Major study reveals why Alzheimer’s patients forget their family, friends

Families often describe a sharp kind of heartbreak when a loved one with Alzheimer’s stops recognizing the people closest to them. New research offers a clearer picture of why this loss happens and points toward a possible way to slow it. The work centers on tiny protective webs in the brain that help stabilize memory. When these nets begin to fall apart, social memories fade long before other abilities slip away.

Inside the hippocampus sits a small region called CA2. It plays a key role in remembering people and social interactions. Neurons in this region are wrapped in thin mesh-like structures known as perineuronal nets. These nets include hyaluronan, link proteins, glycoproteins, and chondroitin sulfate proteoglycans such as aggrecan. They help steady synapses and support long-term memory, especially memories tied to people you know.

Researchers at the University of Virginia and their collaborators studied what happens to these nets in several mouse models of Alzheimer’s disease, including 5XFAD, J20, and 3XTg mice. They found that the nets weaken and eventually break apart as the disease progresses. In 5XFAD mice, the nets looked healthy at three months of age. By six months, they had thinned, and by nine and twelve months, they had almost vanished.

What made the finding more striking was that the neurons themselves were still in place. The backbone of the memory system remained, but the scaffolding that keeps those neurons functioning began to fall apart. Even more surprising, the CA2 region stayed free of the amyloid plaques that dominate most Alzheimer’s research. The nets were breaking down for another reason.

The loss of nets in CA2 matched the loss of social memory in the mice. Young 5XFAD mice behaved like healthy mice during a test where they meet another mouse several times. They normally show less interest after recognizing the familiar animal. By six months, that recognition vanished. The mice behaved the same toward familiar and unfamiliar animals, as if every encounter were brand new.

Their overall sociability stayed the same. Their movement also did not change. When tested with objects instead of other mice, they remembered the objects normally. Only social recognition failed, a close match to what many families see in the earliest stages of the disease.

To test whether the nets themselves cause the memory loss, researchers removed aggrecan, one of the main building blocks of the nets, directly from the CA2 region in healthy mice. Eight weeks later, these mice showed a steep drop in net staining along with a clear loss of social memory. They behaved like mice developing Alzheimer’s even though the rest of their brains were healthy.

The team then tried the opposite experiment. They used an enzyme to temporarily digest the nets in healthy mice. Five days after treatment, social memory collapsed. But once the nets began to regrow two weeks later, the memory returned. This rebound showed that the nets do not only support memory but can also help restore it.

To uncover why the nets degrade, scientists studied gene activity in the CA2 region across early and mid stages of the disease. At three months, memory-related pathways were already starting to decline. By seven months, immune pathways became highly active.

The most important discovery involved enzymes that break down the extracellular matrix. Several matrix metalloproteinases, especially MMP2 and MMP3, were strongly elevated. Other enzymes that remodel the nets, including several ADAM family proteases, also increased. Meanwhile, the genes needed to build nets remained unchanged. The balance had shifted toward destruction rather than repair.

The team then tested whether blocking the elevated enzymes could prevent the nets from falling apart. They used GM6001, a broad MMP inhibitor known to block the same enzymes identified in gene studies. Mice received the treatment daily starting at five months, just before the nets usually begin to weaken.

By six months, untreated Alzheimer’s mice again lost social memory. But the treated mice recognized familiar animals normally. Imaging confirmed that the nets in treated mice remained thicker and more stable.

In healthy mice, the drug did not change memory or net structure, which suggests that its protective effect was specific to the disease process. This finding hints at a new way to preserve memory by slowing the breakdown of the brain’s support system.

Harald Sontheimer, chair of neuroscience at UVA, said the results mark a major shift in understanding what drives memory loss. “Finding a structural change that explains a specific memory loss in Alzheimer’s is very exciting,” he said. “It is a completely new target, and we already have suitable drug candidates in hand.”

Graduate student Lata Chaunsali said the work brings hope that early intervention could slow or prevent the loss of social memory. “When we kept these brain structures safe early in life,” she said, “the mice suffering from this disease were better at remembering their social interactions.”

The breakdown of the nets seen in mice matches patterns in human Alzheimer’s, hinting that similar protections may work in people. More safety testing is needed before any treatment can be designed for humans, but the team says the results point toward a promising path.

Research findings are available online in the journal Alzheimer’s & Dementia.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.