C2N Diagnostics’ Alzheimer's blood test was introduced into the clinic in October of 2020, a breakthrough healthcare innovation for patients, advocates, and physicians who have long awaited an easy to administer test that can help them better understand Alzheimer’s disease. C2N developed this groundbreaking test based upon longtime GHR partner Dr. Randall Bateman’s initial discovery of how to measure amyloid proteins in blood, validating its results in a clinical trial of 686 patients. 

From C2N Diagnostics: ​

"C2N Diagnostics, a leader in advanced brain health diagnostics, today announced the release of the PrecivityAD2 blood test, a clinical care assay that meets the standard of care with currently available PET scans and cerebrospinal fluid tests. This blood test is designed to alleviate the bottleneck and unmet needs of healthcare providers and patients in evaluating patients with signs and symptoms of Alzheimer’s disease (AD) and other causes of cognitive decline. 

'We believe the PrecivityAD2 test represents the next generation in blood biomarker tests and will help establish a new standard in Alzheimer’s disease diagnosis. The 2022 Clinical Trials on Alzheimer’s Disease Task Force report outlined that combined biomarkers can be especially helpful in avoiding misdiagnosis, and PrecivityAD2 does just that by harnessing two established biomarkers in one assay. We believe the test addresses a major unmet need for an accurate, safe, non-invasive, and accessible alternative to amyloid PET scans and lumbar punctures,' says Dr. Joel Braunstein, C2N’s president and CEO. 'This announcement is timely with the approval of new disease modifying therapies and others on the way along with the ability for healthcare providers to more easily refer patients to sites or to mobile phlebotomists where their blood can be drawn for diagnosis.'"

Read the full press release here. 

The A4 Study was the first large-scale clinical trial testing an Alzheimer’s prevention strategy in the general population. It aimed to slow cognitive decline in older persons who were not cognitively impaired but had elevated amyloid levels and were thus at high risk for cognitive decline. The A4 Study tested whether solanezumab, an anti-amyloid drug, could slow the progression of Alzheimer's disease-related cognitive decline. 
 
Solanezumab did not slow cognitive decline as compared to placebo. Additional learnings from the trial will continue to be shared as future analyses are completed, including results from the companion study - LEARN. 

Read the published results of the A4 study in the New England Journal of Medicine. 
 
Background on the A4 Study 
The A4 Study is a landmark public-private partnership, funded by the National Institute on Aging (part of National Institutes of Health), Eli Lilly and Company, Alzheimer's Association, GHR Foundation, Foundation for the National Institutes of Health, and several other organizations and donors. The A4 Study is coordinated by the Alzheimer's Therapeutic Research Institute (ATRI) at the Keck School of Medicine of University of Southern California and is a project of the Alzheimer's Clinical Trials Consortium (ACTC).

"Treating Alzheimer’s patients as early as possible — when symptoms and brain pathology are mildest — provides a better chance of slowing cognitive decline, a large study of an experimental Alzheimer’s drug presented Monday suggests. The study of 1,736 patients reported that the drug, donanemab, made by Eli Lilly, can modestly slow the progression of memory and thinking problems in early stages of Alzheimer’s, and that the slowing was greatest for early-stage patients when they had less of a protein that creates tangles in the brain."

Read more. 

From The Washington Post: 

"Since being diagnosed five years ago with Alzheimer’s, Jay has felt desperate, sometimes panicky, about his fate. But now, he sees a sliver of hope: a new drug called Leqembi. It’s not a cure and does not restore memories destroyed by the fatal neurodegenerative disease. But the medication modestly slows progression of the condition, even as it raises significant safety and cost issues that are generating intense controversy.

The test Reinstein is undergoing on this day could help him get the drug. “I want more time to spend with my five grandchildren,” he said.

Leqembi, in a clinical trial, slowed cognitive decline by 27 percent over 18 months compared with a placebo. That represented a five-month delay in progression — dismissed as negligible by some but hailed as a milestone by others for a malady that has been largely untreatable. On Thursday, the Food and Drug Administration granted full approval to Leqembi — the first time such a clearance has been granted to a therapy that changes the course of the disease. Other Alzheimer’s drugs treat symptoms, and often not very well. The FDA action means Medicare, the federal health program for older Americans, will broadly cover the drug, according to Medicare officials."

Read more. 

L: Dr. Randall Bateman updates Board and leadership on therapy research at Washington University’s Bateman Lab. R: GHR and C2N Diagnostics teams reviewed groundbreaking blood tests at the BioSTL innovations building.

Members of GHR’s Board and executive leadership traveled to St. Louis, Missouri for visits with key Biomedical partners at The Washington University School of Medicine and C2N Diagnostics. The trip provided a unique opportunity for the GHR team to gain a deeper understanding of the groundbreaking research supported by the Alzheimer’s Initiative, and to build relationships with leading scientists behind recent and significant breakthroughs.

Beginning with a focus on GHR’s support for prevention trials in the genetic early-onset population, the trip commenced with a visit to the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) at the Washington University School of Medicine in St. Louis. There, Dr. Bateman and team shared progress underway with the DIAN Network, which supports families with genetic mutations that cause them to develop early-onset Alzheimer’s Disease. The group had the opportunity to hear from a dedicated DIAN participant, who shared their personal story and journey with the DIAN team at WashU. The group then toured the Bateman Lab at the Tracy Family SILQ Center where researchers are using basic science to develop novel therapies for Alzheimer’s and other dementias.

This was followed by a visit to the offices of C2N Diagnostics, the company established to bring new diagnostic inventions to patients. Offering an overview of groundbreaking diagnostics development, the visit included a tour of the C2N lab and progress updates from the C2N team.
​
Thanks to these committed researchers and study participants, our shared goal of preventing Alzheimer’s Disease is within reach.

From Nature:

"AD pathology should be targeted before the onset of dementia. Research has shown that AD develops in the course of 20–30 years10,11. By the time AD manifests as dementia, the brain can no longer be rescued. This provides a huge window of opportunity for preventive action. To optimally employ these possibilities, we need a paradigm shift with a focus on (1) individual characteristics and preferences and (2) the stages before dementia to ultimately (3) prevent progression to dementia. Effective deployment of preventive strategies requires timely identification of individuals who would benefit the most. Further development of diagnostic tests to detect early AD pathophysiological changes, also capturing differences in pathological pathways between patients, is therefore warranted. Individual preferences and patient-reported outcomes should be the starting point for high-quality individualized care."

​Read more. 

A recent article in The Wall Street Journal detailed the work of GHR partner C2N Diagnostics and the Alzheimer’s Drug Discovery Foundation, along with the groundbreaking research of C2N co-founder, Dr. Randall Bateman.

From The Wall Street Journal:

"The new Alzheimer’s blood tests, meanwhile, are meant to help determine if memory loss and brain aging are due to early stages of the disease. These tests, available with a doctor’s prescription, include one from lab giant Quest Diagnostics Inc. and one developed at Washington University School of Medicine in St. Louis and licensed to C2N Diagnostics, a company founded by some researchers at the university. The tests have been shown to accurately assess whether amyloid plaques have started to accumulate in the brain based on the ratio of levels of two proteins in the blood. "

Read more.

From The Florida Times-Union:

"The Mayo Clinic in Jacksonville has received a $41 million federal grant for a potentially groundbreaking study to better understand Alzheimer's disease and how the brain disorder affects people of different ethnic groups.  The five-year grant from the National Institute on Aging, part of the National Institutes of Health, is one of the largest in the Jacksonville clinic's history. It will involve at least 80 researchers, from Mayo, Indiana University and 11 other U.S. institutions, and data from thousands of patients.

"Alzheimer's disease afflicts patients from African-American backgrounds at a rate twice as high as that in white populations. For Latino Americans, the risk is one-and-a-half times greater than that in white populations. These populations have traditionally been understudied for Alzheimer's disease, leading to a major knowledge gap. When we try to understand the molecular underpinnings, the disease fingerprints, we need to understand it for all of us to be able to identify biomarkers and therapies." Dr. Nilüfer Ertekin-Taner, a Mayo Clinic professor of neuroscience and neurology and physician-scientist who is a co-principal investigator of the study."

Through our support of this and other studies, GHR lives out its commitment to helping patients and families live full lives in a world where Alzheimer’s Disease becomes a preventable condition. GHR aims to halt Alzheimer's disease prior to the onset of cognitive symptoms by supporting new diagnostic tools and prevention trials. Learn more about our work on Alzheimer’s prevention.

GHR partners Eli Lilly and Brigham and Women's Hospital announced results from the A4 Study, a landmark in Alzheimer’s Disease research as the first large-scale clinical trial testing an Alzheimer’s prevention strategy in the general population. Unfortunately, A4 was not successful in preventing cognitive decline due to Alzheimer’s Disease. 

Funded by a public-private-philanthropic partnership involving the National Institutes of Aging (part of National Institutes of Health), Eli Lilly and Company, Alzheimer’s Association, GHR Foundation, Foundation for the National Institutes of Health, and several other organizations and donors, A4 was a massive ten-year undertaking. It involved dozens of research sites, hundreds of investigators, and thousands of patient volunteers. The study screened healthy adults aged 65-85 for the presence of amyloid plaques. Those with accumulated plaques were treated with Lilly’s anti-amyloid drug solanezumab. 

Although the study did not achieve its goal, A4 is providing key learnings for future prevention trials about how to identify patients at risk, when to intervene, and what level of treatment may be needed.

Read the full press release here.

From Eli Lilly and Company:

INDIANAPOLIS, March 8, 2023 /PRNewswire/ -- Eli Lilly and Company announced today that solanezumab did not slow the progression of cognitive decline due to Alzheimer's disease (AD) pathology when initiated in individuals with amyloid plaque but no clinical symptoms of the disease, known as the preclinical stage of AD1. Solanezumab only targets soluble amyloid beta. The treatment did not clear plaque or halt accumulation of amyloid in participants treated with the drug in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study.

"Results of the A4 Study clearly showed that the primary and secondary endpoints were not met. Therefore, the A4 Study concludes our clinical development of solanezumab and indicates that targeting soluble amyloid beta through this mechanism is not effective in this population," said John Sims, head of medical, global brand development – solanezumab, for Eli Lilly and Company. "While this study was negative, the unique data generated have increased our understanding of preclinical Alzheimer's disease and will advance the next generation of AD prevention studies. Raw data and analyses will be made widely available to researchers through the public-private partnership with the NIH-funded Alzheimer's Clinical Trial Consortium. These data will serve the scientific community and enable Lilly and other drug developers to enhance our clinical trial designs for other potential medicines targeting Alzheimer's disease."

Launched in 2013, the A4 Study was a first-of-its-kind secondary prevention trial, enrolling more than 1,100 individuals between 65 and 85 years of age who had PET-imaging evidence of amyloid plaque accumulation in the brain and who did not have clinical impairment. Participants were randomized to either solanezumab or placebo and then treated for approximately 4.5 years.

Solanezumab binds only to soluble amyloid-beta protein and was not expected to significantly remove deposited amyloid plaques. Donanemab and remternetug, other Lilly investigational antibodies currently being developed in Phase 3, are different from solanezumab in that they specifically target deposited amyloid plaque and have been shown to lead to plaque clearance in treated patients.

More than 6.5 million Americans are currently suffering dementia due to Alzheimer's disease2, and scientists expect this number to nearly triple by 20503. It is estimated that more than 20 million Americans and approximately 315 million people globally have preclinical Alzheimer's disease, the earliest stages of the disease 4, 5.

During the double-blind portion of the study, results showed:

• Solanezumab did not slow cognitive decline on the primary outcome measure, the Preclinical Alzheimer Cognitive Composite (PACC) [mean change (95% CI): placebo -1.4 (‑1.76, ‑1.04); solanezumab -1.69 (-2.13, -1.26); p-value 0.26)]. The PACC was developed to measure the aspects of cognitive decline relevant in preclinical AD and is an equally weighted composite that tests episodic memory, timed executive function, and global cognition.
• Secondary clinical outcome results were consistent with the primary outcome, numerically favoring placebo compared with solanezumab.
• 36.1% of participants starting at the stage of preclinical AD progressed on the Clinical Dementia Rating-Global Scale (defined as CDR-global score greater than 0 at two consecutive visits or final visit). CDR-GS is a clinician-rated scale that provides an overall assessment of the participant's clinical stage of AD. Similar rates of progression were seen with both the solanezumab and placebo groups.
• On amyloid PET imaging, amyloid continued to accumulate over time in both the placebo (65.9 Centiloid baseline, 17.5 Centiloid increase) and solanezumab (66.2 Centiloid baseline, 12.1 Centiloid increase) groups.
• Higher baseline amyloid levels were strongly associated with a greater risk of progression to symptomatic Alzheimer's disease (p-value<0.001). 
• The solanezumab and placebo groups were well-balanced at baseline, and results were consistent across multiple analysis methods and models.
• Safety results in the A4 Study were consistent with the safety profile observed in previous solanezumab Phase 3 studies. Amyloid-Related Imaging Abnormalities with edema/effusion (ARIA-E) were uncommon and similar between treatment and placebo groups.

"These findings indicate that amyloid is a key driver of cognitive decline at the preclinical stage of Alzheimer's disease. Solanezumab did not substantially impact amyloid plaque burden in the brain, and unfortunately did not slow cognitive decline. These data suggest that we may need to be more aggressive with amyloid removal even at this very early stage of disease," said Reisa Sperling, M.D., a neurologist at the Brigham and Women's Hospital, Harvard Medical School and the A4 Study project director. "We are so very grateful to the participants, their study partners, the clinical trial site investigators and staff, and the entire study team for their longstanding dedication to this important study. It is imperative that we learn everything we can to inform ongoing and future trials in our quest to prevent memory loss due to Alzheimer's disease."

The A4 Study is a landmark public-private partnership, funded by the National Institute on Aging (part of National Institutes of Health), Eli Lilly and Company, Alzheimer's Association, GHR Foundation, Foundation for the National Institutes of Health, and several other organizations and donors. The A4 Study is coordinated by the Alzheimer's Therapeutic Research Institute (ATRI) at the Keck School of Medicine of University of Southern California and is a project of the Alzheimer's Clinical Trials Consortium (ACTC).

Full disclosure of the study results will be shared later in the year at a scientific conference.

About the A4 Study 
The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study is a Phase 3, double-blind, placebo-controlled study in males and females ages 65 to 85 years with preclinical AD (that is, in individuals with evidence of brain amyloid pathology on PET amyloid imaging who are clinically unimpaired but at high risk for cognitive decline). 

The A4 Study tested whether solanezumab could slow the progression of Alzheimer's disease-related cognitive decline, brain imaging, and other biomarkers over the course of approximately 4.5 years. The study included more than 1,100 participants at 67 sites throughout the United States, Japan, Canada and Australia.