New Study: 29% Improvement In
Alzheimer’s Disease?!
Mitochondrial
Metabolic Activators Show Promise
A 29% cognitive
improvement in Alzheimer's patients was seen
in a study using Combined
Metabolic Activators (CMA),
showing promise for reversing decline by
targeting brain energy, with significant
gains in memory/thinking scores and brain
volume changes, contrasting placebo effects
and offering hope beyond slowing progression.
Separately, other research highlights how
intensive lifestyle changes
(diet, exercise, etc.) also significantly
improve cognition in at-risk older adults,
with some lifestyle interventions showing
similar percentage improvements or risk
reductions for dementia.
Details on the
CMA Study (2021):
What it was:
Patients received CMA, a combination of
metabolic activators, compared to a placebo.
Key Finding:
A 29% improvement in cognitive function
(ADAS-Cog scores) in the CMA group versus a
14% improvement in placebo.
Biological
Evidence:
Supported by imaging showing improved
hippocampal volume and cortical thickness,
plus changes in NAD+ and glutathione
metabolism.
Significance:
Suggests a potential way to reverse
cognitive decline, not just slow it down, by
restoring brain energy balance
Mitochondrial dysfunction in Alzheimer's
disease: a key frontier for future targeted therapies
Jan 14, 2025
Abstract
Alzheimer's
disease (AD) is the most common
neurodegenerative disorder, accounting for
approximately 70% of dementia cases
worldwide. Patients gradually exhibit
cognitive decline, such as memory loss,
aphasia, and changes in personality and
behavior.
Research has shown that mitochondrial
dysfunction plays a critical role in the
onset and progression of AD.
Mitochondrial dysfunction primarily leads to
increased oxidative stress, imbalances in
mitochondrial dynamics, impaired mitophagy,
and mitochondrial genome abnormalities.
These
mitochondrial
abnormalities are closely associated with
amyloid-beta and tau protein pathology,
collectively accelerating the
neurodegenerative process. This review
summarizes the role of mitochondria in the
development of AD, the latest research
progress, and explores the potential of
mitochondria-targeted therapeutic strategies
for AD. Targeting
mitochondria-related pathways may
significantly improve the quality of life
for AD patients in the future.
The role of mitochondrial dysfunction in Alzheimer's
disease pathogenesis
January 19, 2023
Abstract
To promote new thinking
of the pathogenesis of Alzheimer's disease
(AD), we examine the central role of
mitochondrial dysfunction in AD.
Pathologically, AD is characterized by
progressive neuronal loss and biochemical
abnormalities
including mitochondrial dysfunction.
Conventional thinking has dictated that AD is
driven by amyloid beta pathology, per the
Amyloid Cascade Hypothesis. However, the
underlying mechanism of how amyloid beta leads
to cognitive decline remains unclear.
A
model correctly identifying the pathogenesis of
AD is critical and needed for the development of
effective therapeutics. Mitochondrial
dysfunction is closely linked to the core
pathological feature of AD: neuronal dysfunction.
Targeting
mitochondria and associated proteins may hold
promise for new strategies
for the development of disease-modifying
therapies.
According to the Mitochondrial Cascade
Hypothesis, mitochondrial dysfunction drives the
pathogenesis of AD, as baseline mitochondrial
function and mitochondrial change rates
influence the progression of cognitive decline.
HIGHLIGHTS:
The
Amyloid Cascade Model does not readily account
for various parameters associated with
Alzheimer's disease (AD). A unified model
correctly identifying the pathogenesis of AD is
greatly needed to inform the development of
successful therapeutics. Mitochondria play a
key and central role in the maintenance of
optimal neuronal and synaptic function, the core
pathological feature of AD.
Mitochondrial dysfunction may be the
primary cause of AD, and is a promising target
for new therapeutic strategies.
Mitochondrial dysfunction and oxidative
stress in Alzheimer's disease, and
Parkinson's disease, Huntington's
disease and Amyotrophic Lateral
Sclerosis -An updated review
July 2023
Abstract
Misfolded
proteins in the central nervous
system can induce oxidative damage,
which can contribute to
neurodegenerative diseases in the
mitochondria. Neurodegenerative
patients face early mitochondrial
dysfunction, impacting energy
utilization. Amyloid-ß and tau
problems both have an effect on
mitochondria, which leads to
mitochondrial malfunction and,
ultimately, the onset of Alzheimer's
disease. Cellular oxygen interaction
yields reactive oxygen species
within mitochondria, initiating
oxidative damage to mitochondrial
constituents. Parkinson's disease,
linked to oxidative stress,
α-synuclein aggregation, and
inflammation, results from reduced
brain mitochondria activity.
Mitochondrial dynamics profoundly
influence cellular apoptosis via
distinct causative mechanisms. The
condition known as Huntington's
disease is characterized by an
expansion of polyglutamine,
primarily impactingthe cerebral
cortex and striatum. Research has
identified mitochondrial failure as
an early pathogenic mechanism
contributing to HD's selective
neurodegeneration.
The
mitochondria are organelles that
exhibit dynamism by undergoing
fragmentation and fusion processes
to attain optimal bioenergetic
efficiency. They can also be
transported along microtubules and
regulateintracellular calcium
homeostasis through their
interaction with the endoplasmic
reticulum. Additionally, the
mitochondria produce free radicals.
The functions of eukaryotic cells,
particularly in neurons, have
significantly deviated from the
traditionally assigned role of
cellular energy production. Most of
them are impaired in HD, which may
lead to neuronal dysfunction before
symptoms manifest.
This
article summarizes the most
important changes in mitochondrial
dynamics that come from
neurodegenerative diseases including
Alzheimer's, Parkinson's,
Huntington's and Amyotrophic Lateral
Sclerosis. Finally, we discussed
about novel techniques that can
potentially treat mitochondrial
malfunction and oxidative stress in
four most dominating neuro
disorders.
Mitochondrial
dysfunction in Alzheimer's disease: Role in
pathogenesis and novel therapeutic
opportunities
September 17, 2019
Abstract
Dysfunction of
cell bioenergetics is a common feature
of neurodegenerative diseases, the most
common of which is Alzheimer's
disease (AD). Disrupted energy
utilization implicates mitochondria at
its nexus. This review
summarizes some of the evidence that
points to faulty
mitochondrial function in AD
and highlights past and current
therapeutic development efforts.
Classical neuropathological hallmarks of
disease (β-amyloid and τ) and sporadic
AD risk genes (APOE) may trigger
mitochondrial disturbance, yet mitochondrial
dysfunction may incite pathology.
Preclinical and
clinical efforts have overwhelmingly
centred on the amyloid pathway, but
clinical trials have yet to reveal
clear-cut benefits. AD therapies aimed
at mitochondrial dysfunction are
few and concentrate on reversing
oxidative stress and cell death
pathways. Novel
research efforts aimed at boosting
mitochondrial and bioenergetic function
offer an alternative treatment strategy.
Enhancing cell bioenergetics in
preclinical models may yield widespread
favourable effects that could benefit
persons with AD.
Mitochondrial Dysfunction Present
Early in Alzheimer's, Before Memory Loss
Wednesday, February 23, 2012
ROCHESTER, Minn. — Mitochondria — subunits inside cells that
produce energy — have long been thought to play a role in
Alzheimer's disease. Now Mayo Clinic researchers using
genetic mouse models have discovered that mitochondria in
the brain are dysfunctional early in the disease. The
findings appear in the journal PLoS ONE.
The group looked at mitochondria in three mouse models, each
using a different gene shown to cause familial, or
early-onset, Alzheimer's disease. The specific mitochondria
changes corresponded with the mutation type and included
altered mitochondrial movement, structure, and energy
dynamics. The changes happened in the brain even before the
mice showed any symptoms such as memory loss. The group also
found that the mitochondrial changes contributed to the
later loss of mitochondrial function and the onset and
progression of Alzheimer's disease.
"One of the most significant findings of this study is our
discovery of the impact of mitochondrial dysfunction in
Alzheimer's disease," says Eugenia Trushina, Ph.D., Mayo
Clinic pharmacologist and senior investigator on the study.
"We are asking: Can we connect the degree of mitochondrial
dysfunction with the progression of symptoms in Alzheimer's
disease?"
Enlisting the expertise of Mayo researcher Petras Dzeja,
Ph.D., the team applied a relatively new method called
metabolomics, which measures the chemical fingerprints of
metabolic pathways in the cell — sugars, lipids,
nucleotides, amino acids and fatty acids, for example. It
assesses what is happening in the body at a given time and
at a fine level of detail, giving scientists insight into
the cellular processes that underlie a disease. In this
case, the metabolomic profiles showed changes in metabolites
related to mitochondrial function and energy metabolism,
further confirming that altered mitochondrial energetics is
at the root of the disease process.
The researchers hope that the panel of metabolomic
biomarkers they discovered can eventually be used for early
diagnosis, treatment, and monitoring of Alzheimer's
progression.
"We expect to validate metabolomic changes in humans with
Alzheimer's disease and to use these biomarkers to diagnose
the disease before symptoms appear — which is the ideal time
to start treatment," Dr. Trushina says.
The team looked at neurons of
three different genetic animal
models of Alzheimer's disease. Researchers applied a
mitochondria-specific dye and observed their motion along
axons, a process called axonal trafficking. They showed that
even in embryonic neurons afflicted with Alzheimer's
disease, well before the mice show any memory loss,
mitochondrial axonal trafficking is inhibited. Using a panel
of techniques that included electron and light microscopy,
they determined that in the brains of mice with Alzheimer's
disease, mitochondria tended to lose their integrity,
ultimately leading to the loss of function. Importantly,
dysfunctional mitochondria were detected at the synapses of
neurons involved in maintaining memory.
"We are not looking at the consequences of Alzheimer's
disease, but at very early events and molecular mechanisms
that lead to the disease," Dr. Trushina says. The next step
is looking at the same mitochondrial biomarkers in humans,
she says. As the researchers begin to understand more about
the mitochondrial dynamics that are altered in Alzheimer's
disease, they hope to move on to designing drugs that can
restore the abnormal bioenergetics and mitochondrial
dynamics to treat the disease.
Mitochondrial dysfunction and immune
activation are detectable in early Alzheimer's disease
blood.
Abstract
Alzheimer's disease (AD), like other dementias, is
characterized by progressive neuronal loss and
neuroinflammation in the brain. The
peripheral leukocyte response occurring alongside these
brain changes has not been extensively studied, but might
inform therapeutic approaches and provide relevant disease
biomarkers. Using microarrays, we assessed blood gene
expression alterations occurring in people with AD and those
with mild cognitive changes at increased risk of developing
AD.
Of the 2,908
differentially expressed probes identified between the three
groups (p < 0.01), a quarter were altered in blood from mild
cognitive impairment (MCI) and AD subjects, relative to
controls, suggesting a peripheral response to pathology may
occur very early. There was strong evidence for
mitochondrial dysfunction with decreased expression of many
of the respiratory complex I-V genes and subunits of the
core mitochondrial ribosome complex.
This mirrors changes
previously observed in AD brain. A number of genes encoding
cell adhesion molecules were increased, along with other
immune-related genes. These changes are consistent with
leukocyte activation and their increased the transition from
circulation into the brain. In addition to expression
changes, we also found increased numbers of basophils in
people with MCI and AD, and increased monocytes in people
with an AD diagnosis.
Mitochondrial dysfunction and
Alzheimer's disease.
Abstract
To date, one of the most discussed hypotheses for
Alzheimer's disease (AD) etiology implicates mitochondrial
dysfunction and oxidative stress as one of the primary
events in the course of AD. In this review we focus on the
role of mitochondria and mitochondrial DNA (mtDNA) variation
in AD and discuss the rationale for the involvement of
mitochondrial abnormalities in AD pathology.
We summarize
the current data regarding the
proteins involved in
mitochondrial function and pathology observed in AD, and
discuss the role of somatic mutations and mitochondrial haplogroups in AD development.
Systemic mitochondrial dysfunction
and the etiology of Alzheimer's disease and down syndrome
dementia.
Abstract
Increasing evidence is implicating
mitochondrial dysfunction
as a central factor in the etiology of Alzheimer's disease
(AD). The most significant risk factor in AD is advanced age
and an important neuropathological correlate of AD is the
deposition of amyloid-beta peptide (Abeta40 and Abeta42) in
the brain. An AD-like dementia is also common in older
individuals with Down syndrome (DS), though with a much
earlier onset.
We have shown that
somatic mitochondrial DNA
(mtDNA) control region (CR) mutations accumulate with age in
post-mitotic tissues including the brain and that the level
of mtDNA mutations is markedly elevated in the brains of AD
patients. The elevated mtDNA CR mutations in AD brains are
associated with a reduction in the mtDNA copy number and in
the mtDNA L-strand transcript levels. We now show that mtDNA
CR mutations increase with age in control brains; that they
are markedly elevated in the brains of AD and DS and
dementia (DSAD) patients; and that the increased mtDNA CR
mutation rate in DSAD brains is associated with reduced
mtDNA copy number and L-strand transcripts.
The increased mtDNA CR mutation rate is also seen in peripheral blood DNA
and in lymphoblastoid cell DNAs of AD and DSAD patients, and
distinctive somatic mtDNA mutations, often at high
heteroplasmy levels, are seen in AD and DSAD brain and blood
cells DNA. In aging, DS, and DSAD, the mtDNA mutation level
is positively correlated with beta-secretase activity and
mtDNA copy number is inversely correlated with insoluble
Abeta40 and Abeta42 levels.
Therefore, mtDNA alterations may
be responsible for both age-related dementia and the
associated neuropathological changes observed in AD and
DSAD.
Alzheimer's
Proteins, Oxidative Stress, and Mitochondrial Dysfunction
Interplay in a
Neuronal Model of Alzheimer's Disease
Abstract
In this paper, we discuss the interplay between beta-amyloid
peptide, Tau fragments, oxidative stress, and mitochondria
in the neuronal model of cerebellar granule neurons (CGNs)
in which the molecular events reminiscent of AD are
activated. The identification of the death route and the
cause/effect relationships between the events leading to
death could be helpful to manage the progression of
apoptosis in neurodegeneration and to define antiapoptotic
treatments acting on precocious steps of the death process.
Mitochondrial dysfunction is among the earliest events
linked to AD and might play a causative role in disease
onset and progression. Recent studies on CGNs have shown
that adenine nucleotide translocator (ANT) impairment, due
to interaction with toxic N-ter Tau fragment, contributes in
a significant manner to bioenergetic failure and
mitochondrial dysfunction.
These findings open a window for
new therapeutic strategies aimed at preserving and/or
improving mitochondrial function.
