Any Heterozygotes on Donanemab?

Leonard Shelby

Got my APOE results back and I am E3/E4. Waiting for my next appt with the NP to discuss next steps. I know that E4/E4 is pretty much a no go for Donanemab. E3/E4 is supposedly 50% less chance of ARIA, but still a risk. My Centiloid is 144. So, lots of existing plaques. Donanemab is for clearing those. Lecanemab is for stoping the formation of new ones. I am going to go with what the Doc says. But, curious if any of you with a high plaque burden that have started treatment had that discussion with your Doc, and which you eventually got on. Thank you.

LBC83

I am E3/E4, and I just had my 38th Leqembi infusion.

Both Leqembi and Kisunla clear amyloid plaque. The distinction is that Leqembi is dual-acting, as it removes both amyloid plaque and amyloid protofibrils (small bits of amyloid that have not yet formed into plaques). I recently had blood-work performed, which showed that my amyloid plaque levels are similar to "normal" people (i.e. after 38 infusions, Leqembi has successfully cleared away almost all of the amyloid plaque that was in my brain).

Regarding ARIA rates, you have to be careful with Kisunla. There are two sets of ARIA reates with Kisunla, the rates using the old dosing strategy and the rates with the new dosing strategy. The old dosing strategy used two vials of Kisunla for each of the first three doses, and doubling that to four vials for all later doses. That resulted in high ARIA rates with Kisunla. Some genius suggested moving one vial in the dosing strategy, from dose #1 to dose #3. With this new strategy, patient receive one vial for dose #1, two vials for dose #2, three vials for dose #3, and four vials for dose #4 and all later doses.

For the old Kisunla dosing strategy, the ARIA rates by APOE type were as follows: 57% for E4/E4, 24% for E4/E3, and 15% for noncarriers. So yes, in this case, there is about half the risk of ARIA for E3/E4 compared with E4/E4.

But with the new Kisunla dosing strategy, the ARIA reates by APOE type are: 24% for E4/E4, 16% for E3/E4, and 13% for non-carriers. Note that all of the numbers dropped, but the E4/E4 values dropped the most and the non-carrier values dropped the least.

To say it another way, the ARIA rates for E3/E4 using the old dosing strategy are the same as the ARIA rates for E4/E4 people using the new dosing strategy. So E4/E4 is no longer a "no-go" for those wishing to receive Kisunla.

Dorse

Interesting.. Thank you

Conclusion: How safe is Kinsunla in your opinion in simple language overall after all your research? That one has been my choice if I ever get scheduled after 5 months of being approved. I am 80, therefore, both infusions have given me conflicting thoughts. This is all so confusing as to the best choice for me. Thank you

Leonard Shelby

https://alzconnected.org/discussion/comment/260117#Comment_260117

That is so great to hear about your plaques. Do you mind me asking what your centiloid score was when you started and current? I am of the impression that my brain is littered with these things.

LBC83

https://alzconnected.org/discussion/comment/260146#Comment_260146

Excellent question, but I have no idea what my centiloid level was when I started, nor my current CL level, as I have never had an amyloid PET scan.

For confirmation of amyloid pathology needed for an AD diagnosis, I had the option of a lumbar puncture (in the network of my health care provider) or an amyloid PET scan (out of network). I chose to stay in network and thus went with the lumbar puncture. I am an Engineer by training, so after receiving my lumbar puncture results, I presumed I would be able to convert the results to CL using an equation. Just like there is a way to convert distances from miles to kilometers, or temperature from degrees F to C, or weight from kilograms to pounds. But after digging around, I found no such conversion factors. It is like the proverbial comparison of apples & oranges, apparently nobody has figured out a correlation between CL levels per an amyloid PET and the results from a lumbar puncture.

Theoretically, it shouldn't be that difficult to determine a relationship. Just ask a few hundred or so volunteers to receive both an amyloid PET scan and a lumbar puncture and then correlate the results. But again, apparently nobody has performed such an analyses. Hence, I'm clueless about my starting CL level and my current CL level.

I'm in the process of enrolling in the LEADS study. This study is conducted by the U.S. gov't to collect data about AD progression. There are no drugs involved, just a bunch of tests. If I am accepted, then I finally will recieve an amyloid PET scan, a tau PET scan, along with a ton of blood work and another lumbar puncture.

LBC83

https://alzconnected.org/discussion/comment/260126#Comment_260126

That is a really hard question. To begin, we have to discuss genetics. A key test before starting on either anti-amyloid medication is a genetic test for the APOE4 gene. You inherit one gene from your biological mother and one from your biological father. If you do not inherit an APOE4 gene from either parent, you are referred to as a noncarrier, and you have the lowest risk of ARIA (16% in the Phase 3 trial for Kisunla). If you inherit one gene from one of your parents, then you have moderate ARIA risk (23% from the Phase 3 trial). But if you inherit one APOE4 gene from your Mom and a second APOE4 gene from your Dad, then you have two genes and your ARIA risk is highest (41% in the Phase 3 trial for Leqembi).

Then there are two kinds of ARIA: one kind results in brain swelling, the other brain bleeding. It turns out that for those who experience brain swelling, 3/4 of these folks don't have any symptoms. This means the Doctors figure out they have this problem by reviewing their MRI scans, as the people are clueless that they have this issue. The other 1/4 of the folks with swelling do experience symptoms, sometimes they are nasty (for example, severe headache). So if you experience brain swelling, you likely won't know you have this problem until you get an MRI scan. If the scan shows you do have the mild/moderate brain swelling, you just stop infusions, and the problem usually goes away by itself. But a small group of people on anti-amyloid drugs do experience severe brain swelling which can result in some nasty side effects. The recommendation for those with severe brain swelling is to stop treatment. The determination of whether brain swelling is mild / moderate / severe is pretty easy: mild brain swelling is define as confied to one area less than two inches in size. If the swelling is 3-5 inches in each place then this is referred to as moderate. Severe swelling is define as swelling over 5 inches in size.

For ARIA cases that involve brain bleeding, as you might guess, the severity of the problem is determined by how many brain bleeds you have. It is sort of like getting paper cuts on your hand. If you have 1 or 2 paper cuts, no big deal, your hand will heal by itself. But if you have a dozen paper cuts on your hand (ouch!), well, maybe you need to go to the Doctor and get your hand wrapped. In a similar way, Doctors categorize brain bleeding by the severity and quantity of brain bleeds. If the bleeding amount is small and you have nine or less bleeding locations, and you have no symptoms, then the recommendatoin is that treatment is paused until the bleeding goes away. It isn't like anybody does surgery to apply bandaids to the areas that are bleeding. Just stopping the anti-amyloid medication and allowing the brain to heal is usually sufficient to solve the problem. But if you have 10 or more bleeding locations, then the recommendation is to stop treatment altoghether.

I get this is not so easy a decision for people to make. But let us compare the risks of ARIA with anti-amyloid medications with the risks of bad accident when driving. I've seen estimates that over the lifetime of the average Jane/Joe living in the U.S., their chance of dying in a motor vehicle accident is 1 in 95. I find that a pretty astounding statistic - you have an excellent chance of dying in a motor vehicle crash over your lifetime! Further, the National Safety Council has estimated that 44,762 people died in motor vehicle accidents in 2023. That is a lot of dead people. I was involved in a bad accident as a kid. My Dad and I were in a car stopped at a traffic light on a busy road near an airport. A guy not paying attention to the road (he was returning his rental car to the airport) rear-ended our car at a moderately high speed. This was way back when seat belts were not regularly used. I was in the back seat, and when flying into the back side of the front seats. Neither my Dad or I were injured, but it was scary. My wife injured her knee in a car accident decades ago, and it still bothers her sometimes. A friend of mine from my church died in a car accident in Alaska. The point is that driving (or even riding in a car as a passenger) is a risky endeavor. Yet many of us ignore all of the above when we go on car rides.

To summarize, ARIA is a very dangerous possible side effect of anti-amyloid medications. However, the protocol for anti-amyloid medications requires frequent MRIs to check for ARIA early in the infusion sequence. This is a protection scheme designed with the cooperation of the FDA to offer the best safety to people taking the drug. If you started on anti-amyloid medications, there is a relatively small chance you could develop ARIA with no symptoms. This would be detected on an MRI scan, and they would probably recommend that you pause infusions (unless you had only very minor ARIA, in which case they might recommend that you continue dosing, with the idea that they would soon be checking on you again with the next scheduled MRI). Usually, in these cases with AIRA and no symptoms, the ARIA goes away by itself. You would then have the option of trying again with infusions, or just stopping. There is an even smaller chance that you might experience ARIA with symptoms that aren't very bad, and a very small chance that you develop a particulary bad version of ARIA with very nasty symptoms. But the odds of this happening might be something like the chances of getting a very bad case of the flu which causes you many problems.

In life, we are always comparing risks and rewards for medical procedures and medications. There are always the possiblities of complications from surgeries and medication side effects. But we weigh that against the rewards of improved health, pain relief, increased quality of life, etc. In this case, we are comparing the risk of AD treatment with an anti-amyloid drug with the reward of having more quality time with good cognition. This is an individual decision, as each person may rationally decide the risk/reward decision leads them to start an anti-amyloid medication to try to slow AD, while others may decide the risks outweigh the possible rewards for them. I belive this truly is a personal decision, and no Doctor (or opinionated person on the internet) can (or should) make the decision for anybody else.

Finally, as noted above, I'm an Engineer by training and thus obviously not an expert in this area. Your Doctor should be your final source of the real information on this topic.