Prior art:

The FDA approves other AD drugs, including rivastigmine (Exelon®), galantamine (Razadyne®), donepezil (Aricept®), and memantine (Namenda®) to treat symptoms of AD.
Early work on an AD vaccine begins.
Many new AD clinical trials, initiatives, and studies are launched, looking at a broad array of translational, treatment, and prevention issues.
New transgenic mouse models, including one that develops both plaques and tangles, are developed.
Pittsburgh Compound B (PiB) is developed, allowing researchers to “see” beta-amyloid plaques in the brains of living people. The growing sophistication of neuroimaging techniques, genetics, memory and cognitive tests, structured interviews, and other technologies improve our ability to identify people at high risk of AD.

Preventing Alzheimer's

While some factors, such as your genes, are out of your control, many powerful lifestyle factors are within your sphere of influence.
The six pillars of a brain-healthy lifestyle are:
  1. Regular exercise
  2. Healthy diet
  3. Mental stimulation
  4. Quality sleep
  5. Stress management
  6. An active social life

Regular Exercise
Do You Want to Avoid Alzheimer's Disease?
  • According to one of the studies referenced above, moderate exercise can reverse normal brain shrinkage by 2 percent, effectively reversing age-related hippocampus degeneration by one to two years.2 Also according to the study, the people in the control group who didn't exercise saw an average of 1.4 percent decrease in hippocampus size.

Alzheimer's Diet

Put eggs back in your diet to improve memory and concentration. One nutrient that many of us are apt to be low on, in our fervor to avoid high-cholesterol foods, is choline. Choline is a B complex vitamin that is concentrated in high cholesterol foods like eggs and liver. A lack of choline can cause impairment of memory and concentration. Choline is a precursor to the brain neurotransmitter, acetylcholine. Acetylcholine is linked to memory. People given drugs that block acetylcholine flunk memory tests. Low levels of acetylcholine have been linked to Alzheimer's disease and poor memory.

Insulin allows glucose to be transported into the brain, where it strengthens connections between neurons. Insulin resistance, caused by too much glucose in the system, inhibits that process. Individuals might have 300x normal insulin levels and be unaware and asymptomatic. There are no standardized tests of insulin resistance, but you can have a fasting test of insulin level, and an oral glucose tolerance test helps even more. And it's treatable simply by aerobic exercise and low-glycemic-load diet (try eating all carbs at supper; eat protein until then). Also, the SNIFF study, completed 2010, in which insulin is inhaled nasally, seems to be beneficial.


Gingko Biloba, from Hofferberth, 2004, Human Psychopharmacology:

Forty patients diagnosed as suffering from senile dementia of the Alzheimer type received either 80 mg Ginkgo biloba special extract (GBE)* or matching placebo t.i.d. for three months in a randomized, double blind study of the efficacy and tolerance of GBE. The patients were assessed using a test battery at baseline and at 1, 2 and 3 months. The test battery included the SKT (a brief test of cognitive function, memory and attention), the Sandoz Clinical Assessment Geriatric Scale, choice reaction time, saccadic eye movements and EEG. Memory and attention, as measured by the SKT, improved significantly in the active treatment group after one month, as did psychopathology, psychomotor performance, functional dynamics and neurophysiology as measured by the above tests. The drug was well tolerated and no adverse drug reactions were recorded during the trial.

Other supplements that may affect the brain: spirulina, melatonin

Memory workarounds

(see also the Workarounds page) Since memory is the first thing to go, it's also the first line of defense. Workarounds like Google, and writing down ideas as soon as they occur to you act against retroactive inhibition, the phenomenon that has you forgetting why you went to the living room (to get the newspaper) because on the way there something else got your attention. You may not want to write down everything, but the more you do write down, the more you'll remember, and you can cross things off as you go. The things you haven't crossed off won't all get done either, but more will than if you never jotted them down. And even if you don't have a pen and paper handy, you can use the hook method (described elsewhere).

This is explicit or declarative memory (unlike implicit memory, which is how you learned your language). You repeat the data in different ways, write it down, recite it, diagram it, relate it to things you already have stored away - and use spaced repetitions to drive it into long-term memory. Implicit memory works by having emotional hooks - sounds, smells, colors, motion, emotion - and you can add these to remember something better.

A virtual building with rooms, each of which is filled with a different category of memories, can be used to store new items and gradually add them to long-term storage. Just use the same rooms until they're as familiar as your own home. And learning to persevere - developing character - is just as important in the long haul.

CONCLUSIONS: Preliminary evidence suggests that statins may offer a protective effect against the development of AD. However, review of the literature does not lend credence to the use of statins in the general nondemented population without hyperlipidemia. Potential confounding variables have not been considered in the majority of trials. Placebo-controlled clinical trials are ongoing and should yield more definitive results.

From (an article on a review of statins and Alzheimer's)
John Ringman, MD, associate professor of neurology at the University of California, Los Angeles, School of Medicine, who was not involved in the review. . . "It is important the blood–brain barrier permeability be taken into consideration" in future studies, he told Medscape Medical News.
Dr. Selkoe and colleagues also recommend that future epidemiological studies and clinical trials uniformly apply an agreed-on set of biomarkers in serum and cerebrospinal fluid, particularly amyloid beta42, tau, and phospho-tau levels; that they employ brain imaging, including amyloid imaging by positron-emission tomography; and that they use cognitive measures such as the cognitive subscale of the AD Assessment Scale and, preferably, more sophisticated and specific tests of verbal and episodic memory.
Dr. Ringman said he "wouldn't bother with more epidemiological studies. What we need now is randomized, blinded, placebo-controlled studies."
It is also "most important," say Dr. Selkoe and colleagues, to conduct statin treatment trials "solely in patients with mild AD, who have the best chance for disease modification."
Dr. Ringman agrees. This patient population "is becoming the standard for testing interventions that are thought to have disease-modifying effects," he said. Future studies "should be prospective studies that include participants with early- and presymptomatic-stage disease and have sensitive cognitive and biomarker endpoints," he added.

Negative Results

It is of course useful to know what approaches have failed to achieve good results. Here's one:

The article does, however, mention two other companies still in the game with other possibilities. Eli Lilly's gamma secretase inhibitor, semagacestat, however, flatlined around August of 2010 (see ), and Wyeth's bapineuzumab and CTS21166, from CoMentis are reported on below

Slowdowns and reversals


Skin cancer drug reverses Alzheimer.pdf
"One of the major advantages of bexarotene is that it's already been approved by the Food and Drug Administration for use in humans, which means the researchers can move into human trials sooner than if it were a completely new drug."

An Alzheimer’s Breakthrough Shows Promise

By Mike Roizen, MD

When three different mice models of Alzheimer’s disease were treated with an already FDA-approved drug, their beta-amyloid plaque melted away. The drug is Bexarotene, made by a small company, for a specific cancer diagnosis.

Your brain cells put out waste products in the form of beta-amyloid protein. Normally, you have a garbage truck in the form of Apo E that comes along and picks up that poop. If one of the Apo E genes you get is a mutant or dysfunctional, your risk of Alzheimer’s disease goes up about 30%. If you have two, it goes up more than 60%. Lack of function of this gene leads to the human form of Alzheimer’s disease.
Case investigators gave this drug to express – or turn on – the Apo E gene and make it more active. You can think of it as putting more garbage trucks in your brain to pick up more of the beta-amyloid waste product; thus, less beta-amyloid remains in your brain to stimulate inflammation, and consequently, less brain cell destruction. With the group at Case Western Reserve (and the study was done at the lead institution of Case Western Reserve but also involved the University of Pennsylvania and Washington in St. Louis, three not-so-shabby institutions), they noted that 25% of the beta-amyloid disappeared in 6 hours!!! And 75% of it in 3 days. If you extrapolate that to human studies, that would be the same thing as 75% of that plaque disappearing in 100 human days.
Okay, so, what is the hold up in trying this in humans? Actually very little. The hold up would be identifying the side effects of this drug and whether there is enough of the drug available.

Magnesium Threonate

The neurodegenerative processes involved in memory loss result from deterioration of connectivity between brain cells but are not a natural function of aging. Memory loss is now known to be associated with loss of synaptic density and plasticity in the brain. Low magnesium levels may contribute to such losses.
Magnesium-L-threonate (MgT), a new magnesium compound, boosts brain magnesium levels better than standard supplements. Studies reveal that MgT produces dramatic increases in synaptic density and plasticity, resulting in similar improvements in memory function itself.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at1-866-864-3027.

Selegiline (Jumex, Deprenyl)

deprenyl has demonstrated efficacy in the treatment not only of Parkinson's disease, but Alzheimer's disease, other dementias and depressive disorders. The first two papers demonstrating the effectiveness of deprenyl in Alzheimer's Disease appeared in 1987.
Improvements in Cognitive PerformanceAlthough primarily prescribed to help people with Parkinson's disease, memory disorder problems, and depression, deprenyl has also been shown to boost mental performance. In animal studies, deprenyl has improved cognitive performance in middle-aged rats and reversed cognitive impairments in aged rats. Combined with other cognitive enhancers, such as hydergine and piracetam deprenyl has significant potential for enhancing memory, intelligence, and concentration. (For an excellent summary of current research in this area, see Morgenthaler J, Dean W, Smart Drugs and Nutrients II.).
Extension of Maximum Life Span
Deprenyl has also been shown to increase the maximum lifespan of laboratory animals by close to 40%. Giving deprenyl to animals is the only experimental treatment—besides caloric restriction—that has been shown to increase maximum life span. . . the maximum life span of a human being is around 120 years. The laboratory animals in the deprenyl studies showed a 40% increase in maximum life span, the human equivalent of living 150 years.
Q: How might healthy people utilize deprenyl for its cognitive enhancing and antiaging benefits?
Dr. Knoll: They should take one milligram of deprenyl daily from sexual maturity until death.The longer treatment is delayed, the less effective it is.The development of BPAP—a synthetic mesencephalic enhancer substance that is at least a hundred times more potent than deprenyl—is by itself a hint that our present knowledge about the mesencephalic enhancer regulation is in a very early stage. The high potency of BPAP indicates already that much more potent natural enhancer substances than PEA and tryptamine might exist. Better understanding of mesencephalic enhancer regulation promises to develop more efficient techniques in the future to slow brain aging and prolong human life beyond the TLSh. According to my judgment, this is the only physiologically well-founded, feasible, anti-aging therapy that I foresee coming along in the future that has a chance, in the long run, to remain the method to continuously improve the quality and prolong the duration of human life.

. . . while selegiline is a potent monoamine oxidase inhibitor, BPAP is only a weak MAO-A inhibitor at high doses, and at low doses produces only the activity enhancer effect. [This is good, actually. High doses of a MAO-B inhibitor tend to be toxic]
BPAP has been shown to have neuroprotective effects similar to those of selegiline, and has been researched for the treatment of Alzheimer's disease, Parkinson's disease andclinical depression.[6]

J147 from Salk Institute

Studies have high hopes for a new drug they have developed that has improved memory and prevented brain damage in mice and is a promising candidate for the first drug capable of halting the progression of Alzheimer's in humans.
Although scientists have as yet been unable to pin down the causes and progression of Alzheimer's, research indicates it is associated with amyloid plaques and neurofibrillary tangles in the brain. "Alzheimer's is a complex disease, but most drug development in the pharmaceutical world has focused on a single aspect of the disease - the amyloid pathway," says Marguerite Prior, a research associate, who led the project along with Qi Chen, a former Salk postdoctoral researcher, working in Salk's Cellular Neurobiology Laboratory headed by David Schubert. "In contrast, by testing these compounds in living cell cultures, we can determine what they do against a range of age-related problems and select the best candidate that addresses multiple aspects of the disease, not just one." . . . testing showed that the compound prevented brain damage in animals with Alzheimer's and that mice and rats treated with the drug produced more of a protein called brain-derived neurotrophic factor (BDNF) - a molecule involved in memory formation that helps support the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. "J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections," said Schubert. "No drugs on the market for Alzheimer's have both of these properties."
The team says J147 could be tested for treatment of Alzheimer's in humans in the near future. 23 Dec 2011
The product of over a decade of work by David Schubert of the Salk Institute in La Jolla, California, J147 reduces oxidative stress and inflammation, enhances long-term potentiation, and lowers amyloid plaques in animals. It also gets into the brain more easily and is more resistant to metabolism than the original curry spice curcumin. If proven safe and effective in humans, J147 could provide a non-Aβ-centric method of treatment for AD, suggest the authors. J147 has “the potential to be an AD therapeutic by slowing disease progression through neuroprotection as well as providing immediate cognition benefits," . . .
The team is currently trying to work out how the drug works. Meanwhile, the next step is to get J147 into clinical trials in people to test safety, said Schubert. He is applying for grants that would provide the necessary funding.

Beta amyloid peptide vaccine

Background, from
One hypothesis that has attracted widespread support proposes that AD is caused by the buildup of the senile plaques, and in particular of their main constituent, amyloid-β peptides (Aβ). Two major forms of Aβ, Aβ40 and Aβ42, have been associated with genetic mutations causing early-onset AD, and have thus received considerable research attention. The role of longer Aβ species, in contrast, which also exist in the brains of Alzheimer's patients, has not yet been fully investigated.
In their current work, the researchers focused on Aβ43, an amyloid-β peptide found just as often in patient brains as Aβ42, but about which relatively little is known. To study the peptide's role in AD, they generated mice with a mutation causing overproduction of Aβ43, and used a highly sensitive system to distinguish between concentrations of Aβ40, Aβ42 and Aβ43.
Their surprising results reveal that Aβ43 is even more abundant in the brains of AD patients than Aβ40, and more neurotoxic than Aβ42. Aβ43 also exhibits the highest propensity to aggregate and considerably accelerates amyloid pathology. Moreover, unlike the other two Aβ species, which exist in human and mouse brains at birth, Aβ43 levels appear to increase with age, consistent with the pattern of AD onset.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, wherein, the accumulation of amyloid beta (Abeta) peptide as cytotoxic oligomers leads to neuropathologic changes. Transgenic mice with brain Abeta plaques immunized with aggregated Abeta have reduced amyloid burden and improved cognitive functions. However, such active immunization in humans led to a small but significant occurrence of meningoencephalitis in 6% AD volunteers due to Abeta induced toxicity. In an attempt to develop safer alternative vaccines, the design of a highly soluble peptide homologous to Abeta (Abeta-EK), that has a reduced amyloidogenic potential while maintaining the major immunogenic epitopes of Abeta is reported. More importantly, this homologue has been shown to be non-toxic, as this peptide failed to exert any observable effect on erythrocytes. The results of the present study suggests that immunization with non-toxic Abeta derivative may offer a safer therapeutic approach to AD, instead of using toxic Abeta fibrils.

Neurogenetic Pharmaceuticals, NGP 555, a proprietary “first in class” molecule for the treatment/prevention of Alzheimer’s disease, is a gamma-secretase modulator targeting the γ-secretase complex, a key enzyme in the amyloid pathway. The compound has excellent brain penetration and is devoid of side-effects seen with other potential amyloid therapies such as gamma-secretase inhibitors and monoclonal antibodies. Based on the pre-clinical studies in rodents, this compound is expected to prevent the formation of Aβ42 and the deposition of amyloid plaques in the human brain, thereby precluding neuronal cell death and the dementia associated with AD.

Tau antibodies

it may be possible to bring Alzheimer’s disease to an abrupt halt early on by preventing cell-to-cell transmission, perhaps with an antibody that blocks tau.

Sniffing Insulin

By David W FreemanJuly 19, 2010 SNIFF stands for Study of Nasal Insulin to Fight Forgetfulness
The study, presented in Honolulu at a meeting of the Alzheimer's Association, builds upon previous research showing that insulin is needed for proper brain function and that there are abnormally low levels of insulin in the brains of people with Alzheimer's or MCI.
"These deficiencies may reduce or eliminate insulin's beneficial roles in the brain," Dr. Suzanne Craft, of VA Puget Sound Health Care System/University of Washington in Seattle, said in a written statement. "We believe that restoring normal insulin function in the brain may provide therapeutic benefits to adults with Alzheimer's."
The study involved 109 patients with Alzheimer's or MCI. One-third of the patients were given a placebo nasal spray, and the other two-thirds got twice daily doses of a nasal spray containing insulin. The researchers found that the patients who got the insulin showed significant improvements in memory and in the ability to perform tasks of everyday living.
"These results provide encouraging support for further study of intranasal insulin as a therapy for Alzheimer's," Craft said in the statement. But she was quick to say that more research is needed - and that intranasal treatment is far from being ready for prime time.
I think I can adjust my diet and exercise to lower my blood sugar level. I'm concerned about possible insulin resistance. My understanding is that insulin allows glucose to be transported into the brain, where it strengthens connections between neurons. Insulin resistance caused by too much glucose in the system may inhibit that process. There are no standardized tests of insulin resistance, but I would like to have a fasting test of insulin level, and an oral glucose tolerance test.
Japanese researchers combing through the preserved brain samples of 135 men and women who lived and died in the town of Hisayama have found that those who developed insulin resistance and other metabolic disturbances during their lives were more likely to show plaque deposits in the brain that are a hallmark of Alzheimer's disease.
The study, published Wednesday in the journal Neurology, sheds light on how Alzheimer's may gain a foothold in the brain -- very likely years before a patient or her family sees any sign of cognitive lapse -- and rob it of memory. The study builds upon mounting evidence that people who develop Type 2 diabetes -- as well as those with diabetes risk factors such as obesity, insulin resistance and high blood pressure -- are at far higher risk for developing dementia later in life.
Some researchers suggest that the hormone chaperones glucose to brain neurons and thereby helps them maintain their energy production, in which case, memory loss might result when brain cells lack insulin and become glucose starved. Others hypothesize that insulin has other beneficial roles, such as spurring neuronal growth and inhibiting the formation of brain lesions called neurofibrillary tangles that characterize Alzheimer's. Current study, but you have to live in Minnesota.

Coconut oil

Similar to the insulin-sniffing above, but it seems that ketones can serve the same function of feeding the neurons as glucose does: and

It seems that insulin resistance increases with aging, and the ketones in coconut oil can nourish the neurons in place of the glucose that no longer gets through.

From: and
In Alzheimer’s disease, the neurons in certain areas of the brain are unable to take in glucose due to insulin resistance and slowly die off, a process that appears to happen one or more decades before the symptoms become apparent. If these cells had access to ketone bodies, they could potentially stay alive and continue to function. According to the author of the book, Alzheimer's - What if There Was a Cure?, a couple of tablespoons of coconut oil can reverse Alzheimer's damage if it hasn't gone too far, and the press and Dr. Oz' attacks on coconut oil and saturated fats may be part of industrial damage control, which is plausible, although to understand all the ins and outs would require advanced degrees in biochemistry and allied fields. Too bad; it'd be nice to know if two tablespoons was helping or hurting.

There IS a controlled, double-blind study going on at Oxford University in England with respect to the active ingredient in coconut oil, ketone esters:

Added CBP protein

Protein Restores Learning, Memory in Alzheimer's Mouse Model
ScienceDaily (Dec. 13, 2010) — Scientists at the UT Health Science Center San Antonio restored learning and memory in an Alzheimer's disease mouse model by increasing a protein called CBP. Salvatore Oddo, Ph.D., of the university's Department of Physiology and Barshop Institute for Longevity and Aging Studies, said this is the first proof that boosting CBP, which triggers the production of other proteins essential to creating memories, can reverse Alzheimer's effects.
In patients with Alzheimer's disease. . . enhancing CBP does not alter the Aβ or tau physiology but operates on a different recovery mechanism: It restores activity of a protein called CREB and increases levels of another protein called brain-derived neurotrophic factor (BDNF). "One way by which CBP could work is by setting off a domino effect among proteins that carry signals from the synapse to the nucleus of the neuron," Dr. Oddo said. "Getting signals to the nucleus is necessary for long-term memory."

PKR Inhibitor

Neuroscientists Boost Memory in Mice Using Genetics and a New Memory-Enhancing Drug
ScienceDaily (Dec. 8, 2011) — When the activity of a molecule that is normally elevated during viral infections is inhibited in the brain, mice learn and remember better, researchers at Baylor College of Medicine reported in a recent article in the journal Cell.
Super memory
The authors discovered that mice lacking PKR in the brain have a kind of "super" memory. . . when PKR is inhibited, the increased synaptic activity (that is, the enhanced communication between neurons) is caused by gamma interferon, another molecule involved in immunity.Although Costa-Mattioli's memory pill may be years away from approval by the U.S. Food and Drug Administration, its impact on society and medicine could be very profound. There are roughly 6 million Americans and 35 million people world-wide with Alzheimer's disease and more than 70 million Americans over the age of 60 who may suffer from aged-associated impairment of memory.

TA-65 Telomerase supplement

The Harvard Study
That's where this recent study was focused. Ronald DePinho and a team of Harvard colleagues experimented on mice to see what happens when steps are taken to stop telomeres from shortening.
The group looked at the enzyme telomerase, which can replenish the telomere after replication and effectively lengthen it so that a cell can live for longer.
They bred a group of genetically-engineered mice that lacked the ability to produce telomerase – and watched as these mice showed rapid and very early onset symptoms of aging.
Then, they gave the mice injections to re-activate the telomerase enzyme – expecting to see the aging process slow down to normal levels. Instead, they watched in astonishment as the mice appeared to age backwards, their withered organs repairing themselves even to the point of new neurons beginning to sprout in their brains.
In essence, repairing the telomeres seemed to be able to reverse the aging process and make the mice physiologically younger, despite already suffering the ravages of age.
But it's not so simple for humans
While this study was a huge step forward in our understanding of how telomeres and telomerase impact the aging process, there's a big issue preventing this sort of treatment from going straight into human testing.
Mice produce telomerase all throughout their short lives, but the enzyme is switched off in adult humans with our longer life spans, because when our cells are allowed to divide and replicate unchecked, they have a nasty habit of developing into cancers.
Although a telomerase-activating compound was recently discovered, telomerase rejuvenation in adults is directly linked to the development and spread of cancers throughout the body – so while a telomerase-based anti-aging treatment might produce valuable results in older humans, scientists also believe it would kick the risk of cancer up several orders of magnitude.

New compound approved for supplementation
Researchers at Sierra Sciences, in collaboration with colleagues at TA Sciences, Geron Corporation, PhysioAge, and the Spanish National Cancer Research Center (CNIO), have discovered the first compound that activates telomerase – an enzyme that lengthens telomeres – in the human body, potentially opening the door to arresting or even reversing the aging process.
The compound, a natural product derived nutraceutical known as TA-65, was shown to lengthen the shortest telomeres in humans, potentially extending human lifespan and healthspan. Telomerase activation is thought to be a keystone of future regenerative medicine and a necessary condition for clinical immortality. Although TA-65 is probably too weak to completely arrest the aging process, it is the first telomerase activator recognized as safe for human use.

"We are on the cusp of curing aging," said William Andrews, Ph.D., co-author of this study and President and CEO of Sierra Sciences, LLC. "TA-65 is going to go down in history as the first supplement you can take that doesn't merely extend your life a few years by improving your health, but actually affects the underlying mechanisms of aging. Better telomerase inducers will be developed in the coming years, but TA-65 is the first of a whole new family of telomerase-activating therapies that could eventually keep us young and healthy forever."

Multiple benefits
Telomerase activation has potential medical applications beyond extending human lifespan. Epidemiological studies have shown that short telomeres in humans are a risk factor for diseases including, among others, atherosclerosis, diabetes, Alzheimer's, and cancer.

The team’s study also reports encouraging news on the effect of TA-65 on the body's immune system. Infectious diseases lead to telomere shortening in the immune system, as immune cells divide to fight infections. Telomerase activation should prevent this telomere shortening and allow the body's immune system to fight a chronic infection indefinitely.

Robot-assisted brain surgery

I don't know if this is useful, but it could serve to isolate an infected part of the brain:

Frozen MCI Stem cells

from early stages of Alzheimer's. The idea would be to have about twenty packets of stem cells that could be re-introduced to one's brain annually, giving twenty years of mild cognitive impairment (MCI) instead of ten or so years of rapid decline.
What is gene therapy?
Genes, which are carried on chromosomes, are the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders can result.
Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes:
  • A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common.

  • An abnormal gene could be swapped for a normal gene through homologous recombination.

  • The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function.

  • The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered.

From Human Gene Therapy by Kenya Billman, copyright 1996:
"Human gene therapy is a procedure that is being used in an attempt to treat genetic and other diseases. . . Gene therapy techniques will introduce copies of a "healthy" gene into cells of the body. The disease will be controlled if the introduced genes work normally. This is called somatic gene therapy because it introduces the gene into a somatic or body cell.

The identity of a gene responsible for a genetic disease must be known before scientists can begin to consider gene therapy. . . Gene therapy techniques' effectiveness depends upon the life span of the target cells. The whole gene therapy process will have to be repeated regularly if the target cells only survive for a few weeks. "It would be much more effective if the therapy genes could be directed into those stem cells which regularly divide to produce new target cells, especially if all of the new cells produced contained functional therapy genes."

In only a short time, human gene therapy has progressed from speculation to reality. "The first clinical gene transfer (albeit only a marker gene) in an approved protocol took place on 22 May 1989, the first federally approved gene therapy protocol, for correction of adenosine deaminase (ADA) deficiency (Anderson W.F. 1992)." In the early 1980's, retroviral-mediated gene transfer was developed in animal models. This technology is the principal procedure used today.

There are many diseases that are ailing humans and there is no cure or treatment for some of them. If gene therapy could help by eliminating cancers, Alzheimer's disease, AIDS, and many other diseases it would end needless suffering."

Also, from (NATURE | VOL 389 | 18 SEPTEMBER 1997)
"In 1990, the first clinical trials for gene- therapy approaches to combat disease were carried out. Conceptually, the technique involves identifying appropriate DNA sequences and cell types, then developing suitable ways in which to get enough of the DNA into these cells. With efficient delivery, the therapeutic prospects range from tackling genetic diseases and slowing the progression of tumours, to fighting viral infections and stopping neurodegenerative diseases.


But the problems — such as the lack of efficient delivery systems, lack of sustained expression, and host immune reactions — remain formidable challenges.

Although more than 200 clinical trials are currently underway worldwide, with hundreds of patients enrolled, there is still no single outcome that we can point to as a success story. To explore why this is the case, we will use our own experience and other examples to look at the many technical, logistical and, in some cases, conceptual hurdles that need to be overcome before gene therapy becomes routine practice in medicine."

Nerve Growth Factor intervention

Nature Medicine 11, 551 - 555 (2005)
Published online: 24 April 2005; | doi:10.1038/nm1239
A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease
Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Other trials

solanezumab (LY2062430)

Phase: 3
Status: Ongoing, still recruiting
About this trial
Mechanism: Monoclonal (laboratory-produced) antibody to beta-amyloid. May bind to beta-amyloid and remove it from the brain before it accumulates into plaques.

bapineuzumab (AAB-001)

Phase: 3
Status: A number of bapineuzumab trials are active and currently recruiting
external image collapsible-open2close.jpgAbout the trial
Mechanism: A monoclonal (laboratory-produced) antibody targeting beta-amyloid. A monoclonal antibody does not mobilize a recipient's own immune system.

Lessons learned: Phase 2 results suggested that bapineuzumab might have a stronger effect in recipients who do not have the Alzheimer's APOe4 risk gene. As a result, several of the active trials are recruiting specific groups of participants with and without APOe4. Positron emission tomography (PET) imaging with Pittsburgh compound B (PIB) indicated that bapineuzumab reduced brain beta-amyloid levels. While these data support the theory that beta-amyloid is active in the brain of those with Alzheimer's, they do not yet tell us whether reducing beta-amyloid levels is an effective treatment.

davunetide (AL-108)

Phase: 2
Status: Completed, Phase 3 planned
external image collapsible-open2close.jpgAbout this trial
Mechanism: Davunetide is in development for Alzheimer's disease and other neurodegenerative disorders involving tau protein abnormalities, including schizophrenia and frontotemporal dementia. In a Phase 2 study enrolling participants with Alzheimer's disease and mild cognitive impairment (MCI), those receiving davunetide scored better on certain memory tests than those who received the placebo.

intravenous immunoglobulin

(abbreviated IVIG, trade name Gammagard)
Phase: 3
Status: Active, recruiting
external image collapsible-open2close.jpgAbout this trial
Mechanism: IVIG is a human blood product currently approved by the FDA to treat certain immune deficiency disorders. IVIG contains many different types of antibodies, including some that may promote clearance of beta-amyloid from the brain.
Lessons learned: Early stage trials in very small numbers of participants indicated that IVIG might also help those with Alzheimer's disease.

methylene blue (Rember)

Phase: 2
Status: Completed. The results were described as positive by the principal investigator, who presented the data at AAIC but has not yet published them.
external image collapsible-open2close.jpgAbout this trial
Mechanism: Methylene blue is a deep indigo compound currently used as a malaria treatment and for tissue staining. In Alzheimer's disease, it may prevent aggregation of tau protein fibers into the tangles that are one hallmark of the disease.

PBT-2 (clioquinol)

Phase: 2
Status: Completed
Participants who received PBT2 performed better on several tests of thinking and judgment and had lower levels of beta-amyloid in their spinal fluid.
external image collapsible-open2close.jpgAbout this trial
Mechanism: Acts in several ways to prevent aggregation of beta-amyloid into plaques.

Decoded Neurofeedback
Scientists at the two institutions used functional magnetic resonance imaging (fMRI) to observe the visual cortex activity pattern of test subjects. The basic idea is this: using a technique known as decoded neurofeedback, or DecNef, people could be trained to alter their brain activity, so that it matched that of someone already possessing a certain skill.
While the instant acquisition of complex skills, such as flying a helicopter as seen inThe Matrix, might not be possible any time soon, the researchers believe that DecNef might also have therapeutic value, as people with mental disorders could be trained to match the brain activity patterns of healthy individuals.


to remove beta-amyloid plaque (dated Feb 2011)
Reduction of Alzheimer's disease amyloid-β in plasma by hemodialysis and its relation to cognitive functions.
Rapid removal of plasma amyloid-β (Aβ) by blood purification may serve as a peripheral Aβ sink from the brain for Alzheimer's disease therapy. We investigated the reduction of plasma Aβ during hemodialysis and cognitive states.
Aβ concentrations and Mini-Mental State Examinations (MMSE) were investigated in 37 hemodialysis patients (68.9 ± 4.1 years).
The dialyzers effectively removed Aβ(1-40) and Aβ(1-42), 63.9 ± 14.4 and 51.6 ± 17.0% at 4 h dialysis, resulting in the reduction of Aβs in whole-body circulation by 51.1 ± 8.9 and 32.7 ± 12.0%, respectively. Although the plasma Aβs before dialysis (750.8 ± 171.3 pg/ml for Aβ(1-40)) were higher than those reported for Alzheimer's disease patients, the cognitive states of hemodialysis patients were relatively normal, especially of longer dialysis vintages.
Dialyzers effectively reduced Aβs in whole-body circulation. Repeated rapid decrease of plasma Aβs might maintain cognitive state.
Copyright © 2011 S. Karger AG, Basel.