Treatments*

As of this month (August, 2008) there is no substantially effective medical treatment or prevention agent available for Alzheimer's disease. There are a few palliative (comforting) treatments that delay symptoms (substantially, in a few people) and some slightly effective prevention agents and activities (see below), but, again, nothing very effective for most people. That doesn't mean one shouldn't see if one of the available cholinesterase inhibitors (CEIs) has a substantial effect upon the progression of symptoms or learn to juggle to build mental capacity, and it certainly doesn't mean there will not be more effective treatment next year. However, if somebody wants to sell you a nutritional supplement, a 3 minute brain age test, or a set of brain exercises that specifically evaluates your abilities, prevents Alzheimer's or treats Mild Cognitive Impairment, don't buy it. Physical exercise, good nutrition, and actively using the brain are valuable but any "highly specific" claims are in need of verification.** As the Alzheimer's Association*** says, "you can do everything right and still have a serious health problem". However, general preventive tactics (such as substantial physical exercise, low blood pressure, good cholesterol numbers, active social contact, word puzzles, proper nutrition and vitamins) are valuable. Brain training programs should be evaluated for their motivational value. You have to want to use them or you won't. Physical exercise appears at present to be the most powerful preventive intervention but very few people do much of it.

Significant progress is possible within just a couple years in the development of prevention and treatment agents. For example, Elan's vaccine AAB-001 or bapineuzumab (now in phase III) is promising despite some problems with vaccines so far in previous trials.

When you think of a vaccine you probably think it only has to do with wiping out a virus. Not these days. The general mechanism for using a vaccine to reverse AD is the same as for more established purposes (put weak or partial pieces of something in the blood and stimulate the immune system to create specific antibodies that target and eat anything that contains those pieces). What's new is that antibodies might be modified so that they hunt and eat things other than viruses, such as beta-amyloid (a big part of plaques which can be made to appear as suspicious looking to a sensitized antibody as a virus). This approach is consistent with some of the latest Alzheimer's causation findings concering genetics, tau and plaques. The market is so hot for vaccines that a European group (Affiris) that makes all kinds of vaccines is now also focusing on Alzheimer's.

However, no vaccine treatment is currently available, and the most promising first clinical study had to be discontinued because of negative inflammatory effects upon the brain. There may be other, sophisticated ways to target the antibodies so they only go after the most relevant protein bits in the right area of the brain or don't cause inflammation. Elan and Wyeth have been heavily invested in this possibility. Other companies involved include Lilly, MindSet, and Novartis. Training the body’s immune system to stimulate an attack against beta amyloid without causing brain inflammation might be possible. There are some exciting rumors about the effectiveness of immunotherapy. Clinical trials are active in many places and areworth looking into.

Update (August, 2008)

This last month has been very depressing, when it comes to treatment research. First Myriad and Lundbeck's Flurizan bombed. Then Elan reported that for the whole first year of the 18 month comparison of bapineuzumab to placebo, both groups declined about the same amount. There were positive effects, compared to the controls, in the last 6 months, but that might have been due to the unusually steep decline in the placebo patients during that time (for comparison, the Myriad controls declined an average of 7 points on one test but the Elan controls dropped 11). So who knows. It was bad enough to cause their stock to tank.

The use of antibodies (via immunoglobulin therapy) to halt the progression of AD is expanding: you might follow the work of Marc Weksler and Cornell Medical Center as well as that of Sid Gilman at the University of Michigan Medical Center.

Novartis is getting started on clinical trials (Phase 1) of CAD106, another "immunotherapeutic" treatment designed to inhibit plaque formation in AD. The Thuris company is looking at tau inhibitors.

In a kind of shot gun approach, the intravenous drug for boosting the immune system, Gammagard, made by Baxter International, is getting a new look. The beta-amyloid proteins deplete Alzheimer's patients' antibodies and Gammagard is known to generally replenish depleted antibodies.

We expect a breakthrough that can be marketed within a couple years to reduce or stabilize amyloid-beta load - this is certainly an area to look at if you are (or represent) a patient who might be able to participate in clinical trials. The search for a safe way to clear or prevent beta amyloid protein deposition is one likely source of treatment progress and is receiving huge amounts of research attention.

Update (7/08):
The first treatment that attacks the Tau tangles is getting good reviews for preliminary data. The potential treatment was discovered by accident when Claude Wischik noticed that a drop of methylthioninium chloride, a blue lab dye, made a Tau protein change. It will be called "Rember", which is either the smartest or dumbest drug name in a while.

Exciting data came from Antonella Caccamo and Frank LaFerla's work at UC Irvine with genetically modified mice. AF267B is the name given to a compound that passes the blood-brain barrier and reduced both plaques and tangles in the brain regions associated with learning and memory. In other words, this affects the underlying causes of AD.

Prana Biotechnology in Australia has PBT2, a drug that supposedly works by stopping beta amyloid from abnormally combining with zinc and copper in the brain to form plaques. This might be worth following, even though their lead scientist at the University of Melbourne says that women are twice as likely to die from Alzheimer's as men because they have higher levels of zinc in their brains, a claim that might require some replication.

In addition to all the work on the inhibition of plaque FORMATION, there is exciting progress with respect to correcting (compensating for) the poor CLEARANCE of beta-amyloid that is characteristic of AD patients. Follow the work of Berislav Zlokovic, Rashid Deane, Abhay Sagare and Robert Bell in the US as well as Ronan Pendu and Peter Lenting in the Netherlands (Clearance of amyloid- by circulating lipoprotein receptors. Abhay Sagare, Rashid Deane, Robert D Bell, Bradley Johnson, Katie Hamm, Ronan Pendu, Andrew Marky, Peter J Lenting, Zhenhua Wu, Troy Zarcone, Alison Goate, Kevin Mayo, David Perlmutter, Mireia Coma, Zhihui Zhong & Berislav V Zlokovic Nature Medicine 13, 1029 - 1031 (2007) Published online: 12 August 2007). These scientists have focused upon the protein sLRP (soluble low-density lipoprotein receptor-related protein). Normal people have a lot of it that works. AD patients have less and some of theirs are broken proteins. sLRP slurps up huge amounts of the beta-amyloid circulating through the body. These researchers made a synthetic sLRP (called LRP-IV) and it may work even better than naturally-produced sLRP. This could be huge.

At the 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy Lawrence T. Friedhoff (supported by Axonyx Inc.) said that the cholinesterase inhibitor phenserine tartrate (PhT) produced significant improvements in cognitive function in patients with mild to moderate Alzheimer's disease (AD).

People often overlook the high liklihood of an accidental discovery. For example, an epilepsy drug, valproate, seemed to reduce plaques. Most recently (2006), it was found to reduce tangles as well (if you want more detail on this effort, follow research of Pierre Tariot).

There is exciting recent work by Reger at the University of Washington on intranasal insulin (which appears to "improve cognition and modulate -amyloid" in amnestic MCI and early AD. The abstract in October, 2007 Neurology says: "The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of an amyloid peptide (A40; p = 0.0471) "without affecting the longer isoform (A42), resulting in an increased A40/42 ratio (p = 0.0207)." Despite the cherry-picking of significant results, this might be important.

A serendipitous finding came recently from Brian Reynolds of Voyager Pharmaceuticals who says that leuprolide acetate, a cancer drug already approved, appears to produce a significant stabilization of cognitive and global functions for women with mild-to-moderate Alzheimer's disease.

TPM21, a protein that blocks the formation of the beta-amyloid peptide, was recently discovered. Peter St. George-Hyslop, who is in Toronto, is the super researcher on this. This is extremely important basic research.

Transition Therapeutics Inc just initiated a Phase I clinical trial on AZD-103. which they designed to prevent the formation and break down amyloid beta clumps.

Targacept and AstraZeneca recently (5/06) came out with positive results in their Phase 2 trials of TC-1734.

There is increasing evidence that losing insulin in the brain may be a trigger for the onset of Alzheimer's. If insulin is lost in the brain, then cells that need it die, and that, in turn, can cause greater oxidative stress and an increase in the plaques and tangles in the brain. See work of Patrizio Odetti (Pages 243-245) and Enrique J. Rivera (Pages 247-268), Journal of Alzheimer's Disease, Volume 8, Number 3, December 2005.

There are multiple efforts to reduce the beta-amyloid associated with Alzheimer's. For example, Transition Therapeutics has a molecule (AZD-103) in trials that might "disaggregate amyloid-beta fibrils and reduce amyloid-beta load". Many other efforts to reduce or "clear" amyloid are also potentially valuable (e.g. those of TorreyPines Therapeutics and the work on LY450139 - Siemers E, Quinn J, Kaye J, et al. Effect of LY450139, a functional gamma-secretase inhibitor, on plasma and cerebrospinal fluid concentrations A-beta and cognitive functioning in patients with mild to moderate Alzheimer's disease. Neurology. 2004;62(suppl5):A174. Abstract S17.001.).

Bryostatin - This protein has just been reported to counteract the degeneration of neurons in a strain of mice designed to look like Alzheimer's (Proceedings of the National Academy of Sciences). That might seem to be far on the horizon, but this protein has already been approved by the FDA for human trials as a cancer fighter (which means it could move pretty fast through human trials). It already was found to cut down on the beta amyloid secretion in human tissue derived from AD patients. This is a serious contender for reducing beta amyloid deposits (plaques). Watch for the work by Blanchette Rockefeller Neurosciences Institute's Daniel L. Alkon, Ph.D.

Current Treatments

The combination of a cholinesterase inhibitor with memantine has "resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated."
JAMA. 2004 Jan 21; 291(3):317-24.

Cholinesterase Inhibitors (CEIs)

Cholinesterase inhibitors (CEIs) are the most important group of current treatments. Their use is based upon knowledge concerning neurotransmitter deficits associated with AD. These agents don't stop the disease process but can slow down the progression of the disease and sometimes temporarily reverse some of the cognitive decline. To date, however, the effect of these drugs has been best described as "modest and transient". They include:

Physostigmine - This didn't seem to work very well (a conclusion that always makes one respect the researchers who made sure they reported the failure: Leon Thal et al, Neurology. 47, 1389-1395, 1996)

Donepezil (AriceptTM) - Currently the most widely prescribed treatment - it is better, with respect to side effects, than tacrine.

Rivastigmine (ExelonTM) - Widely prescribed but with slightly less history than donepezil. Now available as a generic, rivastigmine tartrate.

Galantamine (Razadyne®, previously ReminylTM) - Recently approved and, in addition to increasing the level of acetylcholine in the brain, it affects nicotinic receptors. Some sustained improvements with this drug, but there have also been some concerns about side effects with use early in the progression of the disease.

Metrifonate (PromemTM) - The initial research was promising because this CEI also seemed to reduce some of the psychiatric behavior problems common with AD patients. This treatment is not available, due to side effects.

Phenserine (GilatideTM) - This agent has promise for treatment because in mouse studies it reduces both the amyloid precursor protein (APP) and amyloid peptide (amyloid-beta) formation. The drug company (Axonyx) says it works "through two mechanisms: (1) it inhibits the degradation of the neurotransmitter acetylcholine in the brains of animals, and (2) it inhibits the production of a toxic form of the beta-amyloid protein in the brain that is thought to be a cause of the death of brain cells in AD. Unlike other acetylcholinesterase inhibitors that simply suppress the activity of the enzyme, Phenserine's dual mechanism of action suggests that it not only has the potential to improve memory and cognition but also to slow the progression of the disease." At the 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy Lawrence T. Friedhoff (supported by Axonyx Inc.) said that phenserine tartrate (PhT) shows significant improvements in cognitive function in patients with mild to moderate Alzheimer's disease (AD).

Other Treatments

Memantine (NamendaTM) - May restore the functional neuronal impairment associated with a number of disorders. It influences cell destruction by affecting glutamate activity. Recent confirmatory results indicate improvement in functional independence and reduction in required level of care in moderate to severe Alzheimer's. This is the first breakthrough in prevention of deterioration for people who already have moderate to severe Alzheimer's. FDA approval was given and Forest started sales in January, 2004. Memantine is especially interesting because it is the first treatment that seems to be useful to people with moderate-to-severe Alzheimer's.

Ampakines (General) - Ampakines might compensate for the decrease of glutamate by increasing the level of a specific neurotransmitter in the brain, AMPA-glutamate, and also increasing production of neurotrophins.

Efforts to alter or "modulate" AMPA are being made by the Servier, Cortex, and Lilly companies.

NCAM mimetics - These will be reviewed here when human trials have progressed further. The neural cell adhesion molecule on the surface of central nervous system cells plays a part in the survival of nerve cells. The way it "binds" to itself and other receptors seems to be something that synthetic peptides can be constructed to mimic. FGLL is one of these that has had very positive effects in animal studies. It looks like FGLL can influence beta-amyloid accumulation and may even keep brain cells from dying and rejuvenate damaged brain cells. Pretty amazing possibilities. The work of ENCAM Pharmaceuticals is at the forefront here.

Herbs
Huperzine (HupA) - This Chinese herb looks very promising, but don't assume that because it is an herb that it comes without side effects. The side effects can be significant (e.g. excitation, diarrhea). Companies selling it have a long way to go in true clinical trials before establishing its effectiveness.** Gingko biloba - Herbal treatment with gingko has received serious research attention but the effectiveness results in rigorous studies have been mixed (most recently, positive). The Chinese herbal based treatment called gastrodine compound granule sounds more promising than Gingko, at least for stroke-related dementia.

Stimulation of muscarinic and nicotinic receptors - Muscarinic receptor agonists might increase or mimic the effects of acetylcholine.

Other treatments
Surgery (COGNIShuntTM) - Replenishing cerebrospinal fluid more rapidly than usual might eliminate toxins and inflammatory factors. Look for the "peer-reviewed" journal articles** (that's a phrase that describes the highest level of scientific evidence) before buying these claims.

Selegiline, alpha-tocopherol (Vitamin E) - These might delay deterioration in moderate AD, specifically with respect to the need for institutionalization.

Intranasal insulin (see above)

Risk Reduction
Risk Reduction agents change in popularity, primarily because they are all, at best, of modest value. They require long-term use. There is no highly powerful agent for the prevention of Alzheimer's. Yet. We would place these in the following order of importance, from most powerful to least:

Exercise - Regular exercise over many years appears to be the most powerful risk-reduction correlate. For example, follow the work of Miia Kivipelto and others at the Karolinska Institutet in Finland. They concluded that "Regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals." (Lancet Neurol. 2005 Nov;4(11):705-11.) These trends were confirmed in a large Group Health study by Eric Larson (Archives of Internal Medicine, 5/22/06). It might be useful for these authors to put their prevention results in perspective, since these case controled studies have limits (but don't expect them to say something like "years of exercise has an effect that is comparable to years of smoking in that both correlate to about the same extent with lower risk of Alzheimer's", even if it's true). Another study of exercise supports the idea that physical exercise just happens to correlate with mental exercise, and it is really the mental activity level that matters (Sturman MT, Morris MC, Mendes de Leon CF, Bienias JL, Wilson RS, Evans DA. Physical activity, cognitive activity, and cognitive decline in a biracial community population. Arch Neurol. 2005 Nov;62(11):1750-4).

Statins - Cholesterol-lowering statin drugs might reduce the risk of AD. They reduce levels of beta amyloid peptide and plaques in mice, and high blood cholesterol levels increase the anyloid "burden" in the brain. They might, therefore, contribute to the prevention of Alzheimer's. The careful management of blood pressure, along with statins, is important for the prevention of mixed (partially vascular) dementias. A daily baby aspirin helps prevent inflammation in blood vessels. Aspirin involves both the vascular and anti-inflammatory properties of risk-reduction agents.

Intellectual activity - This is a non-specific but powerful factor, perhaps accounting for the association between higher rates of AD and lower education levels (possibly just amyloid-related, not tangle-related - Neurology. 2005 Sep 27;65(6):953-5). Some exercises are available that are proposed as specifics, but we think that ANY frequent, active mental challenges along with active social relationships will probably do as much as any set of "brain training" exercises claiming (usually over the web) to prevent Alzheimer's disease (which means delaying the onset until people die of something else). Some recent work by Dr. Arne May at the University of Regensburg in Germany even shows that MRI brain scans reflect specific training (e.g. juggling). We have always felt that everyone over 60 should learn how to juggle anyway. Seriously, cross word puzzles and other forms of language juggling could have protective effects upon functional abilities even if brain damage progresses. Exercises could include such tasks as spelling words backwards or learning the names of the states from Z to A. Highly specific "scientific" (i.e. expensive) brain training programs are snakeoil unless they seem to help by providing a structure that enhances regular activity. A Swedish study showed that people who have much more cognitively complex work than their twins have lower rates of Alzheimer's. That means that a life of complex mental activity has some preventive effect. "Use it or lose it" is a very long-term motto.

Low calorie, healthy diet - In addition to the effects upon blood pressure and cholesterol levels, a low calorie diet may stimulate the production of neurotrophic factors (proteins that promote survival and growth of neurons). Eat foods that have lots of antioxidants (blueberries, spirulina, broccoli, beets, spinach, raisins, red grapes, kale, oranges, and curry). Get your protein from foods with good fatty acids (tuna, salmon); fish consumption appears to have a significant protective effect upon the risk and prevention of Alzheimer's (Kalmijn et al, Ann Neurol, 42:776-782, 1997).

Non-steroidal anti-inflammatory drugs (NSAIDs) - If used regularly for years, these appear to have a significant protective effect against AD. These drugs include such common over-the-counter medications as aspirin, ibuprofen (Motrin, Advil), and naproxen (Naprosyn), but not acetaminophen (Tylenol). Inform your doctor about using any of these for Alzheimer's prevention, even if you get them without a prescription.

Vitamins and Minerals - Selegiline and alpha-tocopherol (Vitamin E) have anti-oxidant properties. Recent research does not support their use for prevention or treatment of AD (Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, for the Alzheimer's Disease Cooperative Study Group. Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. 2005 April 13. N Engl J Med. 2005), but the mineral selenium might be a useful anti-oxidant. Niacin supplements may have some value in this respect as well.

Wine - In a prospective study with a large sample (n=2273), a 3-year follow-up indicated that moderate alcohol consumption might be protective, particularly 3-4 glasses of wine a day (Orgogozo et al Rev Neurol, 153:185-192, 1997) .

Estrogens - These may well be the most over-rated Alzheimer's prevention and/or treatment agent, but, in the future, there may be ways to get the estrogens to the right place or in the right form to enhance their value. This is one of those treatments where increasing other risks with long-term use has to be considered.

Marijuana - The use of marijuana is not counter-indicated and, although performing objective research in this area is impossible in the United States (except in animals), there are some theoretical reasons to believe that administered as a vapor or as food (instead of the more toxic smoke) the active ingredient could have a protective effect. Far out.

You might want to keep updated on sites that report major health discoveries weekly or conferences where new findings are presented, such as the much-anticipated update on anti-amyloid (Current Progress on the Beta-Amyloid Peptide as a Therapeutic Target in Alzheimer's Disease) on July 18, 2006 in Madrid.
You might also want to follow what investors hoping to make money off effective treatment are talking about i.e. follow the money (e.g. about soon-to-be released findings).

*These opinions are not endorsed by any medical authority. On the other hand, the perceived utility of our product, the CANS-MCI, is directly related to the availabilty of effective treatments. Therefore, to avoid bias, we try to keep track of current treatment research progress without being overly optimistic about current treatments.

**Probably the best way to assess evidence behind a claim is to look for the peer-reviewed journal articles that validate a product or program (not the "findings presented" at some conference).
Conference presentations have low acceptance standards and, worse, conferences are sometimes sponsored by commercial interests. Controlled studies (the highest standard) have some potential for bias, particularly in industry-supported journals, and independent replication of findings is usually desirable. The problem with commercial products (e.g brain exercise tools, herbal remedies) is that claims are often unsubstantiated despite the company's website links to long lists of "scientific articles" performed by "Harvard [or some other prestigious university's] researchers" cited on the website. When you look closely, most of them aren't articles at all. They are conference posters/presentations (not so different from ads). For example, "Our training exercises have been shown by Yale University researchers presenting at the XI International Psychoproctology Conference in Geneva, Switzerland to be more effective than all other….blah, blah." Often whatever peer-reviewed articles are cited are actually about the principle behind the product's conception, not specifically about the scientific validity or usability of the product. If an effective prevention or treatment agent or cognition-enhancing program comes along, it will get a lot of continued attention by solid researchers and clinicians, not just PBS infomercials.

***The Alzheimer's Association is a very valuable source of information. There are other "non-profit" organizations out there with newsletters, brain training, nutrition, and testing products. You wouldn't know they were non-profit if you looked at their managers' salaries. The latest scam is the "non-profit" connected to a drug company that not only pays huge salaries to its top dogs but also steers people to the drugs and even asks for donations. Stick with the Alzheimer's Association. They are stuffy and cautious but they are a lot more transparent than the others.

Why Screen for mild cognitive impairment (MCI) in primary care.

Go to top of page

Research Department at Screen, Inc