like drug remains to be tested robustly.

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11. smoki on May 13, 2008 2:10 AM writes...

Of course there is correlation between taking gingko extract and slower memory loss - the patients with better memory remembered to take the pills. :)

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12. Oldtimer on May 19, 2008 3:36 AM writes...

I have two points:

1. The first comment simply says "curcumin". I'm new here, and so I don't know whether everyone else understands what that person is getting at. Could this have been a way of commenting on your failure to include a mention of curcumin in your very interesting blog about Alzheimer's?
What's the scoop?
2. I came across a newsletter mention of an Alzheimer's study comparing plaque incidence (I wonder how this can be measured) of Alzheimer's patients versus a non-Alzheimer's individuals which included a cohort of relatively young people. What was surprising in the finding was that the youngies had Alzheimer's-like plaques without having any evidence of impaired functioning. The researchers concluded that this might indicate that the plaques might not represent a specific symptom of AD. Sorry that I can't supply a reference -- but these are recent findings and shouldn't be too had to pull out of Google.

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13. jiniappa on May 23, 2008 10:55 AM writes...

Hi Derek,

Been a fan of yours. Hope this automatically falls into your inbox cause I want to hear your answer (I will email if I don't hear from you in a week...).

Wonder what you think of Flurizan from Myriad. There was news that Lundbeck is paying 100 million UPFRONT for EU licensing. The compound has just finished Ph3 trial (another ongoing). If you look at the structure, it's definietly an NSAID, although it's not been advertised as such. Hmmm...

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