How come some people have no symptoms?

By Staff 10 Min Read

  • Researchers in the Netherlands have found a subgroup of individuals in a national brain bank whose brains had signs of Alzheimer’s disease but who never showed symptoms while alive.
  • This is a rare occurrence, some experts say, but it can happen since there can be decades between the first amyloid deposits in the brain that characterize the disease and the onset of symptoms.
  • So-called resilience to Alzheimer’s symptoms can develop thanks to genetics or lifestyle choices, but some studies have shown that cognitive-boosting activities can help offset those symptoms.

Researchers in the Netherlands, after studying data from more than 2,000 brains at the Netherlands Brain Bank, recently made a surprising discovery.

Their study — which appears in Acta Neuropathologica Communications — found that a subgroup of people had clear indications of Alzheimer’s disease in their brain tissue, but they showed no symptoms while they were alive.

Granted, they identified only 12 of these individuals from the available brain tissue with the necessary clinical information recorded. But it raised a number of questions about the disease itself and what makes a person resilient to it.

Dementia directly affects more than 55 million people worldwide, and up to 70% of those people have Alzheimer’s disease, which is characterized by a loss of brain cells associated with the toxic buildup of two proteins, amyloid and tau.

The most common symptoms of Alzheimer’s disease are: memory loss, cognitive deficits, problems with speaking, recognition, spatial awareness, reading, or writing, and significant changes in personality and behavior.

Since Alzheimer’s is progressive, these symptoms are usually mild at first and tend to become more severe over time.

The phenomenon of Alzheimer’s disease without symptoms is referred to as “resilience”.

In the resilient group, researchers observed that a type of brain cells called astrocytes — which they described in a press release as “garbage collectors” that play a protective role in the brain — seemed to produce more of an antioxidant called metallothionein.

Astrocytes can increase inflammation as they interact with microglia in the brain, but those pathways linked to Alzheimer’s seemed less active in the resilient group.

Researchers also found that a brain cell response that is supposed to remove any misfolded toxic proteins was relatively normal in the resilient group.

This so-called “unfolded protein response” is generally affected in Alzheimer’s patients. And there were signs that resilient individuals’ brain cells had more mitochondria than the cells of other Alzheimer’s patients, which meant energy production would have been stronger in the resilient group.

Genetics and lifestyle can have a role in this type of resilience, David Merrill, MD, PhD, geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, who was not involved in the study, told Medical News Today.

Cognitive reserve, which is the brain’s resilience to damage, plays a significant role. Additionally, genetic factors, lifestyle, and environmental influences can modulate the onset and severity of symptoms despite the underlying pathology,” Merrill said.

“The authors talk about changes in the function of neuronal support cells like astrocytes and microglia, or the component parts of neurons like energy producing mitochondria,” he added.

Yuko Hara, PhD, director of Aging and Alzheimer’s Prevention at the Alzheimer’s Drug Discovery Foundation (ADDF), who was also not involved in the study, told MNT that there can be a 20- to 30-year lag between the first signs of amyloid deposits in the brain and the onset of symptoms.

Hara explained that there are ways in which people can build up their cognitive reserve in time:

“Cognitive reserve is the capacity of the brain to resist the effects of age-related changes or disease-related pathology, such as beta-amyloid, that typically leads to a decline in cognitive function. Based on this phenomenon, the knowledge and experiences people gain throughout their lifetime allow them to better cope with pathologies like beta-amyloid and maintain cognitive function for longer. There are many things you can do to increase cognitive reserve: Take a class to learn something new, read books, learn a new language, learn how to play a musical instrument, or stimulate and challenge your brain in other ways.”

Merrill said that adult children or spouses of people with Alzheimer’s may come in for testing without symptoms, but in general, most clinic patients seek care when symptoms appear.

He explained that: “It’s not common to have patients without symptoms, be it Alzheimer’s disease or otherwise. That said, the earliest symptoms of [Alzheimer’s] can mimic normal aging, so many individuals come to answer that question: Is what’s happening normal or the beginnings of [Alzheimer’s disease]?“

“We see more of a continuum of symptoms rather than a categorical phenomenon of symptomatic versus not. In that way, it makes sense that brain donors without any symptoms whatsoever was rarely observed in the study,” Merrill added.

“Alzheimer’s pathology is seen in asymptomatic individuals, though that’s the exception not the rule in clinical practice. It aligns with emerging research that suggests Alzheimer’s disease can exist without overt cognitive symptoms, possibly due to cognitive reserve or compensatory mechanisms in the brain, which were reported on in the study.”

– David Merrill, MD, PhD

Hara said the markers of Alzheimer’s disease can begin quite early in life without the presence of typical symptoms. She pointed to a number of interesting studies of the phenomenon.

“There are many people with pathological markers of Alzheimer’s disease without Alzheimer’s symptoms. Beta-amyloid, the pathological marker of Alzheimer’s disease, can start to accumulate in the brain as early as in our 20s,“ she pointed out.

“Amyloid deposition in the brain starts decades before the onset of Alzheimer’s symptoms. One study found that 44% of 90-year-olds with good cognitive function had amyloid pathology,” Hara said.

“There are also examples of genetic mutations that confer protection against a genetic form of Alzheimer’s disease,“ she added.

However, she noted these appear to be rare occurrences:

“A study from 2019 reported that a woman carrying the presenilin 1 (PSEN1) mutation, a genetic cause of early-onset Alzheimer’s disease, did not develop dementia in her 40s as others with the mutation did. Instead, she only had mild memory impairment in her 70s. Researchers found that the woman had two copies of a rare mutation referred to as the APOE3 Christchurch mutation, which possibly made her resistant to the onset of Alzheimer’s symptoms by 30 years, despite having very high levels of beta-amyloid in the brain.”

While there are genetic factors that can determine a person’s vulnerability to developing Alzheimer’s disease, a 2020 report in The Lancet indicated that alcohol use, smoking, poor diet, a lack of education, lack of social interaction, and lack of exercise can all contribute to the disease’s progression.

Alongside this, research suggests that some lifestyle interventions that stimulate brain activity can help to either boost cognitive reserve or stave off some of the symptoms.

For example, a study published in Neurology in 2021 found that high levels of cognitive activity, such as reading, playing games like checkers and puzzles, and writing letters, can delay the onset of Alzheimer’s disease by 5 years among those aged 80 years and over.

Another study, published in 2022 in PNAS, found that more time spent in cognitively passive activities, such as watching TV, is linked to increased dementia risk, whereas more time spent in cognitively active tasks, such as using a computer, is linked to a reduced risk of dementia.

And a study from JAMA Network Open, published in July 2023, found that frequently engaging in brain-challenging activities, including journaling, playing chess, and solving crossword puzzles was associated with a lower risk of developing dementia among older adults.

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