Alzheimer’s treatment: What’s next beyond amyloid?

Alzheimer’s disease affects more than 55 million people worldwide — a number expected to nearly triple by 2050. Despite decades of research and billions invested, Alzheimer’s remains without a cure, and even treatments that slow its progression are rare.

The consequences are big, both human and economic. Alzheimer’s doesn’t just rob people of their memories — it gradually strips away independence, personality, and eventually life. The global cost of the disease is expected to reach $1.7 to $2.8 trillion by 2030.

For years, the main approach has been clearing amyloid plaques from the brain – a strategy that has produced underwhelming results. Now, the field is beginning to pivot.

A new wave of research is exploring different angles: tau tangles, inflammation, synaptic loss, and even genetic risk factors. Some are betting on cell therapies, others are looking at gene editing, or more personalized approaches. After decades of frustration, could the next generation of therapies finally change the storyline?

The long reign — and limits — of the amyloid hypothesis in Alzheimer’s disease

For decades, Alzheimer’s research has been guided by one central idea: that a buildup of amyloid beta in the brain is the root cause of the disease. Known as the amyloid hypothesis, this theory emerged in the 1980s after researchers identified amyloid plaques as a hallmark of Alzheimer’s pathology. Later, genetic studies strengthened the link, particularly in rare, early-onset forms of the disease. The logic seemed solid — target amyloid, and you might slow or even stop the disease. That promise shaped nearly every therapeutic strategy for years, but clinical reality didn’t really follow through.

Drug after drug failed to deliver significant cognitive improvements, despite effectively clearing amyloid. It became clear that amyloid accumulation might not be the whole story — or that, by the time amyloid builds up, it’s already too late to reverse the damage. 

The FDA’s approval of Biogen’s Aduhelm (aducanumab) in 2021 wasn’t the success story you would hope for. Indeed, right from the start, the approval was quite a controversy. While the amyloid-plaques-targeting antibody showed some plaque clearance, the cognitive data were mixed at best. 

Then came Leqembi in 2023. This second-generation amyloid-targeting antibody showed a modest but statistically significant slowing of cognitive decline in early-stage Alzheimer’s. It marked a step forward, but not a breakthrough.

These drugs showed that amyloid can be moved, but not that doing so is enough, quite the opposite. With safety concerns like brain swelling and bleeding still looming, many researchers now argue it’s time to look beyond amyloid. The field is shifting toward new strategies: targeting tau tangles, neuroinflammation, or even attempting to repair the brain through gene and cell therapy.

The amyloid hypothesis may not be dead, but it’s no longer the only path forward.

Tau protein, a new avenue in Alzheimer’s treatment

In healthy neurons, tau proteins stabilize microtubules that help transport nutrients and other materials within the cell. In Alzheimer’s disease, however, tau becomes hyperphosphorylated – it misfolds and detaches from microtubules. The result is the formation of neurofibrillary tangles, toxic aggregates that accumulate inside neurons and prevent them from accomplishing their natural functions.

Unlike amyloid plaques, which can be present in cognitively healthy individuals, the spread and density of tau tangles correlate more closely with cognitive decline. This makes tau protein more than an early biomarker, it’s a driver of disease progression.

Several therapeutic approaches are being explored to interfere with tau pathology. One strategy involves the use of monoclonal antibodies that bind to pathological forms of tau in the brain. These antibodies prevent the spread of tau from one neuron to another and help the immune system clear tau. Others are working on active immunotherapies, such as vaccines, that aim to stimulate the body’s immune response against abnormal tau proteins.

Beyond immunotherapy, small molecule drugs are being developed to modulate tau aggregation. Some of these compounds inhibit the enzymes – kinases, for instance – that cause tau to become hyperphosphorylated, while others seek to stabilize tau’s normal structure and prevent it from clumping in the first place.

A few companies are working on tau-focused candidates to get a first-in-class drug approved:

• AC Immune is developing ACI-35.030 in collaboration with Janssen Pharmaceuticals. It is a liposome-based vaccine designed to trigger an immune response against phosphorylated tau. The candidate is currently in a phase 2b trial.
• Eisai, already active in the amyloid space, is testing E2814, a monoclonal antibody that targets tau in early symptomatic Alzheimer’s patients. The antibody is being studied both as a standalone treatment and in combination with the company’s anti-amyloid drug lecanemab. It is currently in phase 2. 
• Biogen also has a tau-focused candidate in the pipeline, BIIB080, an antisense oligonucleotide currently in phase 2.
• Voyager Therapeutics is developing VY-TAU01, an anti-tau monoclonal antibody intended to inhibit the spread of pathological tau, currently in phase 1.

So far, no tau-targeting therapy has reached the market, and questions remain about how early these treatments must be given to be effective. Still, as understanding of tau biology deepens, the field sees this pathway as one of the most promising avenues beyond amyloid.

Gene therapy in Alzheimer’s disease, another promising approach

While most Alzheimer’s cases are considered sporadic, genetics still play a significant role, especially in determining risk. Among the genes associated with the disease, APOE stands out. Carrying one or two copies of the APOE4 variant increases the risk of developing late-onset Alzheimer’s and is linked to earlier symptom onset and faster disease progression.

Researchers have long known about this genetic risk factor, but only recently have they begun trying to change it.

Gene therapy approaches for Alzheimer’s aim to alter the expression or activity of genes like APOE4, or boost the presence of protective ones like APOE2. The most advanced strategies use adeno-associated viruses (AAVs) to deliver genetic material directly into the central nervous system. The goal is to either silence APOE4, correct its effects, or introduce APOE2.

While these approaches are still early in clinical development, they represent a shift toward intervening earlier, at the level of molecular risk itself.

Lexeo Therapeutics is currently leading the way with LX1001, an AAV-based gene therapy designed to deliver APOE2 into the brains of people who carry two copies of APOE4. In early clinical results, the therapy showed an increase in APOE2 levels in cerebrospinal fluid and encouraging biomarker responses, including reductions in tau-related pathology. 

More experimental approaches are in preclinical stages, including strategies to silence APOE4 expression using antisense oligonucleotides or CRISPR-based gene editing to correct the gene itself, though these remain years from the clinic.

Gene therapy shows clear potential in Alzheimer’s treatment, but whether it will deliver on its promise is still an open question.

Stem cell therapy for Alzheimer’s: Rebuilding the brain from within

In Alzheimer’s disease treatment, cell therapy aims to replace the neurons lost to the disease and help rebuild the brain’s damaged circuits.

This typically involves transplanting neurons derived from stem cells, with the hope that these cells can integrate into existing brain networks and restore some of the lost function. Several types of stem cells are being explored for Alzheimer’s disease.

Neural stem cells (NSCs), for example, have the natural ability to differentiate into various brain cell types — including neurons, astrocytes, and oligodendrocytes. In preclinical models of Alzheimer’s, NSC transplants have been shown to reduce amyloid and tau pathology, curb inflammation, and promote the growth of new synapses, all of which translated into improved behavior and memory in treated animals.

Mesenchymal stem cells (MSCs), often derived from bone marrow or umbilical cord tissue, are another option. They don’t become neurons directly, but secrete neurotrophic and anti-inflammatory factors that support the survival of existing brain cells and create a good environment for regeneration.

Induced pluripotent stem cells (iPSCs) offer a more personalized route. These are adult cells — often skin or blood cells — that have been reprogrammed back into a stem-cell-like state, meaning they can become any type of cell. 

Retro Biosciences is a promising company in this area. It is working on a potential treatment for Alzheimer’s that involves cell therapy to replace degraded brain cells. The company is backed by OpenAI’s chief executive officer (CEO) and promises to prolong human life up to 10 years. This, and the astounding $1 billion series A round the company recently completed, make it a player to follow closely in the Alzheimer’s space and beyond.

New technologies related to Alzheimer’s disease

Microglia and neuroinflammation in Alzheimer’s disease

Neuroinflammation is the activation of the brain’s innate immune system and it is increasingly recognized as a central component of the progression of Alzheimer’s disease. A particular immune cell of the central nervous system, called microglia, has been identified as a factor of neural damage when disregulated. 

Microglia are constantly surveying the neural environment to maintain homeostasis. In the context of Alzheimer’s, these cells become activated in response to accumulating amyloid-beta plaques and tau tangles. While their initial role is to protect, chronic microglial activation can lead to the release of pro-inflammatory cytokines and neurotoxic factors.

One key target is a receptor called TREM2, which is found on the surface of microglia. TREM2 helps regulate the cell’s ability to clear amyloid plaques and cellular waste. Genetic mutations that impair TREM2 function are associated with a higher risk of Alzheimer’s.

Another Alzheimer’s treatment strategy focuses on the NLRP3 inflammasome, a protein complex inside microglia that becomes activated in the presence of amyloid-beta. Once triggered, it drives the release of inflammatory cytokines, which exacerbate neurodegeneration. 

Companies experimenting with these approaches are starting to share promising data about their candidates:

• Vigil Neuroscience is advancing VG-3927, an oral small-molecule TREM2 agonist designed to enhance microglial function. In January 2025, the company reported positive data from its phase 1 clinical trial. VG-3927 was well-tolerated and achieved a significant reduction in soluble TREM2 levels in cerebrospinal fluid. 
• Coya Therapeutics is developing COYA 301, an experimental therapy aimed at enhancing regulatory T cell (Treg) function to suppress neuroinflammation. In October 2024, the company announced positive results from a mid-stage trial, showing that COYA 301 increased Treg levels and was safe. Participants also exhibited slight improvements in cognitive function and reductions in beta-amyloid levels.

Alzheimer’s treatment landscape, opening up to new solutions

After decades dominated by a single hypothesis, the field is finally embracing a broader range of approaches – from gene and cell therapies to inflammation-targeting drugs. And it seems investors are receptive to the emergence of diversified approaches.

The market for Alzheimer’s therapeutics, valued at just over $4 billion in 2022, is expected to quadruple by 2030. Eli Lilly, for instance, recently announced a $1.8 billion investment in production capacity for its Alzheimer’s and obesity treatments. 

At the same time, artificial intelligence (AI) is beginning to gain a foothold in the field. AI models are already being trained to detect Alzheimer’s from brain scans or speech patterns with remarkable accuracy. On the discovery side, platforms are being used to mine genomic and clinical data, helping identify new therapeutic targets that might otherwise go unnoticed.

It’s too soon to say which approach will lead to the next major breakthrough. But what’s clear is that the future of Alzheimer’s treatment will likely rest on combinations of strategies.

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