Alzheimer’s disease (AD) is a devastating condition that causes progressive memory loss and cognitive decline. For many years, research has focused on sticky clumps of amyloid protein, called plaques, which build up in the brain and damage neurons. But growing evidence, including Dr. David Holtzman’s inaugural Morby Prize-winning work, shows that the immune system also plays a critical role in driving the disease. T cells, the immune cells better known for fighting infections, can both protect the brain under healthy conditions and contribute to damage when things go wrong. In their previously funded CureAlz work, Dr. Kipnis and his team found that CD4⁺ T cells play a key role in supporting learning and memory. Building on this, they are exploring whether these same cells can be engineered to actively protect the brain in Alzheimer’s, helping to restore immune balance and preserve cognitive function, rather than targeting plaques directly.
The inspiration for this exciting possibility comes from cancer research. A revolutionary therapy known as CAR T-cell therapy has transformed cancer care by equipping T cells with special “chimeric antigen receptors” (CARs) that allow them to recognize and attack tumors. Dr. Kipnis’s team is pioneering the bold idea that CAR T cells be used not to kill, but to protect. By engineering CD4⁺ T cells, they aim to guide these immune cells to sites of Alzheimer’s damage, where the cells can activate other brain-resident immune cells, help clear plaques, and support neuronal survival. Their preliminary experiments testing this idea in a mouse model of Alzheimer’s are highly encouraging. The team hypothesizes that engineered CD4⁺ T cells, especially when paired with additional protective features, will promote the clearance of amyloid plaques, improve brain health, and slow or halt memory decline.
To test this hypothesis, Dr. Kipnis and colleagues have designed two aims. In the first aim, they will refine the engineered T cells developed in the preliminary work and test their ability to reduce plaque burden and improve cognition in mouse models. Importantly, they are not stopping at only targeting amyloid. Using advanced techniques, they will search for new targets that change in Alzheimer’s. By developing engineered T cells that recognize these targets, they hope to direct protective immune activity to broader disease sites and uncover an entirely new category of Alzheimer’s therapies. The second aim builds on this foundation by enhancing the therapeutic power of engineered T cells with a novel add-on.
Together, these studies will create a new class of neuroprotective T cells, engineered not only to find and target Alzheimer’s pathology but also to strengthen the brain’s own support systems. If successful, this approach could transform how we think about treating AD, offering a strategy that addresses multiple aspects of the pathology at once. Rather than only reducing plaques, it has the potential to rebalance the brain’s immune environment, protect neurons, and maintain cognitive function. For a disease as complex and devastating as Alzheimer’s, this multi-pronged approach may be exactly what is needed to achieve lasting progress.
