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By Sally K. Laden, MS
T his is an exciting time for scientific discovery
in Alzheimer’s disease. Research in diagnosis,
genetics, and drug treatment is moving forward at
a rapid pace. The goals of clinical research are to slow or stop disease progression and prevent Alzheimer’s disease. Early
diagnosis is essential. While there is no simple blood test or
diagnostic procedure, neuroimaging is enabling scientists
to see into the living brain of persons with Alzheimer’s
disease. The Alzheimer’s Disease Neuroimaging Initiative
is determining how imaging technologies, biomarkers, and
clinical/neuropsychological assessments can identify at risk
individuals, enable early diagnosis, and track treatment
response. Geneticists are discovering susceptibility genes to
identify persons who may eventually develop the disease.
Scores of drug trials are ongoing. However, great hopes
often are accompanied by setbacks. Scientists, healthcare
providers, patients and families are anxious to learn if new
drugs can slow the rate of memory loss or improve existing
deficits. News that Flurizan™ (Myriad) and Alzhemed™
(Bellus Health [formerly Neurochem]) failed to achieve
primary endpoints in phase 3 trials is disappointing. We do
not know why these trials failed, but we do recognize that this is difficult science in which questions are answered by
building on previous knowledge. Failed studies must not
be viewed as the end of the road, but as a door that opens
other avenues of discovery.
Indeed, a remarkable number of new studies and
surprising findings have been presented at major meetings
this year. Good news also is coming from other sources.
There are currently 650 studies registered with the National
Institutes of Health, and 299 of these are phase 2 or phase 3
trials (see clinical trials). Several studies have recently captured the
attention of scientists, clinicians, and patients. This article
summarizes just a few new studies that are moving the field
ever closer to effective treatment, prevention and a cure.
New Drugs, New Theories
Dimebon®
Dimebon® (Medivation, Pfizer) is an antihistamine
formerly used in Russia that has garnered a great deal of
attention. Dr. Rachelle Doody and colleagues administered
Dimebon® (60 mg/day) or placebo to 183 patients with
mild to moderate Alzheimer’s disease for 26 weeks and
found that Dimebon® significantly improved a measure of
cognition compared with pretreatment values and placebo.*
Dimebon® inhibits a-adrenergic, histaminergic, and
serotonergic receptors and modulates other basic cellular
functions, but its mechanism in Alzheimer’s disease is not
known.* Dr. Sam Gandy and coworkers presented data at
the Alzheimer’s Association International Conference on
Alzheimer’s Disease (ICAD) in Vienna, Austria in July, 2009
about the effects of Dimebon® on brain levels of amyloid in
mice genetically engineered to mimic human Alzheimer’s
disease. In a surprising turn of events, Dimebon® increased brain levels of amyloid.* These unexpected findings raise
important questions about the amyloid hypothesis and will
most certainly lead to further studies.
Targeting Tau
Apart from amyloid plaque, intracellular neurofibrillary
tangles caused by aggregation of abnormally folded tau
proteins represent the other hallmark lesion of Alzheimer’s
disease. Aggregated tau correlates closely with dementia
symptoms and, though not as well studied as amyloid, has
become a target for new drug development. rember™
(TauRx Therapeutics) is a tau-aggregation inhibitor that is
being closely watched. Dr. Claude Wischik and coworkers
presented findings from a phase 2 study in 321 patients
with mild to moderate Alzheimer’s disease and observed
an 81% reduction in the rate of cognitive decline after 50
weeks of rember™ (60 mg) compared with placebo.* Phase
3 studies are planned.
Davunetide intranasal (AL-108; Allon Therapeutics)
is another tau-based drug in clinical trials. Data from
a 12-week phase 2 study in 144 patients with amnestic
mild cognitive impairment demonstrated that davunetide
intranasal (15 mg) improved scores on memory tests by 47%
(8 weeks) and 62% (week 16) compared with pretreatment
scores.*
Immunotherapy
Anti-amyloid immunotherapy has been studied for
nearly a decade. Immunization with amyloid reduces
brain amyloid levels, but the risk of inflammatory changes
(meningoencephalitis) remains a serious concern. Different
passive or active anti-amyloid immunotherapies
are in clinical development, but the monoclonal
antibody, bapineuzumab (Elan, Wyeth) has
progressed to phase 3 trials. Neurotoxicity, which is
a potentially serious adverse event associated with
previously studied anti-amyloid immunotherapies,
is being addressed in bapineuzumab trials by
switching patients from higher (2 mg/kg dose) to
lower doses (0.5 or 1 mg/kg).*
Tau also has emerged as a viable target
for immunotherapy, but neuroinflammation has been
observed in mice following immunization with fulllength
tau. In order to address this potential toxicity
issue, Dr. Hanna Rosenmann and colleagues immunized
mice with a shortened version of phosphorylated tau.
After 8 months, immunization with phosphorylated
tau resulted in production of anti-tau antibodies, a 40%
reduction in neurofibrillary tangles, and no evidence of neuroinflammation.* Clinical studies have not yet been
conducted.
Omega-3 Fatty Acids
Interesting preliminary data about docosahexaenoic
acid (DHA) — the omega-3 fatty acid found in fish oil
— have been presented. Dr. Joseph Quinn and colleagues
reported data* from an 18-month study of DHA (2 g/day;
Martek Biosciences) in 402 patients with mild to moderate
Alzheimer’s disease.* There was no difference in disease
progression rates between DHA and placebo. However,
patients who did not carry the apolipoprotein E 4 (APOE4)
gene had a slower rate of cognitive decline compared
with APOE4 carriers.* In another study, Dr. Karin
Yurko-Mauro and colleagues administered DHA (900
mg/day) or placebo to 485 healthy elderly volunteers
with age-related cognitive decline. Six months of
DHA treatment resulted in significantly fewer errors
on a memory test compared with placebo.* These
data suggest that DHA warrants further study in
healthy persons with mild memory impairment and
in some patients with Alzheimer’s disease.
New Genes, New Understanding
Geneticists are hard at work identifying genes that
increase the risk of Alzheimer’s disease. Results from a study
conducted by Dr. Allen Roses and coworkers suggest that
the presence of a newly identified gene — TOMM40 —
may identify the risk of developing late-onset Alzheimer’s
disease and predict the age when symptoms first occur.* In
other developments, genome-wide association studies led
by Dr. Jean-Charles Lambert* and Dr. Denise Harold* have
identified 3 new genes that are also associated with lateonset
Alzheimer’s disease: the CLU, CR1, and PICALM
genes. The roles played by these newly discovered genes
are not yet known, but CLU and CR1 may be involved
with the amyloid pathway, and PICALM may mediate
the transport of molecules into neurons. These exciting
findings are certain to open up novel avenues of research.
The APOE4 gene is relatively common (25% of persons
carry it), and scientists have long debated the benefits of
disclosing APOE status to asymptomatic individuals. Some
contend that because there is currently no intervention
to prevent or cure Alzheimer’s disease, genetic testing has
no value. Others argue that disclosure would impose
unnecessary psychological distress or increase the risk
of discrimination. The REVEAL trials are designed to
determine the effects of APOE testing and disclosure to
healthy adults whose parents have Alzheimer’s disease. Dr. Robert Green and colleagues reported that adults who
learned of their APOE status, including those with the
higher-risk APOE4, did not have signifi cantly greater
short- or long-term depressive or anxiety symptoms
compared with persons who were not informed of their
APOE status.* Genetic testing is of great interest, and the
fi ndings from the REVEAL studies further our knowledge
of the impact of disclosure.
New Role for Amyloid?
A team of scientists is studying amyloid in an altogether
new light. They presented provocative unpublished data
at the 9th International Conference on AD/PD in Prague
in April, 2009 about a possible novel role for amyloid in
the pathogenesis of Alzheimer’s disease. According to Drs.
Robert Moir and Rudy Tanzi, amyloid has antimicrobial
properties and may contribute to the innate immune
response. Infection in persons with an inherited weakness
in their immune response may result in compensatory
increases in amyloid production, which could possibly
underlie the development of Alzheimer’s disease.* While
of great interest to researchers, these data are extremely
preliminary and should not be used to guide therapy.
What Will the Future Bring?
Some of the studies summarized here challenge accepted
theories, such as the amyloid hypothesis, and confi rm
the need to continue searching for underlying causes of
Alzheimer’s disease. Others introduce entirely new and
promising paradigms. One thing seems clear: if diseasemodifying
drugs are to be effective in slowing or stopping
Alzheimer’s disease, they should be administered early in
the course of the disease, ideally before symptoms become
apparent. Taken together, these studies reinforce the need
to identify high-risk individuals as early as possible.
Data from basic science, neuroimaging and genetic
studies, and drug trials are converging to move the field
ever closer to finding eff ective treatments and prevention
and, ultimately, a cure. There is a great deal of hope that
with early diagnosis and eff ective treatment, Alzheimer’s
disease will become a preventable and treatable disorder.
SALLY LADEN, MS, is a freelance writer specializing in
clinical therapeutics.
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