Patient one had
two years of progressive memory loss. She was considering quitting her job,
which involved analyzing data and writing reports, she got disoriented driving,
and mixed up the names of her pets. Patient two kept forgetting once familiar
faces at work, forgot his gym locker combination, and had to have his
assistants constantly remind him of his work schedule. Patient three's memory
was so bad she used an iPad to record everything, then forgot her password. Her
children noticed she commonly lost her train of thought in mid-sentence, and
often asked them if they had carried out the tasks that she mistakenly thought
she had asked them to do.
Since
its first description over 100 years ago, Alzheimer's disease has been without
effective treatment. That may finally be about to change: in the first, small
study of a novel, personalized and comprehensive program to reverse memory
loss, nine of 10 participants, including the ones above, displayed subjective
or objective improvement in their memories beginning within three to six months
after the program's start. Of the six patients who had to discontinue working
or were struggling with their jobs at the time they joined the study, all were
able to return to work or continue working with improved performance.
Improvements have been sustained, and as of this writing the longest patient
follow-up is two and one-half years from initial treatment. These first ten
included patients with memory loss associated with Alzheimer's disease (AD),
amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment
(SCI; when a patient reports cognitive problems). One patient, diagnosed with
late stage Alzheimer's, did not improve.
The
study, which comes jointly from the UCLA Mary S. Easton Center for Alzheimer's
Disease Research and the Buck Institute for Research on Aging, is the first to
suggest that memory loss in patients may be reversed, and improvement
sustained, using a complex, 36-point therapeutic program that involves
comprehensive changes in diet, brain stimulation, exercise, optimization of
sleep, specific pharmaceuticals and vitamins, and multiple additional steps
that affect brain chemistry.
The
findings, published in the current online edition of the journal Aging,
"are very encouraging. However, at the current time the results are
anecdotal, and therefore a more extensive, controlled clinical trial is
warranted," said Dale Bredesen, the Augustus Rose Professor of Neurology
and Director of the Easton Center at UCLA, a professor at the Buck Institute,
and the author of the paper.
In
the case of Alzheimer's disease, Bredesen notes, there is not one drug that has
been developed that stops or even slows the disease's progression, and drugs
have only had modest effects on symptoms. "In the past decade alone,
hundreds of clinical trials have been conducted for Alzheimer's at an aggregate
cost of over a billion dollars, without success," he said.
Other
chronic illnesses such as cardiovascular disease, cancer, and HIV, have been
improved through the use of combination therapies, he noted. Yet in the case of
Alzheimer's and other memory disorders, comprehensive combination therapies
have not been explored. Yet over the past few decades, genetic and biochemical
research has revealed an extensive network of molecular interactions involved
in AD pathogenesis. "That suggested that a broader-based therapeutics
approach, rather than a single drug that aims at a single target, may be feasible
and potentially more effective for the treatment of cognitive decline due to
Alzheimer's," said Bredesen.
While
extensive preclinical studies from numerous laboratories have identified single
pathogenetic targets for potential intervention, in human studies, such single
target therapeutic approaches have not borne out. But, said Bredesen, it's
possible addressing multiple targets within the network underlying AD may be
successful even when each target is affected in a relatively modest way.
"In other words," he said, "the effects of the various targets
may be additive, or even synergistic."
The
uniform failure of drug trials in Alzheimer's influenced Bredesen's research to
get a better understanding of the fundamental nature of the disease. His
laboratory has found evidence that Alzheimer's disease stems from an imbalance
in nerve cell signaling: in the normal brain, specific signals foster nerve
connections and memory making, while balancing signals support memory loss,
allowing irrelevant information to be forgotten. But in Alzheimer's disease,
the balance of these opposing signals is disturbed, nerve connections are
suppressed, and memories are lost.
The
model of multiple targets and an imbalance in signaling runs contrary to the
popular dogma that Alzheimer's is a disease of toxicity, caused by the
accumulation of sticky plaques in the brain. Bredesen believes the amyloid beta
peptide, the source of the plaques, has a normal function in the brain -- as
part of a larger set of molecules that promotes signals that cause nerve
connections to lapse. Thus the increase in the peptide that occurs in
Alzheimer's disease shifts the memory-making vs. memory-breaking balance in
favor of memory loss.
Given
all this, Bredesen thought that rather than a single targeted agent, the
solution might be a systems type approach, the kind that is in line with the
approach taken with other chronic illnesses -- a multiple-component system.
"The
existing Alzheimer's drugs affect a single target, but Alzheimer's disease is
more complex. Imagine having a roof with 36 holes in it, and your drug patched
one hole very well -- the drug may have worked, a single "hole" may
have been fixed, but you still have 35 other leaks, and so the underlying
process may not be affected much."
Bredesen's
approach is personalized to the patient, based on extensive testing to
determine what is affecting the plasticity signaling network of the brain. As
one example, in the case of the patient with the demanding job who was
forgetting her way home, her therapeutic program consisted of some, but not all
of the components involved with Bredesen's therapeutic program, and included:
(1)
eliminating all simple carbohydrates, leading to a weight loss of 20 pounds;
(2)
eliminating gluten and processed food from her diet, with increased vegetables,
fruits, and non-farmed fish;
(3)
to reduce stress, she began yoga;
(4)
as a second measure to reduce the stress of her job, she began to meditate for
20 minutes twice per day;
(5)
she took melatonin each night;
(6)
she increased her sleep from 4-5 hours per night to 7-8 hours per night;
(7)
she took methylcobalamin each day;
(8)
she took vitamin D3 each day;
(9)
fish oil each day;
(10)
CoQ10 each day;
(11)
she optimized her oral hygiene using an electric flosser and electric
toothbrush;
(12)
following discussion with her primary care provider, she reinstated hormone
replacement therapy that had been discontinued;
(13)
she fasted for a minimum of 12 hours between dinner and breakfast, and for a
minimum of three hours between dinner and bedtime;
(14)
she exercised for a minimum of 30 minutes, 4-6 days per week.
The
results for nine of the 10 patients reported in the paper suggest that memory
loss may be reversed, and improvement sustained with this therapeutic program,
said Bredesen. "This is the first successful demonstration," he
noted, but he cautioned that the results are anecdotal, and therefore a more
extensive, controlled clinical trial is needed.
The
downside to this program is its complexity. It is not easy to follow, with the
burden falling on the patients and caregivers, and none of the patients were
able to stick to the entire protocol. The significant diet and lifestyle
changes, and multiple pills required each day, were the two most common complaints.
The good news, though, said Bredesen, are the side effects: "It is
noteworthy that the major side effect of this therapeutic system is improved
health and an optimal body mass index, a stark contrast to the side effects of
many drugs."
The
results for nine of the 10 patients reported in the paper suggest that memory
loss may be reversed, and improvement sustained with this therapeutic program,
said Bredesen. "This is the first successful demonstration," he
noted, but he cautioned that the results need to be replicated. "The
current, anecdotal results require a larger trial, not only to confirm or
refute the results reported here, but also to address key questions raised,
such as the degree of improvement that can be achieved routinely, how late in
the course of cognitive decline reversal can be effected, whether such an
approach may be effective in patients with familial Alzheimer's disease, and
last, how long improvement can be sustained," he said.
Cognitive
decline is a major concern of the aging population. Already, Alzheimer's
disease affects approximately 5.4 million Americans and 30 million people
globally. Without effective prevention and treatment, the prospects for the
future are bleak. By 2050, it's estimated that 160 million people globally will
have the disease, including 13 million Americans, leading to potential
bankruptcy of the Medicare system. Unlike several other chronic illnesses,
Alzheimer's disease is on the rise--recent estimates suggest that AD has become
the third leading cause of death in the United States behind cardiovascular
disease and cancer.
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