Alzheimer’s disease (AD) care has shifted from decision making based on phenotypic descriptions to decision making based on biomarker-confirmed diagnoses that enhance certainty and guide next steps. Amyloid-targeting antibody therapy can now complement symptomatic therapy for some patients. However, its real-world use remains selective, prompting the development of new targeted therapies.

When I think about the fundamental difference in diagnosing and treating AD between 5 years ago and now, I think about the fact that, until very recently, we would rely heavily on the phenotypic descriptions of our patients. What is the clinical presentation? What are the clinical and ancillary features? Then we would use an exclusionary approach to diagnose AD. This phenotypic approach was imprecise, as it did not include any biomarker confirmation.

Since then, important changes have occurred that have improved the diagnosis and treatment of AD. The first change was the strong move toward using biomarker confirmation for diagnosis. In 5 years, I went from not using any of the disease-specific biomarkers to using them frequently and in a stepwise approach. Specifically, I evaluate blood-based biomarkers as part of my initial consultation and then use amyloid positron emission tomography scans and cerebrospinal fluid measures as confirmatory analyses. In addition, APOE genotyping has gone from rarely being used to now being routinely used for risk stratification. These are profound changes.

Another change relates to our current focus on the potential for using disease-modifying therapy in AD vs our previous focus on using mainly symptomatic therapies. As of now, the main therapies we have are anti-amyloid therapies (AATs), which are monoclonal antibodies designed to identify and remove amyloid from the brain. AATs are great drugs, but they come with challenges. For example, they are niche drugs, so not everyone is getting them. Many patients either choose not to take them, do not have sufficient amyloid in their brain to warrant the treatment, have too many microhemorrhages on their baseline magnetic resonance imaging scan or are too impaired with AD beyond the mild stage to receive them, or are afraid of potential adverse events. Also, I am cautious about treating APOE4 homozygotes with AATs, as these patients have higher rates of adverse events. So, there are a lot of reasons people do not get disease-modifying therapy.

We have not done a good job to date targeting tau in AD, but we do have second-generation anti-tau monoclonal antibodies that may soon report out additional data. We are also looking at sigma-1 receptor agonists, which appear to demonstrate some good therapeutic signals. Another development that we are likely to see is treatments that target inflammation, particularly with regard to GLP-1. The protective anti-inflammatory effects of the GLP-1 inhibitor semaglutide are being studied in AD.

In the past, we used symptomatic treatments alone for AD, but now we use symptomatic drugs plus AATs, and, eventually, we will likely have other drugs. I believe that, in the future, AATs will become induction therapies with some low-dose maintenance. Five years from now, the multidrug cocktail regimen might look very different than it does today.