The ADDF was well represented at this year’s Alzheimer’s Association International Conference (AAIC) by our own scientific staff and our funded researchers. Our team of neuroscientists attended virtually and shared some highlights from this year’s program, including updates in drug discovery and development, biomarkers to help get us there, and prevention and risk reduction.
ADDF-Funded Investigators Reflect our 360-Degree Commitment to Research
Researchers and clinicians alike know that the recently approved Aduhelm, at best, is just one part of the Alzheimer’s treatment puzzle. The ADDF-funded investigators whose work was featured at AAIC were a good representation of how widely we cast our net in pursuit of innovation that matters, including several phase 2 clinical trials. They presented data on novel and repurposed drugs targeting toxic proteins, brain metabolism, growth factors that help neurons thrive and more.
Progress with Phase 2 Trials
Dr. Sharon Rosenzweig-Lipson of AgeneBio presented baseline data on the patient population enrolled in the company’s HOPE4MCI trial testing AGB101, a novel extended-release formulation of levetiracetam, an FDA-approved anti-epileptic medication. HOPE4MCI is the first and only late-stage clinical trial targeting overactivity in the hippocampus, an area of the brain with a major role in learning and memory. Results are expected in 2023.
Dr. Paul Edison at Imperial College London presented data on a repurposed drug for diabetes that holds promise for reducing brain atrophy and loss of grey matter associated with Alzheimer’s disease. The drug liraglutide, an agonist of a hormone called GLP-1, affects how the brain uses energy in the form of glucose. Results from a 12-month phase 2b trial show there was a significant improvement in executive function, temporal lobe volume and total grey matter in the liraglutide-treated patients compared with placebo.
Dr. Ihab Hajjar at Emory University School of Medicine also presented data on a repurposed drug. The research shows that the antihypertensive medication candesartan may have disease-modifying effects in patients with Alzheimer’s disease and mild cognitive impairment. Treatment with candesartan for one year was safe and reduced brain amyloid accumulation compared to placebo. After one year, the candesartan group had significantly higher amyloid levels measured by a CSF biomarker compared to placebo, reflecting lower brain amyloid accumulation.
Novel Compounds in Development
Asceneuron reported on its novel compound, which inhibits the enzyme O-GlcNAcase, preventing the protein tau from becoming toxic. The ADDF announced a $2.2M investment earlier this year supporting the first testing of the drug in healthy volunteers.
Oligomerix is also testing a novel compound that works on tau proteins. In a departure from other tau-targeting drugs, this one works earlier in the cascade of events, disrupting tau’s ability to attach to itself in its first step toward creating hallmark tau tangles.
Biomarkers Front and Center
The sheer volume of talks discussing biomarkers for early detection of Alzheimer’s was “staggering,” in the words of one of my colleagues. While the jury may be out on the clinical impact of Aduhelm, there is no doubt that the use of the Amyvid PET scan biomarker in its phase 3 trials was pivotal, giving the FDA the data it needed for the drug’s approval.
Like aducanumab, lecanemab (also from Biogen and Eisai) and donanemab (from Eli Lilly) trials are using PET amyloid scans to track drugs’ effect on brain amyloid, but they are also adding new PET tau scans to track reduction in toxic tau protein leading to brain tangles. Biomarkers are improving new trial designs every day, but we need more biomarkers that measure activity of more drug targets.
ADDF-funded investigator and world-renowned expert in Alzheimer’s and related dementia biomarkers Henrik Zetterberg, M.D., presented a plenary talk on Monday. Dr. Zetterberg focused on blood and CSF biomarkers related to more recently identified protein targets (e.g., synuclein pathology) and inflammation (glial activation), in addition to the strides made in measuring amyloid, tau and neurofilament in the blood. He drove home the need for a staged biomarker testing approach to drive differential diagnosis and personalized treatment. The presentations made over the ensuing days showed just how far biomarker research has advanced.
Presentations touched on every biomarker modality—blood, spinal fluid, brain imaging, digital—and the many biological pathways implicated in Alzheimer’s disease. For example, new PET and MRI imaging scans are being validated for targets other than amyloid and tau. One new scan measures the density of brain synapses, one of the most consistent and important changes in the Alzheimer’s brain. Another focuses on tracking brain inflammation. These scans hold promise for giving researchers new tools to enroll patients with these pathologies into trials of drugs designed to treat them. Researchers are also zeroing in on ways to improve the sensitivity of specificity of biomarkers measuring specific toxic forms of tau.
AAIC also featured data on biomarker variability by population, meaning biomarker measurements will not be “one size fits all.” For example, amyloid blood level signaling in early Alzheimer’s may vary from one patient to the next based on sex, race, ethnicity, clinical and other factors. Researchers are also uncovering data showing that specific biomarkers may be valuable at different disease stages.
Prevention and Brain Health: Learning More About Lowering Risk
ADDF board member and dementia prevention expert, Dr. Miia Kivipelto presented a talk titled “Epidemiology and Risk Factors for Dementia Around the World: European Focus.” She highlighted the importance of prevention trials, including the FINGER studies and others in the World-Wide FINGERS network. She stressed the need for tailored interventions for people with specific “at risk” profiles—in other words, personalized care—that combines lifestyle and nutrition-based interventions with drug treatments.
New research presented at AAIC confirmed a connection between air pollution and risk of dementia, adding it to a list of modifiable risk factors like diet, exercise and education that contribute to Alzheimer’s risk. Presentations also focused on the “why” of these risk factors. Researchers are digging deeper into the mechanisms behind how they contribute to resilience against, or susceptibility to, cognitive decline.
ADDF-supported researcher, Dr. Hussein Yassine at the University of Southern California reviewed his group’s findings about the dietary supplement DHA, an omega-3 fatty acid found in fish. DHA treatment for 6 months was shown to preserve the thickness of the entorhinal cortex, a hub area in the brain for memory functions. The ADDF is co-funding Dr. Yassine’s PREVENTE4 trial, which is testing how DHA is delivered in the brain and whether delivery is decreased in APOE4 carriers. Dr. Yassine’s study is enrolling 320 participants to determine whether DHA leads to structural and functional changes in the brain that lead to improved cognitive outcomes. The trial encountered delays due to COVID-19, but results are expected in 2024.
Looking Ahead to Fall Scientific Forums
We are looking forward to learning more of the latest developments from our funded scientists at the ADDF’s virtual 22nd International Conference on Alzheimer’s Drug Discovery, Oct. 4-6. Also, the ADDF is excited this year to be a major sponsor at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) conference, to be held November 9-12, where we are hosting two important forums, a roundtable on value-generating exploratory trials in neurodegenerative dementias and a symposium focused on bringing repurposed drugs to market. We are very much looking forward to our presence and participation at both these scientific forums.