Should testing for APOE-4 be required before treatment with anti-amyloid monoclonal antibodies?

There are now two anti-amyloid monoclonal antibodies that appear to be effective in slowing the progression of cognitive impairment in people with mild Alzheimer’s disease. The benefit may be small, 27% for lecanemab and 35% for donanemab, but it is statistically significant in both cases. 

Amyloid-related imaging abnormalities (ARIA) have occurred in all trials of anti-amyloid monoclonal antibodies.  Usually these areas of swelling and/or bleeding in the brain are mild and resolve when the treatments are paused. But about 2% of the time they can be severe resulting in hospitalization and rarely in death. Three participants died in each of the lecanemab and donanemab phase 3 trials, but details surrounding those deaths have been released in only one case.

People who carry the APOE-4 allele are more likely to get ARIA than those who do not.  In the case of lecanemab, those participants with two copies of the APOE-4 allele were approximately six times more likely to experience symptomatic ARIA with brain swelling and more than three times more likely to experience ARIA with brain bleeding than APOE-4 noncarriers. These comparisons for donanemab have not yet been published. 

A recent opinion paper in JAMA Neurology makes the case that APOE genotyping should be an integral part of prescribing lecanemab. Patients who carry the APOE-4 allele, especially those with two copies, should be informed of their increased risk of ARIA side effects and should undergo regular MRI surveillance similar in frequency to the surveillance used during the trials.  Some have even argued that patients with two copies of APOE-4 (APOE-4 homozygotes) should not receive this drug.  The Department of Veterans Affairs has already excluded patients with two copies of the APOE-4 allele from receiving lecanemab. My personal opinion is this: I agree that regular MRI surveillance will probably be necessary for APOE-4 carriers receiving any of the anti-amyloid monoclonal antibodies.  At this point, I do not agree that these APOE-4 homozygotes should not receive lecanemab and similar drugs.  These patients need to be aware of their added risk and need for surveillance, but they should be offered an informed option to take them. Some experts have raised the concern that healthcare and long-term care insurance companies may refuse or limit coverage based on APOE-4 status. Certainly, there will be ripple effects, but I am optimistic that these financial and ethical issues can be resolved.