CHICAGO, July 24, 2018 /PRNewswire/ -- Four
new studies reported at the Alzheimer's Association International
Conference (AAIC) 2018 in Chicago
investigated how the digestive system, including gut and liver
functions, may be related to changes in the brain, and to brain
disorders such as Alzheimer's disease and other dementias.
The gut microbiome is the community of microorganisms that live
in the digestive tracts of humans and other animals — about a
thousand different species of bacteria, comprising trillions of
cells. Emerging science has correlated certain changes in the gut
bacteria with a variety of inflammatory and autoimmune conditions.
And studies have shown that changes in diet can change the gut
bacteria.
In research reports over the last few years, we've learned a
great deal about how diet, particularly overall eating patterns,
may be linked to brain health, cognitive decline and possibly even
dementia as we age. We've also seen inflammation and its markers —
in the brain and other parts of the body — associated with
Alzheimer's and other dementias.
Exactly how diet and gut microbes interact with the brain, and
influence the brain's health — as a cause, trigger or
risk/protective factor — is a relatively new area of investigation
for Alzheimer's and other dementias. For example, recently,
scientists have reported that some species in the microbiome can
promote protein buildup in the brain. This may be significant
because accumulation of amyloid and tau proteins are hallmarks of
Alzheimer's disease. And recent reports from experiments in mouse
models engineered to have Alzheimer's-like changes and symptoms
suggest that changing the bacterial profile in their digestive
tract — by changing their diet — may reduce amyloid plaques, lower
inflammation and improve memory.
At the same time, an increasing body of evidence suggests that
altered metabolism of certain lipids may be an important factor in
the development of Alzheimer's. Several of the genes associated
with Alzheimer's — including the strongest Alzheimer's risk gene,
APOE-e4 — are involved in lipid transport or metabolism. In
addition, lipids make up most of the brain's mass, so changes in
the production or transport of lipids may have a significant effect
on brain structure and function. Key functions of lipids include
storing energy and acting as structural components of cell
membranes.
"While still in its infancy, gut microbiome research is very
exciting since it may give us a new window into why diet and
nutrition are so important for brain health," said Maria Carrillo, PhD, Alzheimer's Association
Chief Science Officer. "For example, this work may tell us more
about how and why 'good fats' help keep the brain healthy, and help
guide brain-healthy dietary choices."
"In addition, if it turns out these gut bacteria are effective
and accurate markers of Alzheimer's disease cause or progression,
or both, they might be useful as a non-invasive screening tool — a
simple blood test. They could then be used to help identify
high-risk people for clinical trials or track the impact of a
therapy," Carrillo said. "However, we are only at step one. We
don't know yet exactly what the changes we are seeing mean —
especially in animal models — whether they are cause or
effect."
Does the Liver Contribute to Alzheimer's Risk by Failing to
Supply Key Lipids to the Brain?
Researchers of the Alzheimer's Disease Metabolics Consortium
(ADMC), led by Rima Kaddurah-Daouk, PhD, Professor of Psychiatry at
Duke University who leads the ADMC, and
in this study by Mitchel A. Kling,
MD, Associate Professor of Psychiatry in the Perelman School of
Medicine at the University of
Pennsylvania, found that reduced levels of plasmalogens, a
class of lipids that are integral to cell membranes, were
associated with an increased risk of Alzheimer's. Data also
suggested statistically-significant differences in plasmalogen
metabolism between Alzheimer's and comparison groups, and that some
of the plasmalogen levels were correlated with cerebrospinal fluid
(CSF) levels of total tau protein.
Plasmalogens synthesized in the liver are taken up by many types
of tissues, including the brain. The most abundant plasmalogens
contain the omega-3 fatty acids docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA), which have received research interest
due to their potential anti-inflammatory properties. However,
previous studies have failed to convincingly demonstrate a
beneficial effect of these substances in people with
Alzheimer's.
The researchers measured several plasmalogens, including those
containing DHA and EPA, as well as those containing the omega-6
fatty acid adrenic acid and closely-related lipids, in stored
blood-based fluids collected from two groups:
- 304 subjects with Alzheimer's, 876 with mild cognitive
impairment (MCI) or significant memory concerns (SMC), and 367 who
were cognitively normal (CN), enrolled in the Alzheimer's Disease
Neuroimaging Initiative (ADNI)-1, -GO, or -2 studies; and
- 112 subjects including 43 with Alzheimer's, 18 with MCI, and 51
CN enrolled at the Penn Memory Center at the Perelman School of
Medicine, University of
Pennsylvania.
"The data suggest that reduced production of plasmalogens by the
liver may result in reduced availability of these critical lipids
to the brain. This may contribute to impaired cognitive function
and neurodegeneration in Alzheimer's," Kling said. "These data
provide a possible explanation for the lack of effect of fish oil
or DHA on cognitive function or Alzheimer's in previous
studies."
The researchers, who are part of the M2OVE-AD consortium, funded
by the U.S. National Institute on Aging (NIA), are currently trying
to better understand the connection between altered liver and brain
function in Alzheimer's, and possibly identify new targets for
treatment and prevention.
"New data is emerging on the role of billions of bacteria that
live within us and affect our health through the chemicals they
produce — some are beneficial while others lead to disease," said
Kaddurah-Daouk. "The gut microbiome has been implicated in diseases
like Parkinson's, autism and depression, and only recently have we
started to focus on its possible role in Alzheimer's disease —
looking at possible links between gut bacteria, cognitive changes
and brain changes."
Altered Bile Acid Metabolites in MCI and Alzheimer's:
Relation to Neuroimaging and CSF Biomarkers
To date, relatively little research has been done in humans to link
peripheral metabolic changes in cholesterol to biomarkers related
to Alzheimer's, including amyloid and tau accumulation, brain
glucose metabolism, and structural atrophy.
As reported at AAIC 2018, ADMC researchers measured serum levels
of 15 bile acid metabolites and their eight ratios from older
adults with early stage Alzheimer's or who were at risk for the
disease from the Alzheimer's Disease Neuroimaging Initiative (ADNI)
cohort. They assessed the association of bile acids with the
amyloid, tau, and neurodegeneration biomarkers for Alzheimer's
based on the recently proposed National Institute on
Aging-Alzheimer's Association 2018 Research Framework using
cerebrospinal fluid (CSF) and neuroimaging biomarkers (brain
atrophy measured by MRI, and brain glucose metabolism measured by
FDG-PET).
Primary bile acids are those synthesized from cholesterol in the
liver. The main function of bile acids is to allow digestion of
dietary fats and oils, including cholesterol. They also have
hormonal actions throughout the body.
The scientists, supported by the NIA-led Accelerating Medicines
Partnership-Alzheimer's Disease (AMP-AD) program, found an
association between markers of the gut microbiome and liver
function and Alzheimer's-related structural and functional
neuroimaging biomarkers, and also with biomarkers of CSF amyloid-β
and tau burden. In this study population, gut microbiome-produced
bile acids are increased in people with Alzheimer's and are
associated with functional and structural brain changes including
cognitive decline, reduced brain glucose metabolism, and greater
brain atrophy. Further, these same bile acids were associated with
increased amyloid and tau accumulation. For example:
- Lower serum concentrations of one primary bile acid (CA) were
significantly associated with worse cognition, decreased
hippocampal volume and decreased brain glucose metabolism.
- Higher serum concentrations of one conjugated primary bile acid
(GCDCA) and two bacterially-produced conjugated secondary bile
acids (GLCA and TLCA) were significantly associated with higher CSF
p-tau and CSF t-tau values, decreased hippocampal volume and
decreased brain glucose metabolism.
- Higher serum concentrations of three ratios of
bacterially-produced conjugated secondary bile acids to primary
bile acids (TDCA:CA, GDCA:CA, and GLCA:CDCA) were associated with
lower CSF Aβ1-42 values, decreased hippocampal volume and decreased
brain glucose metabolism.
"We believe this is the first study to show that serum-based
altered (higher or lower) bile acid profiles are associated with
amyloid, tau, and neurodegeneration biomarkers of Alzheimer's
disease," said Kwangsik Nho, PhD,
Assistant Professor of Radiology and Imaging Sciences at the Center
for Neuroimaging at the Indiana University
School of Medicine. "Further research is needed to assess
what is causing the changes in bile acids and the specific
mechanisms underlying this association."
Circulating Metabolites Associated with Alzheimer's Disease
Genetic Variants
Recent studies suggest that bile acids involved in cholesterol
metabolism and clearance are somehow associated with Alzheimer's
disease. At the same time, large genome-wide association studies
have discovered more than 25 genetic variants associated with
Alzheimer's, including several that are involved in lipid
metabolism. Shahzad Ahmad, MSc, a
PhD student at Erasmus Medical Center, Rotterdam, and colleagues evaluated if
Alzheimer's genetic variants can influence the level of
cholesterol, bile acids and other biochemical compounds in
blood.
The researchers used 5,974 samples for analysis of subtypes of
cholesterol (known as sub-fractions) — 4,647 from the Rotterdam
Study (RS) and 1,327 from the Erasmus Rucphen family study (ERF).
For bile acid analysis, the dataset consisted of a separate group
of 488 participants from RS.
The researchers found that genetic variations in Alzheimer's
risk genes APOE-e4 and SORL1 were significantly associated with
decreased levels of some of the cholesterol components that may be
important for the health and repair of brain cell membranes
(p<1x10-5). Alzheimer's-associated genetic variants in ABI3,
TREM2, MS4A6A and ABCA7 were associated with bile acids
(deoxycholate, glycodeoxycholate sulfate, and the deoxycholate to
cholate ratio) and certain lipids (p<1x10-3). In addition, the
team found that bile acids cluster with caffeine levels in the
blood, suggesting a possibility for lifestyle interventions.
"Our hope is that, once validated, these associations between
the genome and metabolome in Alzheimer's will reveal causal
pathways," said Ahmad. "These then may become targets for therapies
or prevention strategies."
Ahmad added, "The brain is connected to the rest of the body, so
identifying gut microbes that change the levels of these
biochemical compounds in the body is a plausible next step towards
identifying new potential therapeutic approaches for
Alzheimer's."
Association of Serum Lipids with Alzheimer's Disease in the
ADNI Cohort
Lipids are a major component of brain membranes. It is believed
that they can influence the accumulation of toxic peptides —
amyloid and tau — that are related to Alzheimer's disease. Blood
flow supplies lipids to the brain, and a majority of circulating
lipids are synthesized in the liver and gut, which supports the
idea that our body's organs can influence brain functions.
Researchers in the ADMC and UC Davis-West Coast Metabolomics
Center measured the levels of more than 400 lipids in blood samples
from ADNI-1, which has 200 normal, 400 mild cognitive impaired and
200 Alzheimer's participants. They evaluated the association of
those lipids with Alzheimer's diagnosis, brain atrophy, amyloid and
tau accumulation, and cognitive decline using a new method of
clustering lipids by chemical similarity.
They found that lipid metabolism is disturbed in people with
Alzheimer's in the ADNI-1 study population. Several lipids were
significantly altered in people with Alzheimer's with failures in
proper incorporation of unsaturated fatty acids specifically EPA,
DHA (fish oils) and Arachidonic acid in these lipid classes. Obese
and male subjects had the strongest disturbance. Fish oil intake by
people with Alzheimer's in the study failed to bring the levels of
these lipids back to normal.
"We think these results help explain the poor results of the
clinical trials of fish oil trials for treatment of Alzheimer's,"
said Dinesh Kumar Barupal, PhD, a project scientist and the program
coordinator for the NIH-funded West Coast Metabolomics Center at
the University of California, Davis.
"And they may help uncover new therapeutic strategies targeting
lipid metabolic pathways and failures within the liver."
The Alzheimer's Association International Conference®
(AAIC®)
The Alzheimer's Association International Conference (AAIC) is the
world's largest gathering of researchers from around the world
focused on Alzheimer's and other dementias. As a part of the
Alzheimer's Association's research program, AAIC serves as a
catalyst for generating new knowledge about dementia and fostering
a vital, collegial research community.
AAIC 2018 home page: alz.org/aaic
AAIC 2018 newsroom: alz.org/aaic/press
About the Alzheimer's Association®
The Alzheimer's Association is the leading voluntary health
organization in Alzheimer's care, support and research. Our mission
is to eliminate Alzheimer's disease through the advancement of
research, to provide and enhance care and support for all affected,
and to reduce the risk of dementia through the promotion of brain
health. Our vision is a world without Alzheimer's. Visit alz.org or
call 800.272.3900.
- Mitchel A. Kling, MD, et al.
Serum Indices of Ethanolamine Plasmalogens and Phosphatide
Metabolism in the Combined Adni-1/GO/2 Cohort: Does the Liver
Contribute to AD Risk By Failing to Supply Key Lipids to the Brain?
Funder(s): U.S. National Institute on Aging; U.S. National
Institutes of Health; U.S. Department of Defense.
- Kwangsik Nho, PhD, et al.
Altered Bile Acid Metabolites in Mild Cognitive Impairment and
Alzheimer's Disease: Relation to Neuroimaging and CSF Biomarkers.
Funder(s): U.S. National Institute on Aging; National Library of
Medicine.
- Shahzad Ahmad, MSc, et al.
Circulating Metabolites Association with Alzheimer's Disease
Associated Genetic Variants. Funder(s): European Union Horizon
2020; European Union Innovative Medicine Initiative; Alzheimer
Nederland; ZonMW-Memorabel.
- Dinesh Kumar Barupal, PhD, et al. Association of Serum Lipids
with Alzheimer Disease in the Adni Cohort - an Untargeted
Lipidomics Study. Funder(s): U.S. National Institute on Aging; U.S.
National Institutes of Health; U.S. Department of Defense.
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