Dear Friends,
As summer comes to a close, I am delighted to share an update on our progress and achievements dedicated to advancing research in understanding Alzheimer’s disease (AD). Your support and dedication are instrumental in driving our mission forward, and it is with great pride that I highlight some key developments.

$200 MILLION IN RESEARCH DISTRIBUTIONS

This year we reached the significant milestone of $200 million in research grants distributed to leading scientists since our inception. Henry McCance, Co-Founder and Chair of Cure Alzheimer’s Fund, commented, “CureAlz was founded with one mission: to fund research that will accelerate prevention, treatment and a cure for this disease. Since the beginning, our approach has attracted others to join us in this fight, all who have been vital to what we have achieved. It has been an honor to deploy more than $200 million dollars in funding that is enabling and accelerating extraordinary research pursued by brilliant and determined scientists around the world.”

RESEARCH INITIATIVES

In 2024, as always, CureAlz is stretching to find new ways to extend our impact across the research environment. This year’s annual in-person meeting of our Research Leadership Group (RLG) expanded to a second day and included members of each of our specialty consortia. Researchers had more time together to hear about one another’s work and to find new reasons and opportunities for collaboration. The role of the immune system continues to be a high priority, with new data pointing to peripheral immune involvement and the need to modulate the brain’s immune response, not simply turn it on or off. The many moments during which researchers from diverse projects recognized common immune themes worthy of exploring together reminded us why this meeting is so important.

Epitomizing the spirit of the vigorous yet collegial scientific debate of the RLG, CureAlz awarded the first Jeffrey L. Morby Prize, named for our Founder to honor his vision and passion for science. This award was presented to Drs. David Holtzman and Xiaoying Chen of Washington University School of Medicine in St. Louis in recognition of their groundbreaking paper on T-cell infiltration and impact in response to tau pathology.

As of July 31, 2024, the Research team had funded 55 grants, bringing our total year-to-date distributions to more than $12 million. These grants cover a wide array of scientific topics—but there are notable research trends. For example, uncovering the roles that peripheral immune cells play in maintaining brain health or contributing to Alzheimer’s disease is increasingly seen as a vitally important topic requiring diverse expertise, innovative thinking and coordinated efforts. We are funding several new independent research projects in this area as well as two ongoing consortia (Neuroimmune and Brain Entry and Exit). These projects and teams are exploring how peripheral immune cells, like T-cells, signal and communicate with immune cells inside the brain and how they move across the brain’s barriers. While the field actively seeks answers to these critical “basic science” questions, some researchers already are moving quickly to test how early insights may be translated to potential new therapeutic approaches. We are supporting several of these accelerated efforts, including projects that will test whether manipulating aspects of T-cell biology will reduce Alzheimer’s-related inflammation and pathology in the brain. These specific projects are in early stages, but we are encouraged to see that 20% of currently active AD clinical trials are testing drugs that target neuroinflammation.

The proteins that make up the classic pathological hallmarks of Alzheimer’s disease—amyloid beta in plaques and tau in tangles—also continue to be targeted in the 2024 drug development pipeline. Each presents potential opportunities to intervene at early (amyloid) or middle (tau) stages to prevent or slow down clinical decline. Amyloid beta begins to aggregate and accumulate in the brain years before cognitive symptoms emerge. This “amyloid stage” precedes the accumulation of pathological forms of tau, which is then followed by neurodegeneration. While the field is making progress in understanding how amyloid and tau impact the functions of different brain cell types, what ultimately causes the loss of normal cognition still is unclear. Neurons communicating together in circuits are the foundation of memory and cognition, but the mechanisms by which Alzheimer’s pathology disrupts these circuits remains poorly understood. What is clear is that declining cognitive abilities correlate with the loss of synapses (the connections between neurons) and symptoms emerge concurrent with the time when tau tangles appear in brain regions outside of the hippocampus, making investigating the link between tau and synapse pathology a compelling objective. This year, we are excited to support research that reflects this growing awareness and that will dive deeper into a cellular and molecular level of understanding of how Alzheimer’s disease pathologies impact healthy brain circuit functions.

ALZHEIMER’S DISEASE DRUGS—KISUNLA AND LEQEMBI

The impact of the anti-amyloid immunotherapies on the patient population with the earliest signs of clinical Alzheimer’s disease continues to grow. However, the challenging risk/reward profiles of these drugs make their long-term outlook unclear. Although Eli Lilly’s Kisunla™ (previously known as donanemab) received U.S. Food and Drug Administration (FDA) approval for treatment of early symptomatic Alzheimer’s disease in early July, the European Medicines Agency rejected Eisai and Biogen’s lecanemab (marketed in the United States as Leqembi®) at the end of the month. Initial uptake of Leqembi after approval in the United States a year ago was slow, but Eisai reports sales now are increasing rapidly. However, it remains unclear whether clinician and patient concerns about efficacy and safety will keep market demand for these drugs low, or whether the slow adoption primarily has been due to challenges getting neurology appointments and readying medical centers to offer the therapy. New developments and real-world data will clarify the overall situation in the coming months, but it is clear the possible risks and benefits will look very different for different patients and to different doctors.

Kisunla and Leqembi work similarly, essentially tagging aggregates of amyloid beta to trigger the brain’s resident immune cells, microglia, to digest and clear them. Both are delivered currently via IV infusion and are expected to be available as subcutaneous injections in the next couple of years. These drugs do an excellent job of removing amyloid from the brain, but the topline results from their clinical trials only achieved approximately 25% to 35% slowing of cognitive decline over the trial period, not a halt or reversal. The critical question for patients and doctors is whether this magnitude of difference will be clinically meaningful for a given patient. Another way to consider this question is at what stage of ability or impairment would someone stay longer thanks to the drug, and how much longer would they stay at that stage?

In the Kisunla trial, those with low tau pathology and those who were younger achieved greater benefits, but the study was not designed or powered to generate conclusive findings on these criteria. The window of benefit is narrow for this class of drug because once amyloid pathology has triggered other aspects of the Alzheimer’s cascade, simply removing the original trigger cannot stop the ongoing downstream consequences. Whether amyloid beta will immediately begin to reaccumulate and/or whether clinical benefits will persist if Leqembi or Kisunla treatment is stopped is not yet known.

At $26,500 per year (medication cost alone), Leqembi is less expensive on an annual basis than is Kisunla, at $32,000 per year, but Kisunla’s clinical trial and now prescribing label allows physicians to consider whether to halt treatment once a PET scan indicates the patient’s brain amyloid level is subthreshold. In the Kisunla clinical trial of once-monthly infusions, 47% of treated participants were able to switch to a placebo at 6 or 12 months. In contrast, Leqembi is infused every two weeks and there is no validated treatment stoppage point, although maintenance infusions may be monthly eventually. Both drugs require extensive eligibility testing and ongoing safety and efficacy monitoring that will significantly add to the total cost and burden of treatment.

Although Medicare will cover some portion of the costs of treatment, it is not yet clear how much of the eligibility testing will be covered and what the patient’s co-pays will be for each aspect of the complex treatment regimen.

This class of drug is characterized by a small risk of potentially very serious side effects that is higher for people carrying one or two copies of the APOE4 gene variant. Most people in the trials had no side effects, but approximately 25% had some amount. For most of the people within that 25%, the side effects were asymptomatic, only recognized due to regular safety monitoring done by brain MRI. For a small percentage of people, however, brain swelling and bleeding can be catastrophic, and understanding who is at risk thus is vital to improving these drugs’ risk/reward ratio. CureAlz and others are funding projects trying to identify key patient characteristics, whether the drugs and their delivery mechanisms can be further optimized to improve safety, and what the role may be of a related co-morbidity, cerebral amyloid angiopathy, in which amyloid plaques form inside blood vessels.

PHASE THREE DRUG TRIAL—FORALUMAB

Although this class of drugs is not as effective, safe or accessible as we would like, we are heartened that early-stage patients now have two choices for drugs that change the course of this disease, and that a wide spectrum of other drugs with many other targets are in phase 2 and 3 clinical trials. We also are encouraged by the FDA’s increased flexibility with AD: using biomarkers as phase 3 trial endpoints for approval consideration, allowing nontraditional clinical trial structures and enabling alternative means of access, including its recent approval of compassionate use access to a drug for moderate Alzheimer’s disease, Foralumab. CureAlz has been funding research into whether this drug, originally developed for multiple sclerosis (MS), might beneficially modulate the neuroinflammatory response that causes damage in both diseases. Foralumab is now recruiting for two clinical trials, one for a form of MS and one for early AD.

THE UNFORTUNATE STORY OF CASSAVA SCIENCES

The other news I want to highlight is more discouraging. You may be aware of Cassava Sciences, whose sole products are a drug, simufilam, and a diagnostic blood test, SavaDx. The company’s core hypothesis is that when filamin-A changes its conformation, it triggers amyloid deposition, synaptic dysfunction and tau phosphorylation. The hypothesis is essentially unique to the company and its scientific founders, and the underlying science long has been challenged by the rest of the field as unable to be replicated by other labs and as inconsistent with other scientific data. In recent years, scientific sleuths and financial whistleblowers have accused the early publications supporting Cassava’s hypothesis of image manipulation, and Cassava’s clinical trials have been assailed for failing to follow generally accepted practices for statistical and scientific integrity. Recently, the lead scientist on the studies that led to the development of simufilam and SavaDx, Dr. Hoau-Yan Wang, was indicted by a federal grand jury for falsifying data to fraudulently obtain NIH grants on his own and on the company’s behalf. Although Cassava points out that
Dr. Wang had no part in designing the ongoing phase 3 clinical trial of simufilam, the data he allegedly falsified is the foundation of what justified the trial at all. The company’s board then announced the U.S. Department of Justice and the U.S. Securities and Exchange Commission had launched an investigation into two senior executives; Cassava’s CEO and SVP of Neuroscience both resigned shortly thereafter.

While the moral of this story may be that scientific bad actors do eventually get caught, the costs—to the trial participants and their caregivers, to the better scientific possibilities that lost out in funding and attention as Cassava made its loud public claims, to taxpayers and investors and their trust in the scientific community—are immense. Thanks to thoughtful input from our RLG, CureAlz never joined the Cassava bandwagon, but this incident reminds us to be just as aggressive in our smart skepticism about innovative and unexpected ideas and approaches as we are enthusiastic about recruiting them.

OUR OPERATIONS

CureAlz exists to fund research to end the burden of Alzheimer’s disease; the importance of the science we support deserves an organization similarly dedicated to excellence and impact. Thanks to our Foundation Funders, the CureAlz team has had a highly productive year.

Our 2023 Annual Report rose to the challenge of our record-breaking year with redesigned content and a reconceived, multimedia format. If you have not yet seen it, I hope you will take a look in the About Us section of our website, through the URL https://curealz.org/about-us/2023-results/.

Our Development team and I have been enjoying outreach opportunities across the country. We are deeply grateful to the wonderful CureAlz community members who have shared their stories with us and invited us to share CureAlz’s story and research with friends and families who share our mission. Your trust in us inspires us.

Part of living up to that trust is maintaining the highest possible standards of financial management and transparency. I am very proud to share that CureAlz once again had a clean audit from our external accounting firm and already has filed and published our 990; while reading our tax forms is admittedly less exciting than reading the amazing science in our Annual Report, I invite you to read it.

Finally, the stories we hear from you are powerful reminders for us that our work is urgent. Our CureAlz staff works hard but only some of us get to meet you and hear your stories. To spread this inspiration across our entire team, CureAlz launched a Volunteer Time Off program this year. Employees can choose to spend up to four hours of paid time volunteering with individuals experiencing cognitive decline.

IN CONCLUSION

We are excited by our progress this year in our research, operations and outreach, and enter the important fall season energized to build on this momentum. Our exceptional and passionate researchers turn to CureAlz for support of their unconventional ideas that lead to new and extraordinary contributions to the understanding of the disease. We are deeply grateful to the generosity of all of our donors for making these leaps forward possible, and excited to see the new research discoveries vital for future prevention and treatment of Alzheimer’s disease.

Gratefully,

Meg Smith
Chief Executive Officer