Is Aβ an effective target for the treatment of Alzheimer's disease? See what Harvard experts have to say!

*For medical professionals only

As society ages, the prevention and treatment of Alzheimer's disease (AD) has become more and more important, but despite the efforts of scientists, there is still no single treatment that can achieve the ultimate goal: to drastically reduce cognitive decline
.

Failure after failure makes one wonder if we got it wrong from the start? Neurofibrillary tangles of β amyloid (Aβ) plaques and tau protein aggregation, which have been in the spotlight for decades, are not really targets, which is why drug clinical trials fail?

This was recently explored
in a review article [1] published in PLOS Biology.
The authors argue that this view is incorrect, that many genetic studies "overwhelmingly" support that abnormal Aβ accumulation is a major trigger for AD, and that clinical trials targeting Aβ have not been a complete failure, with researchers observing a decrease in Aβ plaques and even tau protein and neurodegeneration in the brain, which has a "disease-correcting" effect, while cognitive decline has also improved, just not to the desired extent
.

Preclinical evidence that Aβ accumulation is a key trigger for AD

From a genetic point of view, the discovery of genetic risk factors for AD has revolutionized AD research
.
Early in the study, scientists found that patients with Down syndrome typically begin to develop neuropathological and clinical signs of early-onset AD around the age of 40 or even earlier for the simple reason that the amyloid precursor protein gene (APP) is located on chromosome 21, so the extra copy of APP in patients with Down syndrome leads to a lifetime of Aβ overproduction [2,3].

This theory is also supported by other studies that a very small percentage of patients with Down syndrome have translocation Down syndrome, chromosome 21 is only partially copied, and if the translocation part contains APP, the patient will develop AD [4], and if it does not, it will not develop AD [5].

Even young patients with Down syndrome who do not have AD symptoms have diffuse plaques, mainly nonfilamentous deposits of Aβ, which begin to gradually fibrosis around the age of 20-30, "moving closer"
to the Aβ plaques of AD patients.

In addition to Down syndrome, there are some early-onset AD with specific gene mutations that are inherited in families, and their Aβ plaques and neurofibrillary tangles have the same
pathological changes as sporadic late-onset AD.

Pathological manifestations of late-onset and early-onset AD

In early-onset AD, only 3 genes are currently identified to carry disease-causing mutations
.
The first is APP, a mutation of APP located at the site where APP is recognized and cleaved by β secretase, and the mutation causes APP to be more easily cut, so patients with this mutation will have about 3 times the overproduction of Aβ [6,7].

Mutations in another class of apps not only increase Aβ production, but also lead to the production of Aβ42 and Aβ43 (with 42 or 43 amino acid residues) instead of the common Aβ40 [8], these longer and more hydrophobic Aβ enhance the formation of neurotoxic oligomers and the deposition
of Aβ plaques.
In addition to APP, the remaining two genes, PS1 and PS2, can also cause early-onset AD
in this form.

These genetic studies clearly point to Aβ at the top of the pathological change cascade in AD
.

A: The process of secretase cleavage APP to produce Aβ; B:Aβ is at the apex of the AD pathological change cascade

On this basis, can reducing Aβ prevent or slow down the development of AD?

In a large genetic study conducted in Iceland, researchers sought to find genetic variants that could prevent AD and age-related cognitive decline by finding a mutation at the β secretase cleavage site of APP that reduced Aβ production by approximately 40% over the entire lifetime [9].

In an elderly person in Finland who died at the age of 104, researchers found the same mutation, and neuropathological analysis revealed that there were very few Aβ plaque deposits in her brain [10].

These studies support Aβ as a major target for disease-modifying therapies
.

Translational and clinical research evidence targeting Aβ

The discovery of APP, PS1, and PS2 mutations has led to the clinical application of imaging, cerebrospinal fluid, and blood markers, which has helped researchers establish the pathological process before the onset of symptoms of early-onset AD [11].

Studies have shown that the earliest AD marker changes are a progressive decrease in free Aβ42 monomers in cerebrospinal fluid as they begin to form oligomers and plaques, followed by an increase in soluble TREM2 produced by microglia, with PET able to detect Aβ plaques, and later, 18F-FDG PET, which can detect a decrease in brain metabolism and progressive brain atrophy
on MRI.

Similar studies in patients with late-onset AD have yielded a consistent course of change [12].

This also provides evidence
for Aβ's "apical position in the cascade of pathological changes in AD".

Anti-Aβ monoclonal antibody is currently the most validated new therapeutic drug in AD patients, and multiple trial results have shown that anti-Aβ monoclonal antibody can clear Aβ plaques and somewhat slow cognitive and life decline [13-17].

ADtaxi Memories Trip Vol.
01 Professor Henrik Zettberg, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden, takes you through the biomarkers of Alzheimer's disease

Of these monoclonal antibodies, aducanumab was the first to receive FDA approval, but despite this, clinical trial results for aducanumab were inconsistent
.
The EMERGE trial, which observed positive results, demonstrated a significant reduction in the Clinical Dementia Score Sum Scale (CDR-SB) score in the high-dose aducanumab group (P = 0.
0120), a dose-dependent significant reduction in Aβ plaques, and a small number of patients also exhibited a reduction in cerebrospinal fluid p-tau compared with placebo patients [15].

However, the ENGAGE trial, which observed negative results, showed no significant difference in cognitive endpoints between the same high-dose aducanumab compared with the placebo group [15].

As a result, aducanumab was required to continue clinical trials to solidify evidence of its effectiveness
while it was approved.

The FDA emphasized that the results of the aducanumab clinical trial showed a clear relationship between reducing Aβ plaque and maintaining cognitive function in patients, which was also consistent
with the results of the other 6 anti-Aβ monoclonal antibody studies.

Not only aducanumab, but several other anti-Aβ monoclonal antibodies are not "green light" in clinical trials, with 12-month results from lecanemab's phase II trial showing that lecanemab was more likely to improve AD composite scores (ADCOMs) than placebo, but did not meet a preset minimum threshold, while 18-month results showed that lecanemab significantly slowed the rate of cognitive decline by 27% (P= 0.
00005), all key secondary endpoints also improved significantly (p<0.
01) [18].

In clinical trials of anti-Aβ monoclonal antibodies, there is a relationship between plaque reduction and cognitive decline

The review authors note that although there are some arguments that many clinical trials targeting Aβ, including secretase inhibitors, have failed, supporting evidence that Aβ is the wrong target, most of these trials were conducted prior to the aforementioned mAb clinical trials, did not use PET to measure Aβ levels in the brain, and there were safety concerns that led to early termination of trials, and these early failures did not constitute rigorous scientific evidence
against the Aβ hypothesis.

How does anti-Aβ therapy move from the current "mixed results" to real success?

Both preclinical and clinical studies have shown that Aβ plaques are an early, unchanging and necessary feature of the onset of AD, but our drugs have not achieved good results
.
The most plausible explanation that can be obtained from current understanding is that it is very difficult
to translate the results of preclinical and biomarker studies of Aβ pathology into clear clinical benefits.

In the authors' view, clinical trials of anti-Aβ monoclonal antibodies have many shortcomings, including low dosing doses, suboptimal patient screening, late initiation of treatment, and trial execution errors, such as early termination of trials or short trial endpoint setting times (12-18 months).

However, the authors believe that this situation has improved
in current phase III clinical trials.
Therefore, it is unwise
to slow down or abandon the development of anti-Aβ monoclonal antibody drugs.

Of course, there is still a lot to be done for developers to achieve real success, including more accurate quantification of the effective concentration of mAb, rigorous design and execution of clinical trials, and longer trials, and finally, the need to find more validated AD virology markers, as well as mutually confirmed different cognitive and functional endpoints
, especially fluid and image markers of synaptic dysfunction.

To date, there are a number of sensitive markers that are expected to be used to monitor the pathological progression of AD, mainly soluble fragments of tau protein, or p-tau, and the Aβ42/Aβ40 ratio in the blood, and research is exploring whether they and other markers can be used to monitor AD progression or even as evidence of
drug efficacy.
In addition, we also lack blood tests for immune cell activation in the brains of AD patients, which is one of
the hurdles that need to be overcome in the future.

In their final outlook, the authors point out that current treatments are aimed at the early stages of the disease, when mild AD, there is a degree of benefit from receiving anti-Aβ antibodies, and further, to prevent AD, effective interventions
are required before symptoms appear.
In addition, if intravenous antibody drugs can achieve broader success, subcutaneous administration and vaccines, as well as more economical therapies
, can continue to be explored.
With 40 years of research, these advances are also promising
.

References:

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If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline? [J].
Plos Biology, 2022, 20(7): e3001694.

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The author of this article Ying Yuyan