For most of the past two decades, working on a drug for Alzheimer’s disease meant getting comfortable with failure. A 2014 study of every Alzheimer’s clinical trial run between 2002 and 2012 found that 99.6% of drug candidates failed, significantly higher than the pharmaceutical industry’s overall clinical failure rate of roughly 89.6%.
Historically, the primary target for Alzheimer’s drug development has been amyloid-beta – the peptide responsible for the sticky protein plaques that accumulate in the brains of Alzheimer’s patients. The working hypothesis was that clearing the plaques would halt the disease. Yet, multiple clinical trials failed to show that removing these plaques translated into meaningful cognitive improvements for patients.
The infamous 2021 FDA approval of Biogen’s aducanumab (Aduhelm) ended a decades-long drought in Alzheimer’s treatments, but sparked widespread controversy over its limited clinical benefit, safety risks and the regulatory process – ultimately leading to its withdrawal in 2024.
Subsequent anti-amyloid therapies like lecanemab (Leqembi) and donanemab (Kisunla) followed – showing modest, incremental benefits in slowing decline, but the fundamental challenge remained. Monoclonal antibodies require frequent intravenous infusions, carry safety risks and act as a costly maintenance therapy rather than a definitive fix.
The search for more durable interventions has therefore expanded beyond amyloid clearance, fueling an interest in gene editing approaches. Instead of attempting to mop up toxic proteins after they have already accumulated and damaged neurons, researchers are turning to CRISPR to address the genetic basis for the disease.
Scientists are currently exploring several distinct strategies to leverage CRISPR against Alzheimer’s:
- Silencing high-risk alleles: The APOE4 gene variant is the strongest known genetic risk factor for late-onset Alzheimer’s disease, which makes up the majority of cases. 40% and 65% of Alzheimer’s patients carry at least one copy of APOE4 and researchers are testing CRISPR systems designed to silence the expression of this high-risk variant in the brain.
- Toggling the genetic switch: Another compelling avenue involves editing the APOE4 gene to convert it into the neutral APOE3 or the protective APOE2 variant. By using base editors – a highly precise iteration of CRISPR that changes single DNA letters without breaking the double helix – scientists have achieved successful in vivo proofs-of-concept, rewriting the genetic risk profile directly inside the brain tissue of model animals.
- Downregulating APP production: Other teams are using CRISPR to target the Amyloid Precursor Protein (APP) gene to reduce the production of the precursor protein itself, thereby stopping the cascade of plaque formation.
These are all preclinical studies, and significant hurdles remain before a CRISPR-based therapeutic for Alzheimer’s enters a human trial. Delivering CRISPR machinery safely across the blood-brain barrier and ensuring precise editing of target neurons are formidable challenges that will need to be overcome. While daunting, these obstacles are at the frontline of a broader paradigm shift. The industry is moving away from treating the downstream symptoms of chronic diseases and moving toward correcting the underlying genetic architecture.
As Alzheimer’s & Brain Awareness Month draws to a close, we are proud of the years we’ve spent working alongside the Alzheimer’s Association of Illinois, helping translate a field that has swung between despair and hope more than almost any other in medicine into something patients, caregivers and clinicians can actually use to make decisions.
A key piece of this work has been partnering on the “Your Brain Will Thank You” campaign – an initiative dedicated to putting risk reduction into the hands of Illinois communities. The face of the campaign is Sarabella, an anthropomorphic brain rocking a pair of sneakers, designed by our creative team to break down the complex science of cognitive health into approachable, daily habits. Efforts like this ensure that while researchers pave the way for future genetic breakthroughs, families have the tools they need to protect their brain health today.
