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 researchers 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 known as amyloid plaques and tau tangles accumulate in the brain, which are widely believed to cause cognitive decline. But not everyone with these hallmarks has symptoms — a phenomenon known as resilience. in 2022 Henne Holstege at Amsterdam University Medical Center in the Netherlands and her colleagues found that some centenarians maintain good cognitive abilities despite these plaques and tangles.

Now she and her colleagues have conducted another studies to better understand why this is so. The team analyzed the brains of 190 deceased individuals, 88 of whom had been diagnosed with Alzheimer’s disease and 53 of whom showed no signs of the condition when they died, aged between 50 and 99. The remaining 49 participants were centenarians who did not have Alzheimer’s disease or any other type of dementia, although 18 had shown signs of cognitive impairment a year earlier.

The researchers focused on an area of ​​the brain called the middle temporal gyrus, which is one of the first areas where amyloid plaques and tau tangles co-occur in Alzheimer’s disease. They found that a group of 18 centenarians—eight of whom showed no cognitive impairment—had amyloid plaque levels 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 the accumulation of tau is key to Alzheimer’s resistance, Holstege says.

However, amyloid plaques are still associated with cognitive decline. Holstege believes this is because they set the stage for tau to build up in the brain, causing the symptoms of Alzheimer’s disease. However, it is possible to have amyloid plaques and never develop significant tau tangles. “Without amyloid, we don’t see the spread of tau,” he says.

The researchers found further evidence of this when they examined nearly 3,500 proteins in the group’s brains. Only five of these proteins were significantly associated with the amount of amyloid plaques, but nearly 670 were associated with the amount of tau balls. 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 with tau everything changes,” says Holstege.

When the researchers looked at tau in 18 centenarians with increased amyloid plaques, they found that 13 of them had substantial tau expansion, with tangles appearing throughout the middle temporal gyrus. Although this spreading pattern resembles that seen in Alzheimer’s disease, the total amount of tau remained low in these individuals.

This difference is crucial, says Holstege. Alzheimer’s disease is diagnosed in part based on how widely tau has spread in the brain, but these findings suggest that cognitive decline is driven by the accumulation of tau, not its spread. “We should really understand that proliferation doesn’t necessarily mean abundance,” says Holstege.

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

Consistent with a previous study, the team found that tau spreads, but does not accumulate, in the brains of people with Alzheimer’s resistance. It’s not clear how this might happen, but Prater believes part of the answer may lie in microglia. These are immune cells that specialize in the brain and play a key role in regulating inflammation – which is rampant in Alzheimer’s disease – maintaining neurons and removing debris, including plaques and tangles.

Previous research shows microglia become dysfunctional in Alzheimer’s diseasepotentially 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 her colleagues also genetically analyzed the microglia of their cohort, specifically those in the dorsolateral prefrontal cortex. This area of ​​the brain is critical for managing complex tasks such as planning, decision making, and problem solving. It also shrinks and worsens in Alzheimer’s disease.

The researchers found that microglia from resistant 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 carry these instructions to where the proteins are made. Activity along these genes in resistant individuals was comparable to that seen in people without Alzheimer’s disease, suggesting that this is one of the processes that goes wrong in the condition.

“If this process is interrupted, we know it’s really bad for the cells,” says Prater, who presented the findings at the meeting Society for Neuroscience last year in San Diego, California. But we don’t yet know how this might relate to Alzheimer’s resistance, he says.

Microglia from resistant individuals also showed reduced activity in genes involved in energy metabolism compared to genes in Alzheimer’s disease. This activity was similar to that seen in people without the disease, suggesting 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.

“Both of these studies suggest that the human brain has ways to reduce tau burden,” says Prater. Understanding how it does this could lead to new treatments that could prevent Alzheimer’s disease, rather than just slowing its onset and progression. “We’re certainly not close to a cure yet, but I think biology is showing us that there is hope [and] there is promise,” he says.

topics:

• brain/
• Alzheimer’s disease