ARIAs in Alzheimer’s Patients

What have we learned about amyloid-targeted treatment

For over 30 years research efforts have been made to better understand both the link between β-amyloid plaque formation in the brain and Alzheimer’s disease progression and to assess whether reducing these plaques offers a therapeutic approach for patient treatment.

Whilst β-amyloid plaques are described as a hallmark of Alzheimer’s disease, it is worth bearing in mind that some patients with Alzheimer’s dementia are β-amyloid negative whilst up to 30% of the healthy aged population have equivalent levels of β-amyloid plaques to Alzheimer’s patients yet show no measurable cognitive decline.

Therapeutic antibodies designed to reduce the levels of amyloid in the brain have been assessed clinically, including lecanemab and donanemab with both achieving FDA approval for their use to treat Alzheimer’s. Although lecanemab targets soluble β-amyloid whilst donanemab targets insoluble β-amyloid, both these treatments were shown to slow down the disease but they did not stop or prevent it. Common side effects of these treatments have been detected by magnetic resonance imaging (MRI) as Amyloid Related Imaging Abnormality (ARIA). 

There are two types of ARIA: edematic, ARIA-E and hemorrhagic, ARIA-H. Whilst many ARIA are asymptomatic, the symptomatic ones can manifest as headaches, confusion or dizziness, in some cases they can be severe including brain swelling and/or brain bleeding in response to anti-β-amyloid treatment. 

In the majority of cases these symptoms are temporary and resolve on their own, even with continuing treatment. In rare cases these symptoms can be severe and lead to hospitalization and even disability, illustrating the critical need for monitoring and in some cases pausing or stopping the treatment completely.

The mechanism for this response is believed to be related to the removal of amyloid plaques in blood vessel walls in the brain. These plaques are laid down over decades and their impact on blood vessel integrity is masked by their presence in the vessel walls, it is only when these plaques are depleted through treatment that we start to see increased permeability of proteinaceous fluids leading to edema, detected as ARIA-E, and potentially breakages within the blood vessels walls leading to microbleeds, detected as ARIA-H. Thus, ARIAs are indicator of amyloid angiopathy.

In addition to the dose related risks of amyloid depleting therapeutics in ARIAs, carrying the APOE4 allele (increased risk of ARIA-E) and evidence of pretreatment haemorrhage are the strongest indicators of ARIA risk in Alzheimer’s patients. While the APOE4 gene is already associated with a higher risk of Alzheimer’s disease, it is interesting to speculate on the role it plays in facilitating plaque formation as its presence alone does not definitively predict disease.

Whilst our focus on ARIAs has been driven through its association with amyloid depleting therapies, increased level of monitoring in all patient cohorts has also flagged that these events occur in untreated patients too, although with a generally lower rate of occurrence.

The use of therapeutics designed to deplete amyloid plaques has opened the door to our understanding of both the risks in such approaches in slowing disease progression but also to potential mechanisms of plaque related disease pathology and presentation.