In a significant development, scientists have reported the first evidence suggesting that a biologic medication designed to eliminate sticky beta amyloid plaques from the brain may effectively postpone the onset of Alzheimer’s dementia in at-risk individuals.
Researchers have been evaluating amyloid-reducing treatments in a cohort of individuals carrying rare genetic mutations that predispose them to a near certainty of developing Alzheimer’s.
This study, while involving a limited number of participants, serves as an extension of a prior randomized-controlled trial. The initial trial had indicated no substantial advantages for individuals receiving amyloid-lowering therapies compared to a placebo. However, this extended study lacks a placebo control group and could be influenced by biases. Consequently, external experts advise interpreting the seemingly remarkable results with prudence.
This research is part of the Dominantly Inherited Alzheimer’s Network (DIAN) initiative. Study participants prefer a more distinctive moniker.
“We like to think of ourselves as the X-Men because we are mutants, endeavoring to rescue the world from Alzheimer’s disease,” stated Marty Reiswig from Denver, a participant in the trial since 2010.
The findings of the new study, published in Lancet Neurology on Wednesday, revealed that the risk of developing symptoms was halved in a small group of 22 patients. These patients, who exhibited no prior memory or cognitive issues, had been receiving an amyloid-lowering drug, gantenerumab, for approximately eight years. The results demonstrated statistical significance in certain analytical aspects but not others, leading to some confusion among external specialists.
Dr. Tara Spires-Jones, Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, who was not involved in the research, commented in a media statement: “While this study does not definitively prove the delay of Alzheimer’s disease onset, and involves a drug unlikely to become widely available, the scientific implications are encouraging.”
Study authors hypothesize that initiating therapy at an early stage and maintaining it for a sufficient duration could potentially impede disease progression, possibly for several years.
Dr. Eric McDade, neurology professor at Washington University in St. Louis and lead author of the study, stated that this is “the first data to intimate the potential for a considerable delay in symptom onset and progression.”
McDade emphasized that this study provides the most extended data for patients who commenced amyloid-lowering biologics before symptom manifestation.
“We believe there is a delay in the initial onset, possibly spanning years, and even among individuals displaying mild symptoms, the progression rate was reduced by approximately half,” he elaborated.
Despite the optimism surrounding this long-sought outcome, a sense of urgency also prevails.
The research team reports that National Institutes of Health grant funding review meetings have been postponed twice. Grant review is necessary before progressing to a council meeting for funding decisions. Missing the May council meeting could jeopardize funding for the study, which has been ongoing since 2008.
“This creates a genuinely precarious situation for us and the participants,” McDade noted.
Patients may lose access to study drugs, particularly in countries where the medications lack approval. Discontinued drug access could hinder researchers from determining the long-term benefits and answering crucial questions about medication efficacy across different individuals.
Maintaining the cohort with prolonged amyloid drug exposure is “absolutely vital,” McDade stressed.
Long-Term Alzheimer’s Studies Yield Promising Results
In the 1980s, investigations into post-mortem brains of Alzheimer’s patients revealed the presence of sticky plaques, formed from beta amyloid proteins, and toxic tangles of tau protein. This led to the theory that removing these proteins could slow or even reverse the disease, prompting a search for effective therapies.
For decades, numerous biologic medications targeting beta amyloid proteins have been tested, largely with underwhelming results.
In late-stage trials involving over 1,800 individuals with early Alzheimer’s, gantenerumab showed a slower symptom progression compared to placebo. However, the benefit was not statistically significant, suggesting the result could be due to chance. Consequently, it was deemed a failed drug.
Concurrently, two similar drugs, lecanemab (Leqembi) and donanemab (Kisunla), secured FDA approval for treating mild Alzheimer’s symptoms.
These therapies are costly and carry potential side effects like brain swelling. Clinical trials indicated only a modest delay in symptom progression compared to placebos, leading some doctors and patients to hesitate using them.
Researchers conducting the DIAN study on individuals with Alzheimer’s-predisposing gene mutations obtained FDA permission to continue gantenerumab treatment as long as possible. Upon discontinuation of gantenerumab, participants transitioned to lecanemab.
Sue, a Texas-based study participant, joined the gantenerumab arm in 2012. Her enrollment followed the discovery that she and three of her five siblings carried a gene mutation significantly increasing their risk of early-onset Alzheimer’s.
Out of six siblings, four, including Sue, have the mutation. One brother tested negative, and another remains untested but symptom-free. Two brothers and a sister developed symptoms around age 57. Sue, the youngest at 61, remains asymptomatic.
“I’m fine, completely fine,” Sue stated, requesting anonymity for family privacy regarding the mutation.
Her brothers, also trial participants but starting medication after symptom onset, showed less benefit.
Sue joined the study 13 years ago hoping to contribute to Alzheimer’s research. Since then, she has undergone 40 MRIs, 30 PET scans, and over a dozen lumbar punctures for spinal fluid collection.
Tests indicate normal brain function and cognition. She consistently achieves top scores in the New York Times Spelling Bee.
“Initially, my motivation was to advance science, but now, it’s personally beneficial,” she acknowledged. “I genuinely believe that.”
Sue believes the medication has delayed her disease by approximately four years, citing a familial pattern of symptom onset at a specific age, which she feels the drug has pushed back.
Witnessing her brothers’ cognitive decline prompted her to save aggressively and plan for early retirement. Currently, she continues part-time employment.
Hopeful Signs for Alzheimer’s Treatment
For the study, researchers enrolled DIAN members who were cognitively normal or mildly symptomatic, within a 15-year pre-diagnosis to 10-year post-diagnosis window, based on family history of symptom onset.
The initial study phase randomized participants to gantenerumab, solanezumab (another amyloid-lowering drug), or placebo, from late 2012 to early 2019.
Upon completion, participants could continue gantenerumab at escalating doses for three years, across 18 sites in seven countries. In 2023, Roche ceased gantenerumab development due to unfavorable trial results hindering FDA approval prospects.
The Wednesday report details findings from this extension study, involving 73 participants who remained on gantenerumab, aware of their medication.
Participants receiving gantenerumab, either throughout the entire study or solely during the extension, experienced a modest benefit, with about a 20% reduced risk of developing symptoms, though not statistically significant.
However, for 22 participants on gantenerumab longest (average eight years), the benefit was more pronounced and statistically significant, nearly halving their symptom risk compared to an observational study group.
Reiswig, like many relatives, carries a presenilin-2 gene mutation causing amyloid plaque overproduction. Family members with the mutation typically show Alzheimer’s symptoms between 47 and 50. Reiswig is 46.
“I’m facing it head-on,” he acknowledged.
His father, also a DIAN observational study participant, declined the drug trial believing he was too advanced in the disease. He died from Alzheimer’s in 2019 at 66.
“That’s old for our family,” Reiswig commented.
Reiswig avoided genetic testing for years, finally undergoing it in 2020. Upon learning he had the mutation, “I was devastated,” Reiswig recounted. “It was the worst day.”
However, he resolved to “get busy living,” uncertain about his quality of life post-47.
Reiswig initially participated in the solanezumab arm, transitioning to gantenerumab during the extension.
He remains asymptomatic but lacks certainty about the drug’s personal efficacy.
Marty Reiswig’s father, Lawrence, succumbed to Alzheimer’s at 66. “That’s considered old in our family,” Reiswig noted. – Courtesy Marty Reiswig
Further Alzheimer’s Research Imperative
Researchers external to the study acknowledge its preliminary nature and limited size, lacking placebo control, yet emphasize its importance.
Dr. Paul Aisen, Director of the Alzheimer’s Therapeutic Research Institute at USC, stated via email, “Considering our accumulated knowledge on amyloid removal efficacy in sporadic AD, these findings are promising.”
Aisen spearheaded a solanezumab trial in individuals with brain amyloid but no symptoms, which showed no benefit over placebo after four years.
He attributes his study’s negative outcome to using an earlier-generation drug with weaker amyloid removal capabilities than newer medications.
Aisen currently leads a lecanemab study in asymptomatic patients, anticipating results in 2028 or 2029 due to the extended treatment duration needed at this disease stage.
“Much more work is necessary, with significant ongoing studies,” he added.
Other experts find the latest research results challenging to interpret due to potential biases within the study group.
Dr. Michael Greicius, neurology and neurological sciences professor at Stanford University, not involved in the study, commented, “I don’t see a definitive indication of efficacy here.”
Greicius highlights difficulties in comparing the 22-person gantenerumab extension group with the observational study group. Extension participants were limited to those who completed the placebo-controlled trial, excluding phase 3 dropouts. This suggests extension participants were initially healthier and progressing better.
“These are significant caveats,” Greicius emphasized.
He acknowledges biomarker data indicating increased amyloid removal with higher drug dosages.
However, other biomarker data, like PET imaging of tau protein levels, shows less clear changes even after prolonged treatment.
Greicius suggests that if a real treatment effect exists, it’s likely not permanent. “Patients are still progressing, albeit slower than the control group.”
Despite considerable uncertainty associated with the data, Greicius argues for continued research prioritization.
“This is an invaluable study population,” he stated. “Continued treatment monitoring may offer the most robust assessment of the amyloid hypothesis, providing vital evidence either supporting or refuting it. Sustained funding should be a high priority.”
Reiswig expressed deep concern about potential study termination due to funding shortfalls.
“Personally, I’m terrified. Being withdrawn from a potentially life-saving drug and left to wait for symptoms to appear before accessing Kisunla or Leqembi is a frightening prospect,” he admitted.
He emphasizes the substantial contribution of DIAN participants to research and treatment development, highlighting the injustice of potential drug denial after their extensive involvement.
“Frankly, it feels like a betrayal,” he concluded. “We are on the cusp of preventing the world’s most devastating and costly disease.”
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