The amyloid hypothesis of Alzheimer's disease: New treatments bring new insights

The amyloid cascade hypothesis of Alzheimer's disease is the most widely studied hypothesis in this disease area.

After the accelerated approval of aducanumab, three monoclonal antibodies targeting Aβ (lecanemab, donanemab and gantenerumab) have also been granted breakthrough therapy designation by the US FDA

Theoretical basis for Aβ-targeted therapy

The amyloid cascade hypothesis states that soluble Aβ oligomers and insoluble amyloid are deposited in the brain to form amyloid plaques due to excessive production or untimely clearance of Aβ42 or other Aβ polypeptide fragments

Over the past decade, scientists have used positron emission tomography (PET) technology to gain a better understanding of the pathological development of amyloid and tau proteins in the brains of Alzheimer's patients

▲ Illustration of the amyloid hypothesis (Image source: Reference [1])

The review authors say the current data support the hypothesis that amyloid promotes the expansion of tau pathology, ultimately leading to neuronal death

Based on these studies, the therapeutic hypothesis for Aβ-targeted therapy is that if the levels of soluble Aβ and/or amyloid plaques in the brain are reduced to non-pathogenic levels—that is, to levels that do not promote the expansion of tau pathology, That can bring clinical benefits

So, what insights can we draw from past clinical trial results to guide future clinical studies of Aβ-targeted therapy?

Lessons learned from clinical trials of Aβ-targeted therapy

Therapies targeting soluble Aβ

Therapies targeting soluble Aβ include γ-secretase inhibitors, BACE1 inhibitors, and anti-Aβ monoclonal antibodies

Two monoclonal antibodies targeting Aβ monomers, solanezumab and crenezumab, failed to significantly clear amyloid plaques in the brain in phase 3 clinical trials, nor did they show efficacy in improving cognition

Antibody therapy targeting amyloid plaques

Several monoclonal antibodies targeting amyloid plaques have been evaluated in clinical trials, and they bind to Aβ monomers and Aβ fibrils with different specificities because they target different epitopes of Aβ

▲Aβ protein epitope and antibody binding characteristics bound by different monoclonal antibodies for the treatment of Alzheimer's disease in clinical trials (Image source: Reference [1])

These monoclonal antibodies include aducanumab, which received accelerated FDA approval, and donanemab, lecanemab and gantenerumab, which received breakthrough therapy designation

A previous study of PET markers of brain amyloid showed that a PET marker of less than 20 CL ​​was considered the threshold for amyloid negative

The relationship between the rate of amyloid plaque clearance and clinical response

The authors pointed out that there are currently 4 anti-Aβ monoclonal antibodies in the field of Alzheimer's disease that can clear amyloid plaques

The authors note that there is likely to be a delay in the time patients show clinical benefit compared to the time when amyloid levels decline

▲The relationship between amyloid clearance and clinical response (Image source: Reference [1])

The authors say that the lagged relationship between patient clinical response and amyloid clearance has important implications for the clinical development of anti-Aβ mAb therapy

In addition, baseline amyloid levels in the patient's brain became critical when recruiting patients

One way to address these issues is to develop new, more sensitive clinical markers capable of revealing more subtle changes in cognitive levels at earlier stages of clinical trials

Another approach is to conduct preventive treatment clinical trials, which typically require large numbers of patients and long clinical trials
.
The new Phase 3 clinical trial announced by Roche recently falls into this category
.

The authors say that the approval of aducanumab has had a major impact on the Alzheimer's disease field, but it has also caused a lot of discussion in the industry
.
It is their sincere hope that, with sufficient numbers of patients, Phase 3 or 4 clinical studies evaluating Aβ-targeted therapy can be finalized to provide a robust and definitive assessment of the clinical benefit of Aβ-targeted therapy
.

References:

[1] Karran and Strooper.
(2022).
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics.
Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-022-00391-w