Potential new treatment for Alzheimer’s disease

By on
amyloid cleared from brain by aducanumab

Aducanumab is an exciting potentially new treatment for Alzheimer’s disease and may possibly be the first potential cure.

A human monoclonal antibody, aducanumab, has been shown to remove amyloid beta plaques from the brains of patients with early or mild Alzheimer’s disease. The drug was more effective at higher doses. This was shown using PET brain scans (see below).

Specalists in the field have responded to these results with excitement. "This is the best news we’ve had in my 25 years of doing Alzheimer’s research,” says Stephen Salloway, a professor of clinical neurosciences and psychiatry at Brown University and a co-author of the paper.

The study was reported in Nature.

The study was not designed to be powerful enough to show change or improvement in cogitive ability, but analysis showed a dose-dependent slowing of clinical progression on the Mini Mental State Examination (MMSE). More research is needed. The drug penetrates the blood brain barrier and was found to be safe. There were some side effects which included headache, urinary tract infection and upper respiratory tract infection.

The drug aducanumab is given monthly by intravenous infusion (injection) and was found to slow progression in those in he early stages of this devastating disease.

The study involved 165 patients over 1 year.

It is thought that Alzheimer's disease is caused by the accumulation of a protein called amyloid-beta iwhich damages or kills nerve cells in the ageing brain. This is believed to cause the memory and cognitve problems suffered by those with Alzheimer’s disease.

In the study, the strongest signs of cognitive improvement were shown in those given the highest dose of drug. These patients also had the most marked reduction in beta amyloid plaques on their PET brain scan. It is exciting that these patients did not get any worse at all after six months of  aducanumab treatment.

However this is a small study. Two larger trials are now starting involving 2,700 patients over 20 countries. 

Amyloid plaque reduction with aducanumab: example amyloid PET images at baseline and week 54

Figure 1: Amyloid plaque reduction with aducanumab: example amyloid PET images at baseline and week 54. Individuals were chosen based on visual impression and SUVR change relative to average one-year response for each treatment group (n = 40, 32, 30 and 32, respectively). Axial slice shows anatomical regions in posterior brain putatively related to AD pathology. SUVR, standard uptake value ratio.

Here is the abstract summary from Nature:

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Response from the media:

John Hardy, a neuroscientist at UCL who iitially suggested that amyloid was a a major factor in Alzheimer’s disease, said: “It’s very interesting and nice to see all these positive data, and it has caused genuine excitement in the field, but it’s a very small number of patients and too small to draw any definitive conclusions from.”

The results from the trial led by the US biotech firm, Biogen, and a Swiss company called Neurimmune, are reported in the journal Nature. The data were first released at a scientific conference in March last year. Aducanumab was hailed as a potential treatment for Alzheimer’s when scientists found the antibody in people who aged without suffering the sort of mental decline that goes hand in hand with old age. It appeared that the antibody prevented the build-up of amyloid plaques and staved off dementia. 

When injected into Alzheimer’s patients, one or two in every thousand of the antibodies enter the brain where they latch on to wayward amyloid-beta proteins. Researchers at Biogen believe that other cells called microglia then arrive and clear the aberrant proteins from the brain. The drug appears to be most effective if the accumulation of amyloid protein is blocked before it causes too much damage. The process may start 15 years before people show symptoms.

In the latest trial, some patients experienced side effects. MRI scans showed a shift in the brain fluid that was more common at high doses and in people who carry the APOE type-4 gene, which is a major risk factor for Alzheimer’s disease. The scientists are now working on ways to avoid the side effect or diminish the problems by reducing the doses patients receive.

David Allsop, professor of neuroscience at Lancaster University, said the side effects will have to be overcome if the therapy is to find widespread clinical use. “Nevertheless, these findings could be a gamechanger if the effects on memory decline can be confirmed in more extensive follow-on studies.”

There are 850,000 people with dementia in Britain, a number that is expected to reach one million by 2025. Alzheimer’s is the most common form of the condition. “If this drug works, we’ll have a treatment for patients suffering from this devastating disease,” said Biogen’s Alfred Sandrock.

“These results provide tantalising evidence that a new class of drug to treat the disease may be on the horizon, said David Reynolds at Alzheimer’s Research UK.

James Pickett at the Alzheimer’s Society was similarly optimistic: “These results are the most detailed and promising that we’ve seen for a drug that aims to modify the underlying causes of Alzheimer’s disease.”

See the study in Nature

"This drug had a more profound effect in reversing amyloid-plaque burden than we have seen to date," Alzheimer’s researcher Eric Reiman from the Banner Alzheimer’s Institute in Phoenix, Arizona, who is not involved in the study, told Erika Check Hayden at Nature. "That is a very striking and encouraging finding and a major advance."

It is still not certain what causes Alzheimer’s disease to develop, but a major pathology is buildup of two types of lesions in the brain: amyloid deposits - or 'plaques' - and neurofibrillary tangles.

The beta Amyloid deposits appear between the brain nerve cells as dense clusters of beta-amyloid molecules - a sticky type of protein that easily clumps together - and neurofibrillary tangles which are caused by defective tau proteins that clump up into a thick, insoluble mass inside the neurons.

This causes disruptions to the transportation of essential nutrients around the brain, which is thought to bring on the cognitive decline and memory loss associated with Alzheimer’s disease.

Over the years, the roles of amyloid deposits and neurofibrillary tangles in the onset of Alzheimer’s have been debated, because it’s not yet clear if one causes the other, or if one has a greater overall effect. But this new trial suggests that if you can get rid of the amyloid deposits, you have a chance at stalling the progression of the disease.

The researchers report that they saw slower cognitive declines in 91 patients treated with the drug. "Aducanumab also showed positive effects on clinical symptoms,"

Nitsch explained in a press statement. "While patients in the placebo group exhibited significant cognitive decline, cognitive ability remained distinctly more stable in patients receiving the antibody." The results are definitely exciting, but it’s time to replicate them in a larger group of patients. The team is now recruiting another 2,700 patients from 20 different countries to participate in a new 18-month trial, the results of which are expected in 2020.

"These results are the most detailed and promising that we’ve seen for a drug that aims to modify the underlying causes of Alzheimer’s disease,” James Pickett, head of research at the Alzheimer’s Society, who was not involved in the study, told Ian Johnston at The Independent.

"No existing treatments for Alzheimer’s directly interfere with the disease process – and so a drug that actually slows the progress of the disease by clearing amyloid would be a significant step."

Read more about Alzheimer's disease