Can Alzheimer's really be overcome?

About amyloid

More than 140 drugs are being trialled in 170 Alzheimer's disease clinical trials – most of them disease-modifying treatments aimed at preventing or delaying the onset or progression of the disease (Figure 1).

A 2014 study found that 99 percent of Alzheimer's drug trials failed, the highest
incidence of any disease.

Figure 1.
A number of therapeutics with different mechanisms of action are in clinical trials

Many factors can explain the poor performance of drugs, from late intervention, to the use of the wrong drug and targeting the wrong target
.
But Michael Murphy, a neuroscientist at the University of Kentucky, says all the explanations ultimately reveal how much remains unknown about the disease, including its cause.

"We still don't know what drives neurodegeneration," he said
.
"From a therapeutics perspective, if you don't know how this happens, you're working
in the dark.
"

Still, the most funded and researched to date is the amyloid hypothesis, which holds that the disease is caused
by amyloid plaques that accumulate in the brain β, harming neurons and causing cognitive problems.
Interest in these protein aggregates can be traced back to the discovery of the disease by German physician Alois Alzheimer, who found sticky plaques
in the brain of a 51-year-old woman who died of dementia in 1906.

Alzheimer's disease also found filamentous tangles, which were later identified as tau proteins
.
Both amyloid-β and tau proteins have become biological factors and rational drug targets for disease definition
.
But much of the research and drug development has focused on
amyloid.

When the gene associated with Alzheimer's disease was discovered in the 90s of the 20th century, this sticky amyloid protein gained additional attention
.
Scientists at the time noticed that people with mutations in these genes showed increased levels of amyloid-β in the brain and early onset
of disease.
Further studies also showed that eliminating amyloid β mice reversed memory and cognitive loss
.
This evidence supports the notion that
amyloid causes the disease.
As a result, a series of drugs have been developed to clean up or stop the accumulation
of β amyloid deposits.

However, although a few of these drugs have successfully cleared the plaque, patients have not shown cognitive improvement
.
The most notable of these failures were Janssen and Pfizer's bapineuzumab, a monoclonal antibody that reached a phase 3 trial but showed no clinical benefit, and Eli Lilly's Solanezumab, another monoclonal antibody of much concern that didn't even show a significant reduction
in amyloid β plaques.

Ronald Peterson, a neuroscientist at the Mayo Clinic Alzheimer's Center for Research, said that after successive failures, the field is increasingly turning to the idea that amyloid is one of the components of Alzheimer's disease, but not necessarily the cause or the most important
.

Inflammation and metabolism

Although amyloid remains the focus of many current Phase 3 drug trials, recent research on alternative drug targets for Alzheimer's disease has begun to grow
.
According to the latest analysis of this year's drug pipeline, more drugs in clinical trials target inflammation
than amyloid.

Studies believe that chronic neuroinflammation plays an important role
in the occurrence and development of Alzheimer's disease.
Genetic studies have shown that more than 60 percent of genes associated with a high risk of Alzheimer's disease are also immune-related
.
Some studies suggest that amyloid plaques may even have anti-inflammatory effects, protecting microorganisms
.
A decade ago, many clinical trials using anti-inflammatory drugs failed, but new trials using drugs with different mechanisms, from monoclonal antibodies to small molecules, are now in phase 2 trials
.

There is also room for drug development approaches that consider Alzheimer's disease as type 3 diabetes in the brain
.
Years of research have shown that people with diabetes have an increased
risk of dementia.
The study also confirmed that glucose metabolism in the brains of Alzheimer's patients is altered, which can lead to neuronal starvation and death
.
Most drugs targeted to metabolism tested so far have difficulty crossing the blood-brain barrier
.
But preliminary results from the Phase 2 trial showed improved cognition in patients using T3D-959 (T3D Therapeutics), a drug that activates two proteins called PPAR-δ and PPAR-γ, regulating energy expenditure and blood sugar levels, thereby correcting impaired sugar and lipid metabolism
.

Targeting tau has also yielded promising results
.
As with amyloid-β, all trials targeting tau fibers have so far failed
.
But this year, preliminary results from Lucidity's Phase 3 trial showed that a trial of a new drug called hydrogen-methylthiopansy (HMTM, TauRx Pharmaceuticals) that removes tau protein was able to slow cognitive decline
in early and mild Alzheimer's patients.
The drug is currently in the
U.
S.
for registration.

More amyloid antibodies

Researchers still hope to target amyloid
.
Levey said: "The amyloid hypothesis is still possible
.
He believes that one of the reasons for the failure may be to intervene
too late.
Most failed trials recruited patients in the mild to moderate stage of advanced Alzheimer's disease, when the brain may be too
badly damaged.
Therefore, it is critical
to develop biomarkers that can detect the biology of disease before symptoms appear.

With the release of preliminary results from Eisai and Biogen's CLARITY AD trial of lecanemab, hopes for University of Nevada neuroscientist Cummings and other researchers defending amyloid have been rekindled
.
Monoclonal antibodies targeting plaque and amyloid oligomers slowed cognitive decline by 27% compared to placebo, meeting its primary endpoint
.
For Cummings, the discovery is a "breakthrough" that helps support the central role
of amyloid-β in Alzheimer's disease.

Combination therapy

Biomarkers of other components of the disease are also emerging, such as neuroinflammation imaging
, and research is ongoing.
These advances will lead to earlier detection and better treatment
for different targets.
Marwan Sabbagh, a behavioral neurologist at the Barrow Neurological Institute, said a combination of treatments with precision medicine would make Alzheimer's a manageable chronic condition, not a terminal illness
.
"Treatments will become more personalized, with drugs
developed for patients with specific genotypes and mutations," he said.
”

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