Alzheimer’s Breakthroughs Beyond Amyloid: A New Era of Treatment on the Horizon

Alzheimer’s disease, a condition affecting over 55 million people worldwide, continues to challenge scientists and healthcare systems alike. Despite years of research and billions of dollars invested, a cure remains elusive. With global cases projected to nearly triple by 2050, the pressure to develop effective therapies has never been greater. The economic toll is staggering, with costs expected to climb to between $1.7 and $2.8 trillion by 2030.

For decades, the dominant theory guiding research has been the amyloid hypothesis—the idea that the accumulation of amyloid beta plaques in the brain is the root cause of Alzheimer’s. This focus led to the development of several amyloid-clearing drugs, but many failed to show substantial cognitive benefits. As a result, researchers are now broadening their focus, exploring alternative pathways including tau tangles, inflammation, synaptic damage, and even genetic risk modification.

The Rise and Fall of Amyloid-Centric Therapies:

The amyloid hypothesis emerged in the 1980s, when researchers identified amyloid beta as a major component of plaques in Alzheimer’s patients’ brains. It gained traction with genetic findings and shaped drug development for decades. The first real breakthrough came in 2021, when the FDA granted accelerated approval to aducanumab (Aduhelm). Though it removed amyloid plaques, the treatment’s cognitive benefits were limited and its approval sparked controversy.

In 2023, lecanemab (Leqembi) received traditional FDA approval after showing modest slowing of cognitive decline in early-stage patients. A year later, donanemab (Kisunla) also gained approval. Despite these advances, the underlying issue persisted: removing amyloid doesn’t necessarily reverse the damage already done.

Tau Tangles Take Center Stage:

Unlike amyloid, tau tangles inside neurons closely correlate with the severity of cognitive decline. These misfolded proteins disrupt normal cell function and are now viewed as a major contributor to disease progression. Several approaches are being tested to target tau pathology, including monoclonal antibodies and small molecules designed to prevent its aggregation.

Promising candidates include:

ACI-35.030 by AC Immune and Janssen, a tau-targeting vaccine currently in a Phase 2b trial.

E2814 by Eisai, being tested alone and alongside lecanemab in Phase 2 trials.

BIIB080 from Biogen, an antisense oligonucleotide targeting tau, also in Phase 2.

Voyager Therapeutics’ VY7523 and VY1706, both anti-tau antibodies, are under early development.

While no tau-based therapies have yet been approved, they represent one of the most promising frontiers in Alzheimer’s research.

Gene Therapy: Tackling Alzheimer’s at the Source

Genetics plays a critical role in Alzheimer’s, particularly the APOE4 variant, which significantly raises disease risk. Recent advances aim to modify this risk at the genetic level using adeno-associated viruses (AAVs) to deliver corrective or protective genes to the brain.

Lexeo Therapeutics leads the charge with LX1001, designed to introduce the protective APOE2 gene into APOE4 carriers. Early results show increased APOE2 levels and reductions in tau markers. Meanwhile, preclinical studies are exploring CRISPR-based editing and gene-silencing techniques.

Stem Cells: Rebuilding Damaged Brains:

Stem cell therapy offers another promising route by attempting to replace neurons lost to Alzheimer’s. Researchers are experimenting with:

Neural stem cells (NSCs), which can become various brain cells and reduce pathology in animal models.

Mesenchymal stem cells (MSCs), which secrete supportive factors rather than becoming neurons themselves.

Induced pluripotent stem cells (iPSCs), offering a personalized approach to regeneration.

Retro Biosciences, backed by the CEO of OpenAI, is exploring stem cell therapies to replace degenerating brain cells and potentially extend human lifespan by up to 10 years. The company is currently raising a $1 billion Series A round.

Targeting Inflammation and Immune Dysfunction:

Increasing attention is being paid to the role of inflammation, particularly the brain’s immune cells—microglia. These cells, while protective initially, can become harmful when chronically activated.

Key targets include:

TREM2, a receptor on microglia linked to amyloid clearance. Vigil Neuroscience’s VG-3927, a TREM2 agonist, showed encouraging early trial data in January 2025.

NLRP3 inflammasome, a key driver of inflammation triggered by amyloid.

COYA 301 from Coya Therapeutics enhances regulatory T cells to dampen neuroinflammation and showed promising cognitive and biomarker results in late 2024.

A More Holistic Future:

After years of single-minded focus on amyloid, the Alzheimer’s field is finally opening to a diverse array of strategies. The therapeutic market, valued at $4 billion in 2022, is expected to quadruple by 2030. Major players like Eli Lilly are investing heavily, and artificial intelligence is beginning to play a role in early diagnosis and drug discovery.

It’s still unclear which approach will deliver a breakthrough, but one thing is certain: the future of Alzheimer’s treatment will likely involve a blend of therapies, addressing the disease from multiple angles—and offering new hope to millions around the world.

Source :https://www.labiotech.eu/in-depth/alzheimer-treatment/

This is non-financial/medical advice and made using AI so could be wrong