Anti-amyloid drugs have transformed the Alzheimer’s disease (AD) treatment landscape, marking the first time clinicians have had access to disease-modifying treatments. Yet their use is limited to a relatively small subset of patients with early symptomatic disease.

Beyond amyloid, researchers are pursuing a wide range of therapeutic targets, including tau pathology, neuroinflammation, immune dysfunction, metabolism, synaptic health, and vascular biology. This expanded focus reflects growing recognition that multiple biological pathways contribute to AD rather than a single pathologic process.

The change in the research trajectory is evident in the latest annual Alzheimer’s drug pipeline report, led by Jeffrey Cummings, MD, ScD, of the University of Nevada, Las Vegas, which shows that amyloid-targeting therapies now make up only about 20% of agents currently in clinical development.

“There really has been a fundamental shift in how the development of drugs is being targeted. We’ve really moved beyond an amyloid-centric approach to a more biological, precise, and diversified treatment landscape,” Laura Nisenbaum, PhD, executive director of drug development at the Alzheimer’s Drug Discovery Foundation in New York City, told Medscape Medical News.

“Amyloid is absolutely a component of the disease, but it’s not just about amyloid anymore, and it’s important to drive home that message,” said Rebecca Edelmayer, PhD, vice president of scientific engagement at the Alzheimer’s Association in Chicago.

Tau Takes Center Stage

While amyloid accumulation remains a defining hallmark of AD, many investigators believe tau may ultimately prove to be a more clinically relevant therapeutic target.

“Whereas many people have many amyloid plaques in their brain for decades prior to the onset of Alzheimer’s symptoms, soon after they begin to accumulate tau tangles, symptoms begin,” Adam Boxer, MD, PhD, principal investigator of the Alzheimer’s Tau Platform, told Medscape Medical News.

“Moreover, the severity and types of symptoms that people experience from AD are strongly correlated with the amount of tau that has accumulated in the brain and in which brain regions it accumulates,” added Boxer, endowed professor in memory and aging, Department of Neurology, Weill Institute of Neuroscience, University of California, San Francisco.

Boxer said the most promising tau-directed strategies fall into two broad categories: therapies that reduce tau production by lowering levels of tau messenger RNA, such as antisense oligonucleotides and small interfering RNAs, and immunotherapies designed to clear pathologic tau by targeting its microtubule-binding region, including monoclonal antibodies and therapeutic vaccines.

One of the most closely watched tau-targeted therapies is Biogen’s BIIB080 (diranersen), an antisense oligonucleotide designed to reduce tau production by silencing tau messenger RNA. The drug received Fast Track designation from the FDA last year.

Although topline results from the phase 2 trial did not meet its primary clinical endpoints, BIIB080 was associated with substantial reductions in tau biomarkers and signals suggestive of slower clinical decline in patients with early AD.

Bepranemab (UCB), a monoclonal antibody targeting tau, has also shown encouraging results. In the phase 2 TOGETHER trial, the drug reduced tau accumulation by 33% to 55% relative to placebo in patients with prodromal or mild AD.

Although the study did not meet its primary endpoint — a change in Clinical Dementia Rating Scale Sum of Boxes score at week 80 — in the overall study population, predefined subgroup analyses demonstrated consistent treatment benefits across multiple cognitive and functional outcomes.

Another hopeful anti-tau monoclonal antibody is Eisai’s etalanetug (E2814). It targets specific tau species containing microtubule binding region (MTBR) implicated in seeding and spreading of tau pathology. In Early testing in patients with autosomal dominant AD, there were significant and sustained reductions in MTBR-tau biomarkers in both cerebrospinal fluid (CSF) and plasma.

Etalanetug is currently under study in combination with the anti-amyloid lecanemab, reflecting growing interest in attacking multiple disease pathways simultaneously. Etalanetug also has FDA Fast Track designation.

Active immunotherapies designed to stimulate the immune system to clear pathologic tau before neurofibrillary tangles form are also in development. Among them, AADvac1 (Axon Neuroscience) has produced some of the most encouraging early efficacy signals.

In a phase 2 trial involving patients with biomarker-confirmed AD, the vaccine was associated with slower clinical and functional decline and significant reductions in neurofilament light, a biomarker of neurodegeneration.

Another promising candidate is JNJ-64042056, a tau-targeting vaccine based on AC Immune’s phosphorylated-tau vaccine platform and developed with Janssen. Early studies suggest the vaccine can safely generate a strong and sustained immune response against pathologic tau, though evidence of clinical efficacy remains limited. This therapy has also received FDA Fast Track designation.

The Rise of the Neuroimmune Axis

For years, inflammation was viewed primarily as a downstream consequence of neurodegeneration. Increasingly, however, evidence suggests neuroinflammation may actively contribute to AD progression.

“Inflammation is consistently present in the brain of Alzheimer’s patients, and reducing the inflammatory response promises to slow the disease process,” Cummings said in a statement.

Edelmayer told Medscape Medical News that therapies targeting the neuroimmune axis now make up one of the largest and fastest-growing segments of the AD drug pipeline. 

Activating TREM2, a receptor found on microglia — the brain’s resident immune cells — has emerged as a promising therapeutic strategy. VG-3927 (Vigil Neuroscience), a first-in-class oral TREM2 agonist, recently advanced to phase 2 testing after phase 1 studies showed favorable safety, strong brain penetration, and changes in CSF soluble TREM2 levels consistent with target engagement.

TNF, a potent inflammatory signaling molecule implicated in neurodegeneration, has also emerged as a promising therapeutic target. XPro1595 (pegipanermin; INmune Bio), a selective TNF inhibitor that neutralizes soluble TNF while preserving beneficial immune signaling, recently received FDA Fast Track designation for early AD.

Although the phase 2 MINDFuL trial failed to meet its primary endpoint in the overall study population, XPro1595 demonstrated signals of benefit in a biomarker-defined subgroup of patients with both amyloid pathology and elevated inflammation, along with a favorable safety profile.

Intranasal foralumab (Tiziana Life Sciences), a fully human anti-CD3 monoclonal antibody designed to induce regulatory T cells and suppress neuroinflammation, is under evaluation in phase 2 studies after early imaging data suggested it reduced microglial activation in patients with AD.

“We’re very excited about the potential of agents targeting inflammation to make a true impact in the Alzheimer’s and related dementia space,” said Nisenbaum.

The Metabolic Connection

Metabolism and insulin signaling have also emerged as important therapeutic targets. The concept of AD as “type 3 diabetes” stems from evidence that impaired glucose utilization and insulin resistance in the brain may contribute to neurodegeneration.

Most clinical attention has focused on GLP-1 receptor agonists such as semaglutide. A 2022 study examined data from trials of GLP-1s in nearly 16,000 patients with diabetes and showed that the drugs were associated with a 53% reduction in dementia risk.

That promising signal was the impetus for the EVOKE and EVOKE+ trials that explored whether the GLP-1 semaglutide could slow disease progression and cognitive decline in adults with early AD.

Although patients treated with semaglutide showed a 30% decrease in C-reactive protein and other markers of inflammation, these biomarker changes did not translate into significant cognitive or functional benefit. Nonetheless, research exploring metabolic pathways to potentially influence disease progression through anti-inflammatory effects continues. 

Other metabolic therapies under investigation include metformin, which is under study for its potential to improve insulin signaling in the brain, and benfotiamine, a synthetic derivative of vitamin B1 designed to correct abnormalities in brain glucose metabolism. Benfotiamine is currently being evaluated in a phase 2 trial involving more than 400 patients with early AD. 

This ongoing phase 2 trial builds on findings from earlier pilot studies, which showed that the drug was well tolerated and associated with favorable signals on cognitive and functional measures.

Keeping the Brain Connected

Beyond inflammation and metabolism, researchers are also targeting synaptic dysfunction, a hallmark of AD that is closely linked to cognitive decline.

Zervimesine (Cognition Therapeutics), an oral sigma-2 receptor modulator designed to displace toxic amyloid oligomers from neuronal synapses, demonstrated a favorable safety profile in the phase 2 SHINE study in patients with mild-to-moderate AD. Exploratory analyses suggested potential cognitive benefit in biomarker-selected patients.

Another synaptic-focused approach involves modulation of the sigma-1 receptor, which plays a role in cellular stress responses and neuronal survival.

Blarcamesine (Anavex), an oral sigma-1 receptor agonist designed to enhance cellular resilience and protein-clearance pathways, was associated with slower cognitive and functional decline in a phase 2b/3 study of patients with early AD.

Following Oncology’s Lead

As the Alzheimer’s therapeutic pipeline expands beyond amyloid, many researchers believe the future of treatment will mirror advances in oncology, where combination drug regimens target multiple disease pathways simultaneously.

Nisenbaum said that combination regimens tailored to individual biomarker profiles represent the long-term vision for AD treatment, much as multidrug approaches have transformed cancer care.

Edelmayer agreed, noting that the field is increasingly moving toward precision medicine and combination therapy. She said it is likely that similar approaches will eventually be used to treat Alzheimer’s and other types of dementia.

Such strategies could account for genetic risk factors, family history, coexisting health conditions, and biologic markers to determine which “cocktail or multi-pronged approach” would be most effective for a particular person, Edelmayer said.