Omega-3 fatty acids might require larger doses to be effective
-- especially for people with high-risk gene -- suggest findings from the Keck
School of Medicine of USC
For years, a scientific puzzle
has bedeviled researchers aiming to fight Alzheimer's disease, a common and
incurable form of dementia.
The
results of numerous lab investigations and population studies support the
preventive potential of omega-3 fatty acids, "good fats" found
abundantly in fish. However, to date the majority of studies evaluating
omega-3s for averting or curtailing cognitive decline in human participants
have failed to show benefits.
Now, a
small clinical trial from USC provides important clues about this discrepancy,
in the first Alzheimer's prevention study to compare levels of omega-3s in the
blood with those in the central nervous system. The findings suggest that
higher doses of omega-3 supplements may be needed in order to make a difference,
because dramatic increases in blood levels of omega-3s are accompanied by far
smaller increases within the brain. Among participants who carry a specific
mutation that heightens risk for Alzheimer's, taking the supplements raised
levels of a key fatty acid far less compared to those without the mutation.
"Trials
have been built on the assumption that omega-3s get into the brain," said
senior author Dr. Hussein Yassine, associate professor of medicine and
neurology at the Keck School of Medicine of USC. "Our study was
specifically designed to address this question."
The
paper was published today in the journal EBioMedicine.
The
researchers recruited 33 participants who had risk factors for Alzheimer's but
were not cognitively impaired. All participants had a family history of the
disease, a sedentary lifestyle and a diet low in fatty fish. Fifteen carried a
gene variant called APOE4, which is linked to inflammation in the brain and
increases Alzheimer's risk by a factor of four or more; the other 18 were
noncarriers.
At
random, participants were assigned to a treatment group or control group.
Members of the treatment group were asked to take supplements containing more
than 2 grams of an omega-3 called docosahexaenoic acid (DHA) daily for six
months. Control group members took placebos each day over the same period.
Participants in both groups also were asked to take daily B-complex vitamins,
which help the body process omega-3s.
Dr.
Yassine and his colleagues gathered samples of blood plasma and cerebrospinal
fluid -- a gauge for whether the omega-3s reached the brain -- from
participants at the outset, and again at the end of the study period. The
scientists looked at levels of two omega-3 fatty acids: DHA and
eicosapentaenoic acid (EPA), a potent anti-inflammatory that the body derives
from a small portion of its DHA intake.
Higher doses for omega-3s to be effective?
The
researchers found that at the end of the six months, participants who took
omega-3 supplements had 200 percent more DHA in their blood compared to those
who took placebos. In contrast, the DHA found in cerebrospinal fluid was only
28 percent higher in the treatment group than the control group. This result
hints that measuring omega-3 levels in the blood may not indicate how much is
reaching the brain.
Dr.
Yassine and his co-authors also report that, within the treatment group, those
without the risk-inflating APOE4 mutation showed an increase of EPA
(anti-inflammatory omega-3 fatty acid) in their cerebrospinal fluid three times
greater than what was seen in carriers of the gene.
"E4
carriers, despite having the same dose, had less omega-3s in the brain,"
he said. "This finding suggests that EPA is either getting consumed,
getting lost or not getting absorbed into the brain as efficiently with the E4
gene."
Notably,
the 2-gram dose of DHA in this study far exceeded what has been used in major
clinical trials testing the preventive power of omega-3s, which typically
administer 1 gram or less daily.
"If
you use a lower dose, you can expect a less-than-10-percent increase in
omega-3s in the brain, which may not be considered meaningful," Dr.
Yassine said.
The sacrifice of study participants advances Alzheimer's
research
The
investigators worked for two years to recruit participants for the trial. The
barrier to entry came from the only method capable of extracting cerebrospinal
fluid: a lumbar puncture, also known as a spinal tap. It proved challenging to
find people willing to undergo that procedure, which involves a hollow needle
piercing the lower back, two times.
Dr.
Yassine had high praise for the study participants.
"They
were generous with their time, and they were courageous to do the lumbar
punctures," he said. "The main reason they did this was their desire
to advance science."
The
participants' bravery may pay off in the creation of even more knowledge about
omega-3s and Alzheimer's.
The
preliminary data from the current study was intriguing enough that the
scientists were able to attract funding for a larger trial for which recruitment
is underway. Following 320 participants over two years, it will examine whether
high doses of omega-3s can slow cognitive decline in carriers of the APOE4
gene.
Dr.
Yassine believes that the progression from a small study to a bigger one is a
good model for developing therapies and preventions targeting the brain.
"These
pilot studies are so important as a step toward much larger, more complicated
studies," he said. "The bottom line is, before you embark upon very
expensive clinical trials, you need to show proof of concept, that your drug is
getting into the brain and changing biomarkers of disease in the right
direction."
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