A new drug recently approved for Alzheimer’s disease aims to treat the underlying cause of the condition by removing amyloid plaques in the brain.
Though promising, the drug called aducanumab also comes with potential side effects that require careful monitoring.
Key facts:
- Aducanumab is the first drug that targets and removes amyloid plaques, sticky buildups of protein fragments in the brain that are a hallmark of Alzheimer’s.
- By clearing amyloid plaques, the drug may slow cognitive decline in early Alzheimer’s patients with mild symptoms.
- However, removing amyloid can also cause temporary swelling or bleeding in the brain called ARIA (amyloid-related imaging abnormalities). Most cases are mild but need monitoring.
- Patients getting aducanumab require regular MRIs to check for ARIA. How this monitoring is handled can determine if patients can continue treatment.
Source: RadioGraphics (Vol. 43, No. 9) (Aug 2023)
Breaking Down Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia, causing memory loss and problems with thinking and behavior.
It develops slowly, starting with mild forgetfulness that worsens over time.
The two main brain changes driving Alzheimer’s are amyloid plaques and tau tangles.
Amyloid plaques build up first, while tau tangles form later.
Amyloid plaques develop when protein fragments called beta-amyloid stick together in the spaces between nerve cells.
They accumulate into clumps that disrupt cell function.
Tau tangles arise when a protein called tau twists into abnormal strands inside nerve cells, harming connections.
This process follows amyloid buildup.
Together, amyloid plaques and tau tangles damage brain areas involved in memory, thinking and planning.
As more neurons die, brain tissue shrinks and symptoms worsen.
Targeting Amyloid to Treat Alzheimer’s
Drugs approved for Alzheimer’s so far only ease symptoms temporarily.
But researchers believe that removing amyloid plaques could treat the underlying disease process and slow progression.
Aducanumab is the first Alzheimer’s drug designed to target and clear amyloid.
It’s a lab-made antibody that binds to clumps of amyloid and breaks them apart.
Results from clinical trials found that patients getting a high dose of aducanumab showed less cognitive decline compared to those getting a placebo.
Amyloid PET scans also revealed less amyloid buildup in treated patients.
Based on this evidence, the FDA granted accelerated approval for aducanumab in 2021 for early Alzheimer’s patients with mild cognitive impairment or mild dementia symptoms.
Side Effects Require Monitoring
Despite benefits for some, aducanumab also comes with risks.
The drug can trigger brain swelling and bleeding called ARIA.
ARIA stands for “amyloid-related imaging abnormalities.”
It’s believed to happen when amyloid is cleared from weakened blood vessels, causing them to leak fluid or blood.
There are two types of ARIA:
- ARIA-E – Brain swelling from fluid buildup. Shows up on MRI as white patches.
- ARIA-H – Tiny bleeds or hemorrhages. Seen as dark spots on special MRI sequences.
Most cases of ARIA are mild with no symptoms. But moderate to severe ARIA can cause headaches, confusion, balance issues and other problems.
MRIs are required before starting aducanumab and at regular intervals during treatment to check for ARIA. How ARIA is managed guides whether patients can continue on the drug.
FDA recommendations for Aducanumab
Aducanumab was approved for early-stage Alzheimer’s patients based on studies showing it can slow decline in this group.
But experts advise careful selection of patients due to mixed trial results and potential side effects.
The FDA recommends aducanumab for patients with all of the following:
- Mild cognitive impairment or mild dementia from Alzheimer’s
- Confirmation of amyloid buildup through PET scan or spinal fluid test
- Regular brain MRIs to monitor for ARIA
The drug comes as a monthly intravenous infusion.
Dosing starts low and increases gradually over several months to reduce ARIA risk.
Even with precautions, ARIA occurred in about 35% of patients in trials.
The most important risk factors were high dose and a genetic trait called APOE4 that raises amyloid levels.
Weighing the Potential Benefits and Risks
Aducanumab represents an important shift in Alzheimer’s care by treating an underlying disease process rather than just symptoms.
Reducing amyloid may delay worsening for some in early stages.
However, benefits seen in studies were modest at best.
Some experts argue that evidence is insufficient to recommend the drug for wide use given potential harms.
All Alzheimer’s drugs have downsides that need balancing against possible gains.
The risks of ARIA with aducanumab require vigilant safety monitoring and management.
More research on long-term outcomes will help determine the role of amyloid-targeting therapies.
For now, aducanumab provides a potential option for informed patients willing to undergo required testing and monitoring.
Ongoing Research and Future Directions
Aducanumab has opened doors to disease-modifying Alzheimer’s treatment.
But many questions remain about its efficacy, safety, and optimal use.
Several other anti-amyloid drugs now in late-stage testing may offer alternatives in coming years.
These include: lecanemab, donanemab, and gantenerumab.
Tau-targeting drugs are also being explored as possible Alzheimer’s therapies.
Some experts believe combining anti-amyloid and anti-tau drugs could enhance benefits.
Beyond amyloid and tau strategies, research is pursuing ways to improve neuron health and function.
Combination treatment approaches may ultimately provide the best results.
While incremental, new Alzheimer’s therapies bring hope that better understanding of the disease is leading to rational, targeted treatments.
Ongoing research promises continued progress in effectively combating this challenging condition.
References
- Study: Amyloid-related Imaging Abnormalities in Alzheimer Disease Treated with Anti-Amyloid-B Therapy
- Authors: Amit Agarwal et al. (2023)
