Researchers working to unlock the secrets of Alzheimer's disease say they've been given a major clue that could help protect people at risk for this type of dementia.
A man who seemed fated to develop memory loss in his 40s or 50s, based on family history, kept normal function for decades longer than he should have. He seems to have been protected by a rare gene change that enhanced the function of a protein that helps nerve cells communicate.
Scientists say that understanding how this gene change defended his brain may help prevent Alzheimer's in other people.
The man is part of a large family in Antioquia, Colombia, with many members who have inherited a mutated gene called presenilin-1, or PSEN1. Carriers of PSEN1 are almost certain to develop Alzheimer's disease at a relatively young age.
The man, who had the PSEN1 mutation, did eventually develop memory and thinking problems. He was diagnosed with mild dementia at the age of 72, then experienced more memory decline and an infection. He died of pneumonia at age 74.
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Antioquia University's Neurobanco coordinator, Colombian doctor Carlos Villegas, dissects a brain section at the laboratory in Medellin, Antioquia department, Colombia in December 2014.
But by all indications, he should have had memory and thinking problems decades earlier. When doctors examined his brain after death, they found it loaded with beta amyloid and tau, two proteins that accumulate in the brains of people with Alzheimer's.
However, he had something working in his favor, too. A genetic analysis revealed that the man had a rare change in a gene that codes for a protein called reelin, which helps nerve cells communicate.
"In this case, it was very clear that this reelin variant makes reelin work better," said Dr. Joseph Arboleda-Velasquez, an associate professor of ophthalmology at Harvard University and lead author of a new study on the man.
"That gives us a huge insight," he said. "It makes it very obvious that just putting more reelin in the brain may actually help patients."
The study was published Monday in the journal Nature Medicine.
The enhanced reelin protein seemed to be protecting a very specific part of the man's brain, an area that sits behind the nose at the base of the brain called the entorhinal cortex.
"Another big insight from this case is, it seems like maybe you don't need this everywhere in the brain," Arboleda-Velasquez said.
The entorhinal cortex is particularly sensitive to aging and to Alzheimer's. It's an area of the brain that also sends and receives signals related to the sense of smell. Loss of smell is often a harbinger of brain changes that lead to memory and thinking difficulties.
"So when people have Alzheimer's, it starts in the entorhinal cortex, and then it spreads," Arboleda-Velasquez said.
This is the second time Arboleda-Velasquez and the team studying this extended family have found someone who defied their genetic odds.
In 2019, the scientists reported the case of a woman who should have developed early Alzheimer's but instead maintained her memory and thinking abilities until her 70s.
She carried two copies of a change in her APOE3 gene that was nicknamed the Christchurch mutation. It seems to have decreased the activity of the APOE3 protein. Like reelin, APOE is a signaling molecule that is known to play a role in shaping a person's risk for Alzheimer's.
And it turns out that there is a link between these two cases: The receptors on cells for reelin are the same receptors for APOE.
"So these two patients are pointing with like big arrows. They're telling us, 'Hey, these is the pathway. This is the pathway that is important for extreme protection against Alzheimer's,' " Arboleda-Velasquez said.
But the pathway may not be as protective for everyone. The sister of the man in the new study also shared the rare protective gene change, and it helped her, but not as much. According to her family, she began experiencing cognitive decline at age 58.
Arboleda-Velasquez said that may be because in women, the activity of the gene seems to drop off with age, so it doesn't make as much reelin protein. "They can have the variant, but they don't express it as much as men," he said.
The Harvard team says they're already working toward develop a therapy based on these findings.
Dr. Richard Isaacson, a preventive neurologist at Florida Atlantic University, says studies like this show us something important: "In certain cases, we can win a tug of war against our genes."
Does this mean a cure is around the corner? That remains to be seen.
"Can we use a study like this to transform care and improve care? I hope so. I wouldn't say that we're there just yet," said Isaacson, who was not involved with this research. "But I think this is this is an important study."
10 potential early signs of dementia
Memory loss that disrupts daily life
Forgetting recently learned information is one of the earliest signs of dementia. Name recall, as well as remembering important dates and events, becomes difficult for people in the early stages of dementia. Often they need to rely on memory aids, like wall calendars, sticky notes, digital reminders, or help from family members for things like taking medications at the correct time and arriving on the right date to appointments. Asking the same question several times or repeating stories is very common. While this sign is seen often in dementia, it is also a typical sign of aging as well as mild cognitive impairment, which can be, but is not always, an early warning indicator of Alzheimer’s disease. Memory loss may also be a sign of depression; B12 deficiency; kidney, brain, thyroid, or liver disorders; or a side effect of certain medications.
Challenges in planning or solving problems
An occasional mix-up while balancing a checkbook can be a common sign of aging. Losing track of monthly bills can be a more serious sign. An inability to concentrate or difficulty following a familiar recipe may warrant a doctor’s visit. Planning may become almost impossible for those in the earliest stages of dementia and indicates a deficit in executive functioning. Difficulties with problem-solving can also signal other health issues ranging from serious conditions like a brain tumor to less insidious conditions such as stress.
Difficulty completing familiar tasks at home, at work, or at leisure
Often in early dementia, the simplest tasks become increasingly difficult. While older people may have trouble with operating a computer or the settings on a television remote—and this can be a normal symptom of aging—those with dementia can’t perform daily tasks that were once a part of their routine. Getting dressed can become a major undertaking. The real difficulty actually comes with the sequence or order of doing things. Writing out the steps to tasks such as preparing a meal and leaving them in easily accessible places can be helpful.
Confusion with time or place
Often people in the early stages of dementia forget the time and even lose track of months and seasons. While many retired people may forget what day it is because they no longer go to work and live by a calendar, the sort of confusion surrounding time is much more severe in those with dementia. Losing track of where they are or how they got to certain places is common and should be investigated by a doctor. This type of confusion may be acute and occur suddenly or may happen over time. Those afflicted will often experience periods of confusion surrounding time and place and then revert to their old selves. Perception of time and time distortion are also issues for those struggling with dementia. They may believe they haven’t seen a loved one for months or years, when in fact it was only days ago.
Trouble understanding visual images and spatial relations
Difficulty understanding visual images and spatial relations can impact depth perception, which can cause an increased risk of falling and can make feeding and bathing more challenging. Driving difficulty due to problems with spatial relations is quite common, and navigating turns and changing lanes can become dangerous. Often people with dementia are forced to give up driving. Reading also becomes a problem, not only because of the visuospatial issues, but also due to an inability to understand words. A 2016 study of visuospatial skills in dementia patients found that those with certain types of dementia, including Alzheimer’s disease, dementia of Lewy bodies, and vascular dementia, performed poorly in comparison to controls when examining space and object perception. The study found that significant impairment of visuospatial functions occurs in the early stages of dementia and worsens as the disease progresses.
New problems with words in speaking or writing
While aging can cause an occasional problem with finding the right word, communication issues are much more significant in the early stages of dementia. Following conversations and finding the correct words for objects is difficult for those with dementia, and this early warning sign should be brought to a doctor’s attention. Aphasia, a type of language disorder, impacts communication including speech, writing, and language comprehension. According to the Mayo Clinic, “Primary progressive aphasia is a type of frontotemporal dementia.” Of course, there are other medical conditions that can cause language and communication issues including strokes, brain tumors, and brain injuries.
Misplacing things and losing the ability to retrace steps
Misplacing things could mean putting objects in strange places, like placing car keys in the microwave, and it is a common sign of dementia. Those struggling may also have difficulty in retracing their steps to find the things they’ve lost. This lack of ability to retrace steps differentiates this as a sign of dementia versus a normal sign of aging. It can be both dangerous and frustrating. As the disease progresses, the afflicted person may accuse others of stealing things that have been misplaced.
Decreased or poor judgment
During the early stages of dementia, decision-making is impacted and can cause poor judgment. People may spend money foolishly or have a hard time remembering to feed and walk a pet. They may also pay less attention to grooming and personal hygiene. Those struggling with dementia are especially susceptible to scams involving money. One poor decision should not be considered an indicator of dementia though. Instead, look for a pattern which might include things like constantly wearing summer dresses even though it’s winter, or walking in a busy area and not paying attention to traffic lights.
Withdrawal from work or social activities
Not wanting to participate in social activities once enjoyed, like golf or going to church, may be a sign of dementia. Because of an inability to follow conversations or participate in hobbies and comprehend them in a familiar way, things like watching a favorite sport or going to family dinners might become less enjoyable. This may cause people with dementia to withdraw. They may sleep more frequently or spend more time sitting in front of the television. Social withdrawal could also be a symptom of depression, anxiety, or post-traumatic stress disorder.
Changes in mood and personality
While being sad or experiencing a shift in mood can happen to almost anyone occasionally, mood and personality changes may be early indicators of serious health issues. These can include mental health conditions, hormonal changes, or substance abuse problems. When those with dementia experience these symptoms, they can manifest as fear, suspicion, and getting easily upset or becoming irritable over minor things. Things that never would have bothered them before often will now. They may also lose patience more quickly. The National Institute on Aging recommends doing several things to help navigate these changes in mood and personality, including having a daily routine and using humor when appropriate.
This story originally appeared on Neural Effects and was produced and distributed in partnership with Stacker Studio.
