At the 12th annual Helen and Robert Appel Alzheimer's Disease Research Institute Symposium, scientists and clinicians shared their latest research which is advancing how Alzheimer's disease is diagnosed and treated. Held at Weill Cornell Medicine's Griffis Faculty Club, the symposium gave investigators and community members the opportunity to learn and ask questions about new directions in neurodegenerative research. Alzheimer's disease affects more than 7 million Americans, a number expected to increase to 13 million by 2050.
Helen and Robert Appel established the Institute in 2006, prompted to action when two close friends succumbed to the disease two decades ago. "We were determined to do whatever we could to make a dent in Alzheimer's research," said Helen Appel of her and her late husband Bob's commitment to helping find a cure. "We're going to have to come up with solutions to the problems, and we'll do it."
Indeed, the symposium convenes at a turning point for Alzheimer's disease, said Dr. Li Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell. There are two disease-modifying therapies available, and the FDA recently approved a blood test for Alzheimer's diagnosis. "This is a really huge deal—many more people can be tested earlier, and it's much more accessible to patients with early symptoms," said Dr. Gan, who is also the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases.
Research at the Appel Alzheimer's Disease Research Institute is seizing the momentum by integrating the fundamental discoveries with translational science to fast-track prevention and treatment for this devastating disease.
Every discovery we make brings us closer to changing lives. And today's symposium is a testament of this momentum."
Dr. Li Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell
New discoveries in disease mechanisms
In the last 20 years, human genetic studies have provided insights into the genes, such as APOE4, that increase the risk of developing Alzheimer's disease and the genes that may be protecting against disease, which are called resilience alleles. Dr. Gan presented her research which is untangling the underlying genetic factors impacting the chances of getting Alzheimer's.
She is looking at how abnormal forms of the protein tau accumulate to produce neurofibrillary tangles inside the brain cells of many affected by Alzheimer's and other neurodegenerative diseases. These tangles disrupt the cell's internal structure, hindering communication between neurons and contributing to cognitive decline. With high levels of amyloid, the protein that forms plaques and contributes to Alzheimer's, patients have a "very modest decline," while the combination of amyloid and tau results in a much steeper decline in cognitive function," she said. This difference suggests some people are resilient to the disease's effects.
She pinpointed a surprising culprit in the brain's innate immune system: a pathway meant to fight viruses. This process, centers around the cGAS gene, which appears to be overactive in Alzheimer's, increasing harmful inflammation in the brain. When researchers partially deleted this gene in laboratory models, memory and learning improved, even if tau tangles were already present.
This positive effect was observed with the resilience allele called Christchurch mutation on ApoE3—it protected against tau-induced c-GAS activation, lowering inflammation and improving synaptic density. Dr. Gan's team found that inhibiting c-GAS with a drug could replicate the effects of this resilience allele. "This gives us strong motivation that developing the inhibitor for humans is going to be beneficial," she said.
Dr. Manu Sharma, an associate professor of neuroscience at Weill Cornell Medicine, shared his research on how abnormal tau, can spread from neuron to neuron throughout the brain. His lab has found that tau aggregates can accumulate in lysosomes, membrane-bound compartments inside cells containing digestive enzymes that break down cellular waste before releasing it to the extracellular space outside. They went on to show that once tau was released into the extracellular space, the protein could then seed harmful clumps in neighboring cells.
Using neuronal cultures and preclinical mouse models, Dr. Sharma's team demonstrated that tau aggregates are released into the extracellular space through a process called lysosomal exocytosis, regulated by neuronal activity and cytosolic calcium. By inhibiting lysosomal exocytosis, Dr. Sharma was able to reduce the release of tau aggregates and slow down their spread.
Translating research to the clinic
The final speaker, Dr. Valina Dawson, a professor of neurology, neuroscience and physiology at Johns Hopkins University, discussed her findings on parathantos, a specialized "programmed" cell death pathway named for Thanatos, the ancient Greek god of death, as a key driver of nerve cell degradation seen in Parkinson's disease. This pathway involves a molecule called PAR, or Poly (ADP-ribose), which is elevated in patients with Alzheimer's and Parkinson's diseases. PAR can attach to DNA and repair breaks, but it also appears to trigger parathantos.
In Parkinson's, PAR accelerates aggregation of the protein α-synuclein into toxic Lewy bodies that disrupt cellular function. In Alzheimer's, PAR co-localizes with tau and promotes its aggregation. "When you look in cultured neurons, you see that PAR-tau causes pathologic tau formation in neurons more than just tau itself," she said.
These finding may open the door to a new therapeutic approach to neurodegeneration. Blocking PAR production by inhibiting the enzyme PARP, may slow or stop dangerous protein aggregation. Interestingly, when PARP is absent in mouse models of these diseases, there is a protective effect. If PARP inhibitors work in human Parkinson's disease patients as they have in mice, they could protect cells already affected by Parkinson's and slow the transmission of these harmful proteins.
Another promising direction is an experimental small-molecule drug called PAANIB-1 that is designed to protect neurons from parathantos-related cell death in Parkinson's by selectively blocking the activity of a protein called MIF (macrophage migration inhibitory factor). This drug and similar compounds are being developed for clinical trials. Inhibitors like PAANIB-1 may have therapeutic potential across a range of disorders where parthanatos-mediated cell death is a contributing factor.
During the closing panel, the conversation shifted to how lab discoveries could be translated to real-world treatments for people and their diseases. "That's what these scientists are doing, and I hope that message came across," noted panel moderator Dr. Matthew Fink, the chair of the Department of Neurology and Louis and Gertrude Feil Professor in Clinical Neurology at Weill Cornell. The discussion kept returning to a central point: new discoveries build on past efforts, expanding how Alzheimer's is treated today and potentially finding future cures.
"The researchers conducting the science are really keeping their heads high and working hard to make sure that the discoveries don't stop, that the clinical trials don't stop and that patients who need our care are going to get it," said Dr. Robert A. Harrington, Weill Cornell Medicine Stephen and Suzanne Weiss Dean and professor of medicine.
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