Experimental Alzheimer's drug that fights a tough-to-target protein shows promise at slowing cognitive decline in a clinical trial

 Is your competent? doctor closely following this? NO? So COMPLETELY FUCKING INCOMPETENT THEN?

Experimental Alzheimer's drug that fights a tough-to-target protein shows promise at slowing cognitive decline in a clinical trial

An experimental drug might slow early Alzheimer’s disease by targeting a hallmark of the illness that researchers have historically had less success with: toxic tangles of tau proteins inside the brain.

Accumulations of these tau tangles and sticky clumps of the protein amyloid beta are the neurodegenerative disease’s defining features. In recent years, two drugs that clear amyloid plaques have been approved by the Food and Drug Administration—the first new Alzheimer’s therapies in about two decades. Meanwhile, many experimental treatments targeting tau have failed, despite research suggesting that tau tangles are a stronger predictor than amyloid of brain deterioration.

Now, findings from a mid-stage clinical trial presented on July 14 at the Alzheimer’s Association International Conference in London could change that. Researchers revealed that an experimental anti-tau drug slowed cognitive decline at a level on par with the approved anti-amyloid drugs—although puzzlingly, that result came about in the treatment group that received the lowest dose. The work offers hope for the treatment of a disease that affects more than seven million Americans ages 65 and older, though a larger follow-up study will need to confirm the therapy’s benefits.

“This is really quite promising if it were to hold up” in further testing, says Jessica Langbaum, senior director of Alzheimer’s prevention and research at the Banner Alzheimer’s Institute who wasn’t involved in the trial, to Lauran Neergaard at the Associated Press.

The drug, called diranersen, was developed by Biogen, a Massachusetts-based biotech company. It works by attaching itself to genetic instructions for making tau, forcing the brain to produce less of the protein.  

Related video: Study challenges link between super-aging and Alzheimer’s risk genes (KYTX-TV Tyler-Longview)The recent trial involved more than 400 patients with early-stage Alzheimer’s split into four groups. One received 60 milligrams of diranersen every six months via injection into the spinal cord, one received 115 milligrams every six months, one received 115 milligrams every three months and one group received a placebo. They were tracked for 18 months and given several cognitive tests.

In all three treatment groups, the drug lowered tau levels in brain and spinal fluid by 50 to 65 percent compared to the participants’ starting baseline. Brain imaging of 131 participants also showed decreases in tau tangles relative to baseline across all doses.

But the drug defied one of the researchers’ main expectations: that cognitive outcomes would strengthen with dose. In the trial, the lowest-dose group experienced the greatest slowing of cognitive decline—by 26 percent in one test—and the smallest decrease in tau levels. The middle-dose group’s cognitive decline slowed by 14 percent based on that test, and the highest-dose group’s slowed by 9 percent.

While many outside experts welcome the findings, they highlight the deviation from the expected dose-dependent response. And some participants who received higher doses suffered from a state of confusion for up to one week following injection. That’s why the findings represent “a double, not a home run,” says Adam Boxer, a neurologist at the University of California, San Francisco who is working on a different anti-tau therapy, to Jennie Erin Smith at Science.

Rob Howard, a psychiatrist at University College London who wasn’t involved in the study, explains to R.J. Mackenzie at Science News that the counterintuitive cognitive results could be due to the study’s small cohort or the drug’s small effect sizes.

The size of change in cognitive scores was “pretty tiny,” and it’s unclear how it would translate to patients in the real world, he adds. “It’s the age-old question: Are these clinically meaningful differences?”

What’s more, the side effect of confusion was unexpected, Boxer tells Science. It may have happened because the drug affected something it wasn’t supposed to, but a more troubling possibility is that it’s related to lowering tau, he says. “Maybe we can’t knock down tau without some effects.” Biogen, for its part, notes that the confused state was temporary.

“This was a well-tolerated trial where people wanted to continue on treatment,” neurologist Cath Mummery of University College London said as she presented the study at the conference, reports Andrew Joseph at STAT.

The company now plans to test diranersen in a late-phase clinical trial to see how it fares with a larger group of participants. And perhaps it could one day be tested in conjunction with amyloid-targeting drugs, Heather Snyder, a neuroscientist and senior vice president of medical and scientific relations at the Alzheimer’s Association, tells Science News. She notes that other trials are studying combinations of different anti-tau and anti-amyloid drugs.   

“We are seeing the entire movement of thinking about these different targets and how [we can] start putting tau together with amyloid,” Snyder says.

This article was originally published on Smithsonian Magazine. Read the full story here: Experimental Alzheimer's Drug That Fights a Tough-to-Target Protein Shows Promise at Slowing Cognitive Decline in a Clinical Trial © 2026 Smithsonian Institution.

AAIC: Biogen bolsters hopes for Alzheimer's pivotal push as anti-tau oligo slows cognitive decline

 You might need this, will your competent? doctor be ready?

Your risk of dementia, has your doctor told you of this?  Your doctor is responsible for preventing this! Is s/he willing to prevent this?

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

AAIC: Biogen bolsters hopes for Alzheimer's pivotal push as anti-tau oligo slows cognitive decline

Biogen's leading tau-targeting candidate has slowed cognitive decline across a suite of different clinical assessments, backing up the pharma’s decision to race the molecule into phase 3 development. In a closely watched presentation at the Alzheimer’s Association International Conference in London, Biogen shared results from the phase 2 Celia study of diranersen, an antisense oligonucleotide that blocks the production of tau by binding to its precursor mRNA. Tau is one of two proteins that become deformed and clumped in Alzheimer’s, with the other, amyloid beta, already successfully targeted by Biogen’s Leqembi and Eli Lilly’s Kisunla. The most drastic slowing of decline was seen in the 60 patients who had 60 mg of diranersen infused into their spinal fluid every six months, the lowest dose level tested in the trial. This strong showing by the low dose is why the trial previously failed its primary endpoint, which was based on a dose-dependent response to the drug. At the 18-month mark, patients in the 60 mg group topped placebo with 26% less decline on the Clinical Dementia Rating Sum of Boxes test, 42% on the cognitive subscale of the Alzheimer's Disease Assessment Scale and 50% on the Mini Mental State Examination questionnaire. These patients also showed 30% and 23% less decline, respectively, on two different measures that combine scores from these tests—the modified Integrated Alzheimer’s Disease Rating Scale and the Alzheimer's Disease Composite Score. Biogen’s head of Alzheimer’s clinical development Szofia Bullain, M.D., told Fierce in advance of the readout that it was “really reassuring” that the composite scores stack up to the individual tests.  “No matter how we look at this elephant, it always looks like an elephant,” Bullain said. However, diranersen was unable to demonstrate an improvement over placebo on a measure of daily functioning, a result that Bullain described as puzzling. “We have working hypotheses at this point,” Bullain said. “Maybe it's a function of time. We know it's a noisy endpoint, it's a care-partner reported endpoint—but we don't want to blame it on the endpoint.” Though the trial was not set up to compare diranersen with Leqembi and Kisunla, the experimental drug’s efficacy “was probably comparable to the existing drugs in some cases, maybe a little bit better on some metrics,” Lawren VandeVrede, M.D., Ph.D., a neurologist at the University of California, San Francisco and investigator in the Celia study, told Fierce. While VandeVrede cautioned that the results still need to be fully confirmed in phase 3, for diranersen developer Ionis Pharmaceuticals, the data are a vindication of the hypothesis that clearing tau tangles can hamper disease progression. “Given the quality of the data that we have to date, it is clear that modulating tau has a positive benefit on patients,” Holly Kordasiewicz, Ph.D., Ionis’ senior vice president of neurology research, told Fierce. Biogen and Ionis’ work on diranersen was powered by the duo’s previous successful collaboration on Biogen’s spinal muscular atrophy blockbuster Spinraza and Qalsody, a treatment for amyotrophic lateral sclerosis. Biogen secured the full license for diranersen from Ionis in 2019. The oligonucleotide “uses the same chemistry as our already proven technologies,” Kordasiewicz said. “Once you crack that code, then you can, at least for neuro, just run through all those targets and advance them.” Biogen plans to rapidly move diranersen into a phase 3 study, but Bullain told Fierce that despite the 60 mg dose’s phase 2 potency, the company hasn’t committed to a late-stage dose just yet. “This is too early to commit to one, but the 60 mg dose definitely distinguishes itself,” she said. 

A bright future

With the first generation of anti-amyloid antibodies on the market and next-gen molecules coming down the pike, tau always made sense to VandeVrede and other neurologists as the next logical focus for treating the devastating neurodegenerative disease. “The next target for me was always tau, the other protein that Dr. Alzheimer saw under the microscope,” VandeVrede said, referring to psychiatrist Alois Alzheimer’s 1906 description of amyloid plaques and tau tangles. But while amyloid plaques live outside of cells, tau tangles are found inside of neurons, making them difficult to reach. Previous antibody approaches have focused on tau as it moves between neurons, Kordasiewicz said, and so while they can stop tau from spreading, they can’t help clear it from the brain. Diranersen, on the other hand, blocks activity of the MAPT gene that codes for tau protein, preventing tau in all its forms from being created. With new tau production reduced, the brain can go to work clearing out the troublesome tangles, the Ionis neuro leader explained.

“Because you're not continuing to feed that pipeline, the natural homeostasis mechanisms can clear that existing tau pathology and lower those tau levels,” she said. “That's when you can start to see the benefits, which we've now seen in Celia.”

By targeting tau, diranersen also avoids the brain-bleeding side effect that has plagued Leqembi, Kisunla and Biogen’s defunct yet first-in-class Aduhelm.

But the experts Fierce spoke to don’t see diranersen, or any other tau-clearing drug, as a replacement for amyloid antibodies. Instead, all eyes are on the potential for combination therapies.

“I don't think it's like chicken or fish,” VandeVrede said. “I don't think you're choosing between two entrees here.”

“The response is incomplete with the amyloid targeting therapies, and the response seems to be predicated on the amount of tau that you have before you start the treatment,” the neurologist continued. While it remains to be seen how diranersen should be used in the clinic if it secures approval, VandeVrede is excited by the chance to attack Alzheimer’s through multiple pathways.

Kordasiewicz, too, finds the possibility of combinations enticing.

“In the future you very well could have amyloid beta antibodies [and] tau oligonucleotides working together to really combat both those key pathologies in the brains of these individuals,” she told Fierce.

For Biogen, though, right now is diranersen’s time to shine.

“We're laser-focused on diranersen as monotherapy,” Bullain told Fierce. “But of course, we understand we'll be launching into a world in which, hopefully, anti-amyloids are going to be the standard of care. So we are thinking about how to bring and maximize benefits to patients.”

While diranersen is the clear frontrunner, others are racing behind Biogen with tau-targeting candidates of their own. Voyager Therapeutics is using AAIC to share preclinical data for a small interfering RNA that is also meant to hinder MAPT mRNA, with plans to enter the clinic later this year. 

Meanwhile, Denali Therapeutics is going after both MAPT for tau as well as amyloid with molecules that can cross the blood-brain barrier by hitching onto iron receptors, building on the success of the recently approved Avlayah for Hunter syndrome. The biopharma’s CEO Ryan Watts, Ph.D., opened this year’s AAIC with a plenary address.