Why people can have Alzheimer’s-related brain damage but no symptoms

Some people develop Alzheimer’s-related brain changes without experiencing symptoms of the disease, such as memory loss. We don’t know exactly why this happens, but two recent studies bring us closer to an answer, with scientists revealing that these people have unusual changes in their brains that may protect them from cognitive decline.

In Alzheimer’s disease, clumps of misfolded proteins, called amyloid plaques, and tangles of Tau protein build up in the brain, which is widely believed to cause cognitive decline. But not everyone with these characteristics shows symptoms – a phenomenon known as resilience. In 2022, Henne Holstege of the University Medical Center Amsterdam in the Netherlands and colleagues found that some centenarians retained good cognition despite these plaques and tangles.

Now she and her colleagues have conducted another study to better understand why. The team analyzed the brains of 190 deceased people, 88 of whom had been diagnosed with Alzheimer’s disease and 53 of whom had no signs of the disease at the time of their death, aged between 50 and 99 years old. The remaining 49 participants were centenarians who did not have Alzheimer’s disease or any other type of dementia, although 18 of them showed signs of cognitive impairment when tested the year before their death.

The researchers focused on a region of the brain called the middle temporal gyrus, which is one of the first areas where amyloid plaques and tau tangles co-appear in Alzheimer’s disease. They found that a group of 18 centenarians – eight of whom had no cognitive deficits – had levels of amyloid plaque comparable to those seen in people diagnosed with Alzheimer’s disease, but their tau levels were similar to those who died between the ages of 50 and 99 without the disease. This suggests that preventing tau buildup is critical to Alzheimer’s resilience, says Holstege.

However, amyloid plaques are still associated with cognitive decline. Holstege thinks this is because they paved the way for tau to build up in the brain, causing the symptoms of Alzheimer’s disease. Nonetheless, it is possible to have amyloid plaques and never develop significant tau tangles. “Without amyloid, we don’t see the Tau protein spreading,” she says.

The researchers found further evidence when they examined nearly 3,500 proteins in the group’s brains. Only five of these proteins were significantly associated with amyloid plaque abundance, but nearly 670 of them were associated with tau tangles abundance. Many of these 670 proteins play roles in cell growth, communication and metabolism, including the breakdown of waste products. “Some things change [in the brain] with amyloid, but everything changes with tau,” explains Holstege.

When the researchers focused on tau in the 18 centenarians with elevated amyloid plaques, they found that 13 of them had significant spread of tau, with tangles appearing throughout the middle temporal gyrus. Although this pattern of spread resembles that seen in Alzheimer’s disease, the overall amount of tau in these individuals remained low.

This distinction is crucial, believes Holstege. Alzheimer’s disease is diagnosed in part based on the extent to which tau protein has spread in the brain, but these findings suggest that it is the accumulation of tau protein, not its spread, that leads to cognitive decline. “We really need to understand that spread doesn’t necessarily mean abundance,” Holstege says.

In the second study, Katherine Prater of the University of Washington in Seattle and colleagues analyzed the brains of 33 deceased people: 10 had been diagnosed with Alzheimer’s disease, 10 had no signs of the disease, and 13 were considered resilient. Most of these individuals were over 80 years old at the time of their death, and all had undergone a cognitive assessment less than a year before their death.

Consistent with the previous study, the team found that Tau spread, but did not accumulate, in the brains of people with Alzheimer’s resilience. It’s unclear exactly how this might happen, but Prater thinks part of the answer might lie in microglia. These are specialized immune cells in the brain that play a crucial role in regulating inflammation – which is prevalent in Alzheimer’s disease – by maintaining neurons and clearing out debris, including plaques and tangles.

Previous research shows that microglia become dysfunctional in Alzheimer’s disease, potentially contributing to neurodegeneration. The team couldn’t analyze microglia “because they’re quite rare in the brain compared to other cells,” says Holstege. “But it’s clear they’re involved.”

Prater and colleagues also genetically analyzed microglia in their cohort, particularly those in the dorsolateral prefrontal cortex. This brain region is essential for handling complex tasks, such as planning, decision-making, and problem-solving. It also decreases and is altered in Alzheimer’s disease.

The researchers found that microglia from resilient individuals showed increased activity in genes involved in transporting messenger RNA, the genetic instructions for making proteins, compared to those from participants with Alzheimer’s disease. This suggests that cells actively transmit these instructions to where proteins are made. The activity of these genes in resilient individuals was comparable to that seen in people without Alzheimer’s disease, suggesting that this is one of the processes that goes wrong in this disease.

“If that process is disrupted, we know it’s really bad for the cells,” says Prater, who presented these findings at a meeting of the Society for Neuroscience in San Diego, California, last year. But we don’t yet know how this may relate to Alzheimer’s resilience, she says.

Microglia from resilient individuals also showed reduced activity in genes involved in energy metabolism, compared to those in Alzheimer’s disease. This activity is similar to that seen in people without the disease, indicating that microglia use more energy in Alzheimer’s disease, potentially because they are more inflammatory, Prater says. This makes sense given that brain inflammation disrupts connections between neurons and contributes to cell death.

“These two studies suggest that the human brain has ways to attenuate tau load,” says Prater. Understanding how it works could lead to new treatments that could prevent Alzheimer’s disease, rather than just slow its onset and progression. “We’re certainly not close to a cure yet, but I think the biology shows us there is hope [and] there’s a promise,” she says.