Alzheimer's Disease Blog

Part 2 - Can Failing Brain Cells Be Rescued in Alzheimer's Disease?

Significant mitochondrial damage has been identified early in the course of Alzheimer’s disease (AD) and often predates the accumulation of amyloid-beta, the cellular waste product historically believed to be responsible for the premature death of brain cells. A growing body of evidence now points to progressive mitochondrial failure as the trigger and driving force of amyloid-beta accumulation, eventually leading to the premature loss of brain cells.

Can Failing Brain Cells Be Rescued?

For the past several years, K-PAX Pharmaceuticals has been developing a safe and effective mitochondrial intervention which we refer to as KPAX002. 

KPAX002 consists of two co-administered components designed to broadly support mitochondrial function: 

1) Low dose methylphenidate (Ritalin)– Ritalin is a mild stimulant that is well known to increase dopamine and norepinephrine levels. Ritalin alone has previously been shown to produce a mild improvement in cognitive functioning in Alzheimer’s patients.            

2) A high potency antioxidant formula (mitochondrial modulator) specifically designed to promote improved mitochondrial metabolism consisting of: 

-N-acetyl-cysteine acts to replenish depleted glutathione reserves, thereby initiating mitochondrial recovery. Treatment with NAC has produced significantly increased survival rates in human nerve cell cultures exposed to rotenone, a potent MT toxin. 

Acetyl-L-carnitine facilitates the transport of fatty acids across the inner mitochondrial membrane shifting mitochondrial metabolism toward a more energy efficient fuel source (i.e. fatty acids).

Alpha lipoic acid (ALA) is an antioxidant molecule that has demonstrated anti-inflammatory and neuroprotective effects in Alzheimer’s disease models.

Coenzyme Q-10 (CoQ-10) is an electron carrier molecule embedded in the inner mitochondrial membrane that stabilizes respiratory chain components and acts as a mitochondrial antioxidant. Supplementation of CoQ-10 improves mitochondrial function and age-associated cognitive decline linked to neurodegeneration. 

Supplementing a combination of the above antioxidants at therapeutic dosages can exert a significant positive effect on stabilizing mitochondrial health and function.

It is our experience that co-administering a low dosage of Ritalin, augmented by antioxidant mitochondrial support, works synergistically to improve cognitive function (alertness, concentration, etc.) in patients with mitochondrial diseases.*

Here is an example of an Alzheimer’s patient who recently took KPAX002:

“Steve is a 74 year old male who was diagnosed with Alzheimer’s disease (AD) two years ago. Prior to beginning KPAX002, he was still functional but his driver’s license had to be taken away since he kept getting lost. He couldn’t remember his birthdate and he didn't know the day of the week. Otherwise, he was able to carry on a relatively normal conversation.

Steve’s initial cognitive score was 12 (normal: 28-30) which puts him in the ‘moderate dementia’ range. Three months after beginning to take KPAX002 he was more alert, taking fewer naps and his cognitive score increased by 30%. Five months after beginning KPAX002 his cognitive score had increased by 50% (to 19). He has had no side effects and continues to take the treatment. 

In Alzheimer’s disease, there is currently no approved treatment to slow the progressive decline in cognitive function seen with this disease. Steve experienced a 50% improvement in less than six months.”


K-PAX Pharmaceuticals is currently seeking funding to perform a Phase 2 proof-of-concept trial of KPAX002 to improving cognitive functioning in Alzheimer’s disease. We have applied to several funding sources for grants and are awaiting their response.

For more information about KPAX002, please call 1-800-381-7565.

*The above statements have not been evaluated by the Food and Drug Administration. This information is designed for educational purposes only and is not intended to diagnose, treat, cure or prevent any disease. This information is not intended to be a substitute for informed medical advice. Please consult a doctor with any questions or concerns you might have regarding your health.



Part 1 - Mitochondrial Failure: The Root Cause of Alzheimer's Disease?

Mitochondria, the energy generators of our cells, are essential for life. When they are under attack - from a combination of stress, environmental toxins, poor nutrition and genetic mutations – our cells can no longer function at an optimal level and they begin to shut down.

There is now growing recognition that effective Alzheimer’s disease treatments will need to improve mitochondrial function as a way to slow, and potentially reverse, the negative effects of this disease on cognitive function.

Significant mitochondrial damage has been identified early in the course of Alzheimer’s disease (AD) and it often predates the accumulation of amyloid-beta, the cellular waste product historically believed to be responsible for the premature death of brain cells. A growing body of evidence now points to progressive mitochondrial failure as the trigger and driving force of amyloid-beta accumulation, eventually leading to the premature loss of brain cells, progressive defects in memory and poor cognitive functioning. 

Treatment Approaches

The landscape for treating Alzheimer's disease has been bleak for many years. Following the failure of multiple efforts at targeting amyloid-beta, the pharmaceutical industry has now realized the need to focus on alternative AD targets. 

The mitochondrion is a highly complex organelle and addressing mitochondrial dysfunction in AD will require innovative strategies. These strategies could focus on supporting the thousands of biochemical reactions occurring within the mitochondria with key micronutrient cofactors that can significantly reduce oxidative stress. Also, addressing MT dysfunction by utilizing a compound that broadly supports mitochondrial functionmay prove more effective than relying on a single small molecule that only addresses a single molecular target.

K-PAX Pharmaceuticals is hoping to perform Phase 2 proof-of-concept trial of a repurposed drug (methylphenidate) augmented with high potency mitochondrial support [KPAX002] to demonstrate improvement in cognitive function compared to placebo (24 weeks). 

We have already observed KPAX002’s ability to improve cognitive functioning in patients with mitochondrial diseases in several settings. In three previous clinical trials, we have observed asubstantial improvement in cognitive function, averaging a mean improvement of over 20% after 12 weeks of treatment. Furthermore, we have recently administered KPAX002 to several AD patients in the clinic where it has been both well tolerated and generated substantial improvement in cognitive function (approximately 30% within 90 days) as assessed with validated measurement tools.


There are compelling reasons driving us to understand how altered mitochondrial function can be addressed to inhibit the progressive loss of brain cells, and the memory loss that follows. By delivering a well-studied mitochondrial support compound designed to decrease oxidative stress and promote mitochondrial repair, and by gently stimulating CNS neurons, improvement in cognitive functioning can occur and the rescue of previously failing CNS neurons can be achieved despite conditions of significant metabolic stress.

In Part Two of this series, we will describe in detail the component parts of KPAX002 and how its unique mechanism of action can rescue failing brain cells, thereby improving cognitive function in Alzheimer’s patients.


Olive Oil’s Powerful Protective Effect on Alzheimer’s and Parkinson’s Disease

Oxidative stress caused by a build-up of free radicals has been identified as one of the major contributors to the development of Alzheimer’s and Parkinson’s disease. Free radicals can occur due to exposure to pesticides and other environmental toxins. Degenerative diseases of the nervous system, such as Alzheimer’s and Parkinson’s disease, can occur when the body does not have sufficient amounts of antioxidants to counteract the build-up of these toxins.

A recent study on rats, published in Journal of Food Science and Technology, (Jan. 5, 2016), showed that antioxidant compounds found in extra virgin olive oil (EVOO) can combat the damage caused by free radicals and produces an anti-inflammatory response in the brain. These compounds have been shown in various studies to have neuroprotective effects against, not only Alzheimer’s and Parkinson’s disease, but spinal cord injury, Huntington’s disease, brain ischemia, and peripheral neuropathy.

This study focused on the effect EVOO has on a particular pesticide known as 2,4-Dichlorophenoxyacetic acid (2,4-D). This herbicide is widely used in the agricultural and forestry industries and has a toxic affect on the nervous system

The study results showed that damage caused to the brain by exposure to this pesticide was counteracted with the addition of EVOO to the rat’s diet. EVOO significantly increased antioxidant activity while decreasing the amount of free radicals in the brain.

This early research suggests that EVOO could have a natural protective effect against 2,4-D neurotoxicity exposure as well as provide a therapeutic strategy to protect against other types of pesticide exposure that contribute to neurological disorders such as Alzheimer’s and Parkinson’s.


Mitochondrial Recovery After Damage Reveals Clues to Treating Cancer, Diabetes, and Alzheimer's Disease

Mitochondria, the energy generators of our cells, are essential for life. When they are under attack - from a combination of stress, environmental toxins, and genetic mutations – our cells tear these power stations apart, strip out the damaged pieces and reassemble them into new mitochondria.

Now, scientists at the Salk Institute in La Jolla, California, have uncovered an unexpected way in which cells trigger this critical response to threats, offering insight into disorders such as cancer, diabetes, genetic mitochondrial diseases and neurodegenerative disease including Alzheimer’s and Parkinson’s disease - which are linked to dysfunctional mitochondria.

Researchers have known for years that mitochondria undergo fragmentation when treated with drugs that affect the mitochondria (including antibiotics, statins, and chemotherapy), but the biochemical details of how this mitochondrial damage is sensed and how it triggers the mitochondria to break up has not been clear until now.

In this new work, the Salk team found that when cells are exposed to mitochondrial damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to the mitochondria instructing them to break apart into tiny mitochondrial fragments so they can be recycled into new, healthy mitochondria. Interestingly, AMPK is known to be activated by the widely used diabetes drug metformin, as well as intense exercise and a restricted diet.

The group then looked at a way to chemically turn on AMPK without sending attacks to mitochondria. To their surprise, they found that activating AMPK alone was enough to cause the mitochondria to fragment, even without damage. “I could not believe how black and white the results were. Just turning on AMPK by itself gives you as much fragmentation as a mitochondrial poison,” says Shaw.

The team discovered why this was. When the cell’s power stations are disrupted, the amount of energy floating around a cell—ATP—is lowered. After just a few minutes, AMPK detects this reduction of energy in the cell and hurries to the mitochondria. Like a guard pulling a fire alarm, AMPK activates a receptor on the outside membrane of a mitochondrion to signal it to fragment and prepare for recycling.

Mitochondrial dysfunction has been increasingly linked to Type 2 diabetes, cancer, and neurodegenerative diseases including Alzheimer’s, Parkinson’s, and ALS. Identifying ways to positively intervene and promote improved mitochondrial health holds enormous promise for the development of future therapies.

Publication: AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Erin Quan Toyama et al. Science 2016.


Mitochondrial Dysfunction May Initiate Alzheimer's Disease

Researchers from Harvard University have proposed a new model of Alzheimer’s disease that suggests that mitochondria dysfunction may be the precursor to the disease.

The current model of Alzheimer’s is known as the amyloid cascade model, which assumes Alzheimer’s is driven by the accumulation of protein plaques (beta amyloid) in neurons caused by a genetic mutation. While numerous clinical trials have been conducted based on this model, none have shown positive results. That and the fact that genetic mutations only account for about 5% of the disease prompted Lloyd Demetrius, a researcher in population genetics at Harvard’s Museum of Comparative Zoology and Jane Driver, an assistant professor of medicine at Harvard Medical School, to examine this assumption.

“A lot of people are realizing now that we have been focusing on the usual suspects — genetics and proteins ― and that’s brought us to a point where, despite billions of dollars in research, we are no closer to a disease-modifying therapy,” Driver said. “Of course, that’s not to suggest that genetics isn’t important, but I think what we haven’t done is to take the 20,000-foot view and ask if it is even logical to expect that changes to one protein could be responsible for an age-related disease. It just didn’t add up.”

“The late-onset cases, however, are quite different,” Demetrius said. “They increase exponentially with age, and that is one of the most striking characteristics of the disease. As you age, the chances of getting it increase.”

What occurs during the aging process?

As a person ages, the mitochondria in the cells generate less energy. While the mitochondria that produce cellular energy from nutrients such as glucose are quite efficient, this process has the side effect of producing oxygen-free radicals, which can damage mitochondrial DNA and proteins. Demetrius and Driver believe this accumulated damage leads to an energy deficit, triggering a compensatory event they call “metabolic re-programming” — unaffected mitochondria increase output to make up for the energy deficit.

Both the healthy and impaired nerve cells then compete for nutrients, creating a fragile equilibrium. Researchers believe that stress, both physical and emotional, acts as the tipping point that pushes a person in to a disease state like Alzheimer’s. Illnesses such as a stroke or a major depression disrupt the neural system and put additional stress on neurons. Some die, and others have to increase their energy production in order to survive. As a result, impaired neurons use a larger share of the brain’s resources and leave the healthy neurons starving for nutrients.

“When that happens, you have a rapid shift toward Alzheimer’s — what I call pathological aging,” Demetrius said. “The two types of neurons are competing with each other, but the impaired neurons, in view of the particular environment of the aging brain, have a selective advantage.”

Demetrius states that interventions such as exercise, drugs, or nutrient supplementation can help maintain the equilibrium in the neural environment and prevent the brain from shifting in to pathological aging.

 “The things we need to do to prevent Alzheimer’s, or at least make a dent in the incidence of the disease, are within our hands,” Driver said.

Subscribe to this RSS feed