While it's true that we can cure just about anything in mice (at least once), this is still remarkable ...
BBC News - Alzheimer's brain plaques 'rapidly cleared' in mice
... Scientists at the Case Western Reserve University in Ohio were investigating ways of boosting levels of ApoE, which in theory should reduce levels of beta-amyloid.
They tested bexarotene, which has been approved for use to treat cancers in the skin, on mice with an illness similar to Alzheimer's.
After one dose in [genetically engineered mice with dysfunctional ApoE4] young mice, the levels of beta-amyloid in the brain were "rapidly lowered" within six hours and a 25% reduction was sustained for 70 hours...
What's remarkable is the speed of the result, and that the drug is already FDA approved for another use. That means, although as chemotherapy agent for mycosis fungoides it has nasty side effects, Bexarotene will be very soon studied in humans with advanced dementia. We may find, however, that the drug is primarily useful for people who have remarkably poor ApoE4 directed amyloid clearance.
The role of amyloid in Alzheimer's dementia was well described in a 2010 NYT review ...
Insights Give Hope for New Attack on Alzheimer’s - NYT 12/13/10 - Kolata
... most people with Alzheimer’s seem to make perfectly normal amounts of amyloid. They just can’t get rid of it
... Researchers have also found that amyloid, in its normal small amounts, seems to have a purpose in the brain — it may be acting like a circuit breaker to prevent nerve firing from getting out of control. But too much amyloid can shut down nerves, eventually leading to cell death. That means that if amyloid levels were reduced early in the disease, when excess amyloid is stunning nerve cells but has not yet killed them, the damage might be reversed....
... With Alzheimer’s disease, Dr. Bateman discovered, beta amyloid is made at a normal rate, but it hangs around, draining at a rate that is 30 percent slower than in healthy people the same age. And healthy older people, in turn, clear the substance from their brains more slowly than healthy younger people...
... beta amyloid seemed to be part of a nerve cell feedback loop. A nerve will start firing, but under some conditions, the signal can get too intense. Then the nerve releases beta amyloid, bringing the signaling down to normal levels, at which point the nerve stops releasing beta amyloid... [especially in the 'default network']
... There may be another way to protect nerves from too much beta amyloid, and it involves a different protein linked to Alzheimer’s. Problems with it show up in the brains of Alzheimer’s patients later, after there has already been a buildup of beta amyloid.
The protein is tau, an integral part of normal cells. It becomes tangled and twisted in Alzheimer’s, after cells are already dying, looking like strands of tangled spaghetti...
... New studies by Dr. Lennart Mucke, a neurology professor at the University of California, San Francisco, and director of the Gladstone Institute of Neurological Disease there, and others suggest that tau facilitates beta amyloid’s lethal effects. In genetically engineered mice and in laboratory experiments, the researchers found that without tau, beta amyloid cannot impair nerve cells...
...Amyloid was in ... the default network. It is used not only in daydreaming but in memory and in the sense of self...
... The default network is costly for the brain to run, using huge amounts of glucose, Dr. Raichle said. And one indication that a person is getting Alzheimer’s is that in scans, the brain’s glucose use is markedly lower. The observation that Alzheimer’s attacks the default network, then, explains the observation that a low use of glucose by the brain is associated with Alzheimer’s disease.
... Beta amyloid synthesis increased when they were awake, when the default network is most active, and decreased when they slept...
... the less active the person’s brain, the less beta amyloid it made. That made the researchers ask whether something similar was happening during sleep — the default network was less active, so perhaps less beta amyloid was being made. If so, the implication, which Dr. Holtzman is studying, is that people who are sleep-deprived might be at greater risk of Alzheimer’s.
I am prone to believe in the sleep loss/dementia connection, I wrote about that in 2008 and more emphatically in 2010.
The role of ApoE4, exercise and dementia was also highlighted two weeks ago in the NYT ...
How Exercise May Keep Alzheimer's at Bay - NYT 1/18/2012
... Most of those who carried the APOE-e4 gene displayed much larger accumulations of amyloid plaques than those without it.
Unless they exercised. The carriers of the gene who reported walking or jogging for at least 30 minutes five times a week had plaque accumulation similar to that of volunteers who were e4-negative. In essence, the APOE-e4 gene carriers mitigated their inherited risk for developing Alzheimer’s by working out. Or, as the study authors wrote, a “physically active lifestyle may allow e4 carriers to experience brain amyloid levels equivalent to e4-negative individuals.”..
... An overwhelming majority of the people in the study were sedentary, and for them, an inactive lifestyle seemed to be accelerating the accumulation of amyloid plaques. Those with the e4 variant who rarely or never exercised had the most plaques, putting them at heightened risk for the memory loss of Alzheimer’s in the years to come.
From another angle, another recent article points to a prion like spread of malformed tau protein as a critical component of Alzheimer progression. (see tau references in the 2010 article) ...
Alzheimer’s Spreads in the Brain Like a Virus, Studies Find - NYT Kolata 2/1/2012
Alzheimer’s disease seems to spread like an infection from brain cell to brain cell, two new studies in mice have found. But instead of viruses or bacteria, what is being spread is a distorted protein known as tau...
The studies, done independently by researchers at Columbia and Harvard, involved genetically engineered mice that could make abnormal human tau proteins, predominantly in the entorhinal (pronounced en-toh-RYE-nal) cortex, a sliver of tissue behind the ears, toward the middle of the brain, where cells first start dying in Alzheimer’s disease. As expected, tau showed up there. And, as also expected, entorhinal cortex cells in the mice started dying, filled with tangled, spaghettilike strands of tau.
Over the next two years, the cell death and destruction spread outward to other cells along the same network. Since those other cells could not make human tau, the only way they could get the protein was by transmission from nerve cell to nerve cell...
... beta amyloid, which accumulates in the brain of Alzheimer’s patients, forming hard, barnaclelike plaques. But beta amyloid is very different from tau. It is secreted and clumps outside cells. Although researchers have looked, they have never seen evidence that amyloid spreads from cell to cell in a network.
Still, amyloid creates what amounts to a bad neighborhood in memory regions of the brain. Then tau comes in — some researchers call it “the executioner” — piling up inside cells and killing them...
... it may be necessary to block both beta amyloid production, which seems to get the disease going, and the spread of tau, which continues it, to bring Alzheimer’s to a halt...
These are exciting times in dementia research, particularly given the discouraging state of the art only three years ago.
Alas, good news can't come fast enough for the 40+ set - our brains start running downhill fast at around age 45 [1]. While we wait to see if anything will come of this, our take away lessons are ...
- Avoid head injury.
- Exercise. If somehow you know you have problematic ApoE4 this seems utterly essential. Probably good for all of us.
- Sleep 8 hours a night. (Speculative, but I bet this will be true).
[1] Yes, raising the retirement age is a sick joke.
