>>Some elderly people who die with the disease don't have senile plaques.
Is this the same disease? (One of the key methodologies for advancement of modern medicine has been to divide up 'one disease' by etiology) <<
You can have dementia without having Alzheimers. There is also something called multi-infarct dementia, which is a series of tiny strokes that kill parts of your brain one bit at a time. In the past the only way to reliably distinguish the two was looking for plaques during an autopsy. Plaques meant Alzheimers, lack of plaques implies multi-infarct dementia (or some other cause.) Nowadays you can look for them via MRI or CT scans, but not everyone has that done.
Most elderly patients who die of seemingly natural causes don't have autopsies done.
Multi-infarct dementia (MID) is a common cause of memory loss in the elderly. MID is caused by multiple strokes (disruption of blood flow to the brain). Disruption of blood flow leads to damaged brain tissue. Some of these strokes may occur without noticeable clinical symptoms. Doctors refer to these as “silent strokes.” An individual having a silent stroke may not even know it is happening, but over time, as more areas of the brain are damaged and more small blood vessels are blocked, the symptoms of MID begin to appear. MID can be diagnosed by an MRI or CT of the brain, along with a neurological examination. Symptoms include confusion or problems with short-term memory; wandering, or getting lost in familiar places; walking with rapid, shuffling steps; losing bladder or bowel control; laughing or crying inappropriately; having difficulty following instructions; and having problems counting money and making monetary transactions. MID, which typically begins between the ages of 60 and 75, affects men more often than women. Because the symptoms of MID are so similar to Alzheimer’s disease, it can be difficult for a doctor to make a firm diagnosis. Since the diseases often occur together, making a single diagnosis of one or the other is even more problematic.
Is there any treatment?
There is no treatment available to reverse brain damage that has been caused by a stroke...."
In hockey, as in life, what you want is lots of shots on goal. After years in which most of the scientific firepower in Alzheimer's research was focused on the notorious "amyloid plaques" that gum up brain neurons like a wad of Wrigley's, this field is finally shaking off the amyloid dogma.
Thank goodness. "If everything [now in the drug pipeline] crashes and burns," says Rudolph Tanzi of Harvard Medical School, who is leading a project in which 437 families with Alzheimer's are undergoing genetic screening, "at least we'll have many more potential targets" for Alzheimer's therapies.
As I described last week, the belief that amyloid plaques are the chief cause of this disease so dominated Alzheimer's research that it became "orthodoxy," says Zaven Khachaturian, who oversaw Alzheimer's funding at the National Institute on Aging from 1977 to 1995. "Having one view prevail is harmful; it becomes a belief system, not science."
Orthodoxy also stifles research on other culprits. "Where the field made its mistake was in trying to make everything fit one common [amyloid] pathway," says Robert Mahley, president of the J. David Gladstone Institutes, San Francisco. "We've got to realize there are multiple ways you can wind up with [Alzheimer's]."
With that realization setting in, the search for ways to prevent, slow or treat Alzheimer's is entering what you might call its "let 1,000 flowers bloom" period.
How likely is Dr. Tanzi's crash-and-burn nightmare? Several treatments now in development focus on enzymes that, by snipping a particular protein, produce the sticky brain plaques. Solution: knock out the evil enzymes. But one enzyme, BACE1, also is important for myelination, the process that coats neurons with the insulation they need to work, scientists will report in December in Nature Neuroscience. Poor myelination underlies multiple sclerosis. Targeting BACE1, therefore, sounds like a good way to give Alzheimer's patients MS-like symptoms. The challenge will be to dial down BACE1 enough to prevent or reverse Alzheimer's without hurting myelination.
Another evil enzyme, gamma secretase, turns out to be used in gastrointestinal and lymphoid tissue. Disabling it to strangle production of amyloid may, therefore, produce serious side effects unless scientists can spare its healthy functions. The verdict is out on that, but Dale Schenk, chief scientific officer of Elan Pharmaceuticals, South San Francisco, says he's "optimistic."
A number of companies are pursuing immune approaches. If you sic antibodies on amyloid, perhaps with a vaccine, you should be able to eliminate amyloid and thus prevent plaques and Alzheimer's. But because amyloid is important for normal neuron function, eliminating it might not be a good idea.
If we have wasted decades and hundreds of millions of dollars on a bankrupt theory, that is a tragedy for the 4.5 million Alzheimer's patients in the U.S. today and the nine million expected by 2020. But all is not lost. With recognition that the sticky plaques that mark Alzheimer's are tombstones and not killers, researchers are resurrecting leads long overshadowed by the amyloid dogma.
In 1993, Allen Roses at Duke University discovered that a gene called apoE4 increases the risk of Alzheimer's. About all he got for his trouble was loss of funding and skepticism -- even though apoE4 turns out to be behind 50% to 70% of Alzheimer's cases. (If you inherited two copies of apoE4, one from mom's egg and one from dad's sperm, your risk of developing AD is 50% to 90%; with zero copies, the risk is 20%.)
ApoE4 research hung on by its fingernails, and this month drug giant Merck and Gladstone announced a research collaboration, with a $3.25 million up-front payment, to develop Alzheimer's therapies based on apoE4.
One approach Gladstone scientists are working on is to turn the protein that apoE4 makes into its healthy cousin, apoE3. "We've identified a dozen molecules that do this," says Dr. Mahley. Another is to block an enzyme that snips the apoE4 protein into fragments. These snippets enter neurons, attack their vital energy-making mitochondria, form toxic tangles and thus kill them. If you prevent the snippets from forming, maybe neurons would never face these killers.
In a recent paper, Dr. Roses, now at GlaxoSmithKline, expressed guarded optimism about a molecule called rosiglitazone. In a Phase II trial of 511 patients, it produced "significant clinical improvement" in some patients, GSK reported in January. Rosi seems to increase the number of mitochondria in neurons. Since fragments of the apoE4 protein attack mitochondria, a drug that keeps making new ones would keep neurons alive despite the attacks, like a battalion that remains at full strength, despite casualties, with new recruits.
Anti-inflammatory drugs and statins may protect brain neurons from Alzheimer's. So might blocking an enzyme that changes harmless proteins into the toxic tangles that kill neurons, or compounds that increase synapses as fast as Alzheimer's destroys them, or...
Yes, the approaches are eclectic. This disease won't be felled by a single magic bullet. Researchers must scramble to make up for time lost on overemphasizing one approach. <<
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