Could breaching the blood-brain barrier possibly be useful in treating Alzheimer’s?

Last week in the New England Journal of Medicine, the results of an interesting proof-of-concept study using focused ultrasound to enhance the ability of the anti-amyloid monoclonal antibody aducanumab to cross the blood blood-brain barrier and remove beta-amyloid from the brain were presented. As I described in chapter 13 of my book A Tattoo on My Brain, “the protective blood–brain barrier is designed to keep dangerous pathogens in our blood from circulating directly to the brain. Unlike blood vessels elsewhere in the body, the walls of small arteries and capillaries within the brain have tight, structural barriers that limit the size of molecules that can diffuse from the blood into the fluid bathing the brain. Very small molecules like oxygen and carbon dioxide, as well as sodium and potassium ions, can pass freely across the blood–brain barrier. Some nutrients, like glucose, are actively transported across the blood–brain barrier, but most large molecules such as antibodies, as well as bacteria, viruses and toxins, are usually blocked from entering the brain. So how can a very large protein like a monoclonal antibody that is purposely infused into the blood ever get into the brain to do the work it’s intended to do? The answer is, only a very small fraction of the antibodies cross this blood–brain barrier, unless the barrier is breached – normally an adverse event, since it’s designed the way it is to keep the typically larger pathogenic molecules out.  Molecules that are usually blocked by the blood–brain barrier are now able to enter the brain – large molecules like anti-amyloid monoclonal antibodies.” 

In the NEJM study, three subjects with early Alzheimer’s disease were treated with monthly aducanumab infusions plus focused ultrasound in various areas on just one side of the brain. Amyloid PET scans were before and after the six-month treatment period. The ultrasound treatment was shown to open the blood-brain barrier for about six hours, allowing an estimated five-fold increase in the access of aducanumab to amyloid in the brain. After six months, repeat PET scans showed marked decrease in amyloid in the regions of the brain that received focused ultrasound in addition to aducanumab as shown for one of the subjects in the figure above. No ARIA or other serious side effects were encountered, although one subject had a mild worsening of cognitive impairment. None of the subjects were APOE-4 carriers as the researchers wanted to minimize risk of ARIA.

This is a provocative study.  I have mixed feelings.  On one hand it is an impressive proof-of -concept study: manipulating the blood-brain barrier could be useful in managing some cases of Alzheimer’s in the future. On the other hand, it may not be safe to use in APOE-4 carriers, and it may not be any more effective than the most recent anti-amyloid monoclonal antibody awaiting FDA approval, donanemab. Donanemab alone is very effective in removing all evidence of beta-amyloid. It also appears to be effective at slowing the progression of cognitive impairment in early Alzheimer’s disease.