Treatment of Early Alzheimer Disease: Key Takeaways From AAIC 2025

Biomarkers are largely used to confirm or rule out an AD diagnosis, but I think that is likely to expand.^2,3 For example, I expect we will start to use phosphorylated-tau 217 to predict who is likely to have a positive PET scan as part of a triaging step.

One hope is that BBMs will be useful not only for diagnosis but also to monitor responses during or after therapy, although their utility in this area is still being investigated.^3,4 Currently approved DMTs, such as donanemab and lecanemab, appear to get rid of the targeted amyloid after a certain amount of time, and amyloid reaccumulation appears to be slow.^5-7 For this reason, after a certain period of time on these DMTs, patients with negative amyloid PET scans can either pause therapy or switch to a maintenance dosing schedule.^5,8 However, it would be very helpful to be able to monitor whether amyloid is reaccumulating and treatment needs to be resumed without doing multiple PET scans. This is particularly relevant for patients living in geographically remote areas, where they do not necessarily have ready access to PET scans. Another advantage is that BBMs can be monitored via blood tests by PCPs or other healthcare providers, and their interpretation does not necessarily require a neurologist.

The main difference is that donanemab can be paused after 12 to 18 months if an amyloid PET scan is negative, which is how its use was originally designed.⁵ Lecanemab is given every 2 weeks for 18 months, at which point a maintenance dosing schedule with monthly infusions can be initiated.⁷ As long as patients are followed, either treatment method is acceptable.

One reason that the ability to pause donanemab treatment may be useful is that people receiving biologics can develop their own neutralizing antibodies against the drug.^5,10 While we are not yet sure that this is occurring with donanemab or lecanemab, it could require patients to receive more drug to overcome the level of neutralizing antibodies that their bodies are producing.¹⁰ This topic is being studied now, and we currently do not have enough data or long-term data to know how often it is a problem, but it is a concern.¹¹ If it is occurring, the ability to pause donanemab could give a break in the monthly stimulation of the immune response that could be helpful.⁵

One problem with having patients identify themselves is that AD is often accompanied by loss of insight early on, and patients may not see their symptoms as a problem.¹⁴ For early diagnosis, it is important that family members and physicians be alert to the potential risk for older patients. If there seems to be an important change in memory, behavior, or the ability to navigate normal life, it needs to be brought to the attention of a physician so that screening tests can be performed. There are now some screening tests that individuals can perform on their own online, some of which have been validated, but that does not necessarily get you into the system to get a proper evaluation and treatment.¹⁵

In regard to BBMs, AD pathology begins maybe 20 years before symptoms present, so there is likely to be biomarker conversion prior to symptom onset.¹⁶ This could serve as an early warning, and it would not necessarily require seeing a neurologist. Any physician could order the test, so long as they understand the results and can explain them to the patient.

An important next step will be trying to get PCPs involved in qualifying patients and administering the therapies. Once the subcutaneous form of lecanemab becomes available, and with blood tests approved, there should be some early adopters among PCPs who are willing to get involved in this treatment process.^4,11 Many PCPs may not deal with a lot of infusion therapies, so they may not be used to dealing with the corresponding preauthorization and scheduling. Treating patients with donanemab or lecanemab does require monitoring for amyloid-related imaging abnormalities.^5,7 But in our experience, the side-effect rate has been much lower than we expected. When we started using these drugs, we were concerned it could be a major problem, and while surveillance is still required, it is not an enormous problem in practice by any means.¹⁷

In regard to uptake, there are many busy PCPs who may not be accustomed to getting deeply into discussions about AD with their patients on a regular basis. And while that was perhaps okay 10 years ago, when there were no DMTs available, I am hoping that everyone will start to embrace having these discussions. It should be a priority to actively recruit PCPs to be more proactive with qualifying and treating patients who have AD with DMTs.

It depends on what the data show, and it first has to be demonstrated that presymptomatic treatment is more effective than waiting for a patient to become symptomatic. There are also implications that would have to be considered. For example, if you are diagnosed with AD in some states, your driver’s license is automatically withdrawn.²⁰ Dealing with biomarker results and presymptomatic use requires considering and working through a lot of ethical and legal perspectives before actively beginning to treat in this way.

It is also unclear how insurers and employers are going to react to biomarker positivity. There have been similar concerns with APOE genotyping or any other genetic testing that may forecast a major illness. It has not arisen frequently, but it certainly has intimidated some patients for fear of someone finding out about biomarker or APOE status and discriminating against them or their children. We have a long way to go in demonstrating to patients and families that it is medically helpful, and we have to be sure it does not put them at any risk.

There are a number of important targets being pursued. It is important to find something to target inflammation. It is clear that we need to find some way to modulate the inflammatory response, and I think that will be different depending on the disease stage. As aggregates become larger, and they cannot be completely cleared by activating microglia, microglia still accumulate around plaques and can release cytokines and other inflammogens that can cause bystander damage to neurons and synapses.²¹ The major challenge is finding the right target and determining the right stage.

Tau is another important target in current research.²² For treatments targeting forms of amyloid and other toxic oligomers that we cannot readily detect, it will be important to identify biomarkers or other ways to measure their levels.

This Q&A was edited for clarity and length.