Researchers discover a genetic variant that protects against Alzheimer’s

Researchers Discover A Genetic Variant That Protects Against Alzheimer’s

Sometimes, a single outlier of a patient case might lead to the emergence of new research and the elucidation of disease-related facts.

Researchers frequently draw links between the issues and solutions when they find such a case, which can result in even more compelling and convincing theories regarding the root of the problem and the best course of action.

A multinational team led by Harvard Medical School investigators from Massachusetts General Hospital and Massachusetts Eye & Ear has accomplished this. Their combined research has identified a novel genetic variation that offers protection against Alzheimer’s.

Their research, published on May 11 in Nature Medicine, describes an instance of a patient with a hereditary propensity to acquire Alzheimer’s at a young age. The patient had a high risk of early onset, yet he didn’t develop any cognitive impairment until he was in his late 60s.

The genetic mutation from another person in the same family, whose case was published in 2019, appears in a different gene from the recently discovered variant. The novel variation, however, indicates a common disease pathway.

The findings also hint at an area of the brain that may be an effective therapeutic target in the future.

The ‘Paisa’ Mutation

The case that piqued the interest of the researchers included a family member of the world’s most well-known kindred with a genetic variant known as the ‘Paisa’ mutation.

Those who carry this variant experience mild cognitive impairment at an average age of 44, dementia at an average age of 49, and succumb to dementia-related problems in their 60s.

The neurosurgeon who discovered this family and has been monitoring them for the past 30 years is Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellin, Colombia, and a co-first author of the paper.

The same research team looked at a woman from the same family earlier who was cognitively normal into her 70s. They reported her case in 2019.

The researchers in the latest publication cited a case of a male Paisa mutation carrier who was cognitively normal until age 67. He developed moderate dementia at age 72 and passed away at age 74, which is decades later than the average Paisa mutation carrier.

According to Yakeel Quiroz, a senior co-author of the study, such unusual cases show how people with Alzheimer’s and their extended families can help enhance their understanding of the condition and pave the way for new research. She further stated that the knowledge they are gaining from this second example might help them establish new ideas about the sequence of events that may truly cause Alzheimer’s dementia and may direct them as to where in the brain they need to search to slow and stop disease progression.

Clinical evaluations by researchers at the University of Antioquia in Colombia, genetic and molecular studies at Mass Eye and Ear, Children’s Hospital Los Angeles, neuroimaging and biomarker studies at Mass General, and neuropathological studies by researchers at the University Medical Center Hamburg-Eppendorf in Germany were all part of the work.

What the researchers found in the Biomarker Study

The male patient was participating in the Mass General Colombia-Boston Biomarker Study (COLBOS), which invites 6,000 members of an extended family with the Paisa mutation to Boston for state-of-the-art neuroimaging, biomarker, and genetic testing.

Previously, the same study described a case where a female patient had two copies of the rare Christchurch genetic mutation, which affects the protein APOE3. This protein has a strong connection with Alzheimer’s. According to the researchers, the APOE Christchurch genetic mutation was absent in the male patient.

To find more variants that might have been shielding him against Alzheimer’s, the scientists carried out genetic and molecular tests at Mass Eye and Ear in partnership with Xiaowu Gai and associates from Children’s Hospital Los Angeles.

The newest and rarest variant Reelin gene—never reported before—was the most promising contender. They gave it the name Reelin-COLBOS.

The researchers further confirmed the protective impact of the Reelin-COLBOS variant in mouse models and neuropathological examinations in experiments directed by co-senior author Diego Sepulveda-Falla, a lead investigator at the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf.

According to Sepulveda-Falla, in the postmortem analysis, both the protected cases—the APOE Christchurch and the Reelin-COLBOS case—displayed different protection patterns, one universal and the other highly localized.

He further added that these remarkable cases indicate that there are many different ways that Alzheimer’s protection might manifest itself and that possibly a treatment can be effective even if it only focuses on certain crucial brain regions, like the entorhinal cortex.

They are making us rethink our preconceived notions about neurodegeneration and cognitive decline. We are living in exciting times, and perhaps so is the field of Alzheimer’s research.

How might the Reelin Gene act protective against Alzheimer’s?

According to the researchers, Reelin is a “cousin” of the more well-known APOE protein. Reelin and APOE fight with one another to bind to related cellular receptors, basically vying for the same seat.

Reelin reduces the activation of tau, a protein known to produce pathological tangles in the brains of people with Alzheimer’s. The opposite happens when APOE attaches to the receptor.

Reelin is a protein that is essential for controlling the growth and operation of brain cells. Earlier studies have connected Reelin mutations to conditions like bipolar disorder, schizophrenia, epilepsy, and autism.

Mutations linked to the disease usually reduce protein function; however, in the case of Reelin-COLBOS, the protective variant promotes protein function.

What should we understand?

According to the co-author Arboleda-Velasquez, the first case revealed a variant that affected APOE, while the second demonstrated a mutation that impacted Reelin. It indicates that this signaling pathway, which regulates the phosphorylation of tau, among other effects, may be crucial to understanding why these patients were protected. This observation is significant for guiding therapy because it indicates that additional Reelin could potentially have favorable effects.

The most recent patient experienced neuroimaging tests at Massachusetts General Hospital at 73. These scans showed that although the patient had a significant load of amyloid-beta plaques and displayed tau tangles in several brain regions, the entorhinal cortex had notably sparse pathology.

Memory and learning depend heavily on the entorhinal cortex, and its degradation is known to cause dementia and cognitive decline. The mice studies in this paper further revealed that the Reelin-COLBOS variation protected against tau pathology.

Precisely knowing which part of the brain should be the target for delivery will become more crucial as researchers work to develop gene therapies that deliver treatments that alter or change gene expression.

Many Alzheimer’s treatments, including newly authorized medications by the FDA and others ongoing in clinical studies, attempt to prevent amyloid plaque development.

New Treatment Options

Because the two individuals with almost intact cognitive function had brains with incredibly high amounts of amyloid but were nonetheless protected, the study’s findings offer new therapy options.

The researchers cautioned that they could not completely rule out the possibility that other variables, such as extra gene mutations, contributed to the patient’s resistance to Alzheimer’s symptoms.

However, their experimental data from preclinical investigations suggest that the Reelin-COLBOS variation is involved.

Additionally, they are investigating possible therapeutic approaches that would focus on this defense mechanism.
With the knowledge gained from each unique instance, Arboleda-Velasquez, Quiroz, Lopera, and Sepulveda-Falla intend to continue their search for further protected patients within these Colombian families.


  1. Lopera, F., Marino, C., Chandrahas, A.S. et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat Med (2023).
  2. Arboleda-Velasquez, J.F., Lopera, F., O’Hare, M. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med 25, 1680–1683 (2019).
  3. Haley, B. Newly Identified Genetic Variant Protects Against Alzheimer’s. Harvard Medical School. Published Online: 15th May 2023. Accessed: 17th May 2023.
  4. Sobey, R. Alzheimer’s groundbreaking research: Boston scientists discover genetic variant that protects against Alzheimer’s disease symptoms. Boston Herald. Published Online: 15th May 2023. Accessed: 17th May 2023.

Can Anxiety Lead to Alzheimer’s?

Can Anxiety Lead To Alzheimer’s

Everybody experiences anxiety from time to time. It results from the fear or the worry that something unpleasant will happen. Anxiety disorders, such as Generalized Anxiety Disorder (GAD), PTSD, panic disorder, agoraphobia, and social anxiety disorder, are characterized by excessive fear and anxiety that interfere with a person’s daily life. When feeling anxious, a person may experience physical changes such as increased heart rate, blood pressure, and perspiration.

These disorders are typical; about 30% of adults will experience them at some point in their lives [1]. An estimated 40 million individuals in the United States suffer from them annually [2]. However, as if these sensations of anxiety and fear weren’t enough to deal with, studies indicate that older people who experience worsening anxiety symptoms may be more susceptible to Alzheimer’s [3].

Why is anxiety seen as a risk factor for Alzheimer’s?

Anxiety is regarded as a risk factor for Alzheimer’s due to its effect on the brain. Researchers have discovered links between anxiety and the buildup of several toxic proteins in the brain and brain shrinkage, which can result in a decline in cognitive function.

According to a study, elevated levels of beta-amyloid, a toxic protein that builds up in the brains of those who have Alzheimer’s and causes plaques, are correlated with increased anxiety [3]. The researchers found that compared to other depressive symptoms, such as loss of interest or sadness, anxiety symptoms increased over time in those with elevated brain beta-amyloid levels.

Anxiety-related repetitive negative thinking can also increase the risk of Alzheimer’s. Repetitive negative thinking (RNT), according to a study by scientists at University College London, can cause cognitive deterioration and increased amyloid and tau protein deposition [4]. Even though depression and anxiety in middle age are already risk factors for dementia, there may be an underlying reason why those who suffer from these disorders are more likely to get dementia.

Is anxiety a cause or a symptom of cognitive impairment?

People frequently seek cognitive assessments due to personality changes, such as elevated anxiety. While anxiety may contribute to the development of Alzheimer’s, the stress of MCI (mild cognitive impairment) may also cause the symptoms to appear.

A study presented at the annual meeting of the Radiological Society of North America shows a link between anxiety and the faster progression of moderate cognitive impairment (MCI) to Alzheimer’s [5]. According to one of the authors, Dr. Maria Vittoria Spampinato, it is unclear if anxiety was a factor in the study that linked anxiety to cognitive impairment or if it was just a result of it.

The study indicated that MCI patients who experienced anxiety symptoms developed Alzheimer’s faster than those who did not, regardless of whether they had a genetic risk factor for Alzheimer’s or brain shrinkage.

What if you experience both anxiety and depression?

Many people across the world suffer from both depression and anxiety. According to estimates, 60% of people with anxiety also exhibit signs of depression [6]. When you have both of these symptoms, you increase your chances of acquiring dementia. According to a study published in the Journal of the American Academy of Neurology, anxiety can accelerate the onset of dementia symptoms by three years and depression by two years in persons who develop Alzheimer’s [7]. The disease onset may occur even more quickly for those who suffer from depression and anxiety.

The lead author, Dr. Zachary A. Miller, and his team speculated that the presentation of depression in some patients could indicate a higher burden of neuroinflammation. It is because participants in the study who had depression were more inclined to have an autoimmune disease, and those who had anxiety were more likely to have a history of seizures. Both of these may cause neuroinflammation, increasing the Alzheimer’s risk.

Previous studies have already investigated the relationship between anxiety and reduced brain volume. However, Miller’s team believes that anxiety will lead to increased “neuronal hyperexcitability,” or overstimulation of the brain’s networks.

Having both depression and anxiety increases your risk overall, whether it is due to brain shrinkage or overstimulation.

Do anti-anxiety medications cause cognitive decline?

While taking an anxiety medication can help people with negative symptoms like excess stress, some anxiety and insomnia medications may raise the risk of Alzheimer’s. The New England Journal of Medicine reports that Ativan, Xanax Valium, and other benzodiazepines may increase the chance of developing Alzheimer’s [8]. People can take them as needed or once a month, but using them more regularly can impair cognitive function.

Furthermore, anticholinergic medications may also increase the risk of dementia. These medications raised a person’s chance of dementia by up to 30%, according to research from the University of East Anglia in the UK [9]. Patients with depression, Parkinson’s, and incontinence often use these drugs. However, because some depression and anxiety medications overlap, it is advisable to consult your doctor about the risks of these medications.

Medications may still be helpful, though, if they lessen the symptoms of anxiety that cause Alzheimer’s. It is crucial to assess your level of risk and talk with your doctor about your best course of action.

Does treating anxiety symptoms lessen the risk of dementia?

Whether through prescription drugs, dietary adjustments, or a mix of the two, it can be beneficial to control anxiety symptoms. Reduced stress may lower your risk of cognitive decline and Alzheimer’s. Additionally, overcoming the loneliness and isolation associated with anxiety can positively impact your general health.


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  2. Anxiety may be an early sign of Alzheimers. Medical News Today. Published Online: 12th Jan, 2018, Accessed: 28th April, 2023.
  3. Donovan, N.J., Locascio, J.J., Marshall, G.A., Gatchel, J., Hanseeuw, B.J., Rentz, D.M., Johnson, K.A., Sperling, R.A. and Harvard Aging Brain Study, 2018. Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults. American Journal of Psychiatry, 175(6), pp.530-537.
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Can diet help prevent or treat Alzheimer’s?

Diet Help Prevent Or Treat Alzheimer’s

There are claims that several diets and supplements can help with Alzheimer’s. However, people should be aware that there is no proof that any specific diet or nutrient helps prevent or treat the disease, despite some research suggesting a link between cognitive performance and particular foods or nutrients.

Although no specific diet helps prevent or treat Alzheimer’s, doctors advise people to maintain a balanced and healthy diet. It entails consuming fruits, vegetables, and whole grains while avoiding meals heavy in salt, sugar, and saturated fat.

Research has indicated that the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets have links to reduced incidence of Alzheimer’s.

Furthermore, the findings of another study imply that the ketogenic diet may be beneficial for improving daily function and quality of life in persons with Alzheimer’s. Nevertheless, unlike the Mediterranean and MIND diets, doctors are concerned about the long-term implications of the keto diet.

Can diet stave off or cure Alzheimer’s?

According to statistics, over 6 million people in the United States are living with Alzheimer’s, and this figure will rise to approximately 13 million by 2050. It is a progressive illness that impacts the areas of the brain responsible for thought, language, and memory.

Since Alzheimer’s medications only marginally slow the advancement of the disease, a doctor may also propose non-drug therapies, which include diet and nutrition. The National Institute on Aging (NIA) reports that numerous studies highlight the connection between diet and cognitive function.

Some evidence suggests that Mediterranean and MIND diets, in particular, may assist patients with Alzheimer’s. Although some research backs up the keto diet’s use, it can have potentially dangerous side effects.

Individuals with neurodegenerative disorders, such as Alzheimer’s, are less likely to consume nutritious diets and are more likely to be malnourished. Disease symptoms can cause people to lose their appetite, forget to eat, and have difficulty swallowing. The keto diet may make someone with these symptoms even more undernourished because it can decrease a person’s appetite.

It’s crucial to remember that dietary adjustments aren’t the only way to improve the health of Alzheimer’s patients, and they can also benefit from making other lifestyle modifications.

The Mediterranean Diet

The main components of the Mediterranean diet are fruits, vegetables, fish, whole grains, legumes, and healthy fats like olive oil and nuts. It also contains limited amounts of poultry and meat. The diet also discourages the consumption of red meat and promotes herbs as a salt substitute. Studies have shown that the diet may help those with the condition or at risk of getting it.

A study published in 2021 examined the connection between Alzheimer’s and the Mediterranean diet. Participants with symptoms ranging from no cognitive deterioration to mild cognitive impairment participated in the study, which assessed how well people adhered to the meal plan.

The findings suggested that higher diet adherence was associated with better memory, reduced brain plaque buildup, and protection to some extent against brain shrinkage. While some of these findings might suggest that diet improves brain function, they also demonstrate that those with superior memories are more likely to adhere to a diet.

The MIND Diet

The MIND diet combines the Mediterranean diet with the Dietary Approaches to Stop Hypertension (DASH) diet. Although the researchers developed the DASH diet for persons with high blood pressure, some studies have suggested that it may also benefit those with Alzheimer’s.

According to studies, adopting the MIND diet may lower your risk of getting Alzheimer’s. For instance, 2015 research of 923 individuals between the ages of 58 and 98 discovered that those who followed MIND-style diets had decreased incidences of Alzheimer’s.

The diet prioritizes plant-based foods and restricts animal products and foods high in saturated fat. It emphasizes berries and leafy green veggies in particular.

The Ketogenic Diet

The ketogenic diet is low in carbohydrates and high in fat. Although there are several approaches to the diet, most protocols seek to limit the percentage of carbohydrates in a person’s daily calorie consumption to under 10%. The body switches to utilize fat for energy as a result, instead of glucose.

According to experts who advocate using the ketogenic diet to treat Alzheimer’s, it may lessen plaque buildup in the brain, the hallmark of the disease. Also, it lowers inflammation, which is a crucial component of Alzheimer’s pathology, the aberrant physiology that underlies the disease.

Despite these potential advantages, there are also drawbacks to the keto diet.

The long-term safety of the ketogenic diet is uncertain, in contrast to wholesome, well-balanced eating plans like the Mediterranean and MIND diets.

Potential side effects include atherosclerosis (artery hardening), impaired liver function, decreased bone density, kidney stones, and vitamin and mineral insufficiency. Also, it can make someone less hungry, which may be hazardous for those with Alzheimer’s as they are more prone to consume a diet that is low in nutrients.

Which Foods to Include in the Diet?

The Alzheimer’s Association advises following a balanced diet that includes:

  • Vegetables
  • Fruits
  • Whole grains
  • Dairy products
  • Sources of lean protein

Which Foods to Avoid?

According to the Alzheimer’s Association, you should limit or avoid the foods:

  • High in salt
  • High in sugar
  • High in saturated fat and cholesterol

Supplements & Vitamins

Researchers have conducted several studies to investigate the effectiveness of dietary supplements in Alzheimer’s treatment. The NIA states that no vitamin or supplement has demonstrated efficacy in preventing the illness, despite early signs of a potential benefit.

Although certain supplements may be beneficial, there is little evidence to back up their usage. Docosahexaenoic acid (DHA) and curcumin are among them.

When to Contact a Doctor or Dietician?

Changes in the brain occur years before the first signs of Alzheimer’s manifest. It implies that there is a period when adopting certain lifestyle habits may help to either delay or prevent Alzheimer’s.

Individuals worried about their risk of Alzheimer’s might want to see a doctor. They can assess a person’s risk factors and offer pertinent nutritional advice.


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Sound and Light as Potential Alzheimer’s Treatment

Sound And Light As Potential Alzheimer’s Treatment

A new study describes the first human trials of an experimental cure for Alzheimer’s that uses sound and light. The preliminary findings are intriguing, with the novel treatment resulting in some neurological and cognitive improvements. However, the small trial size implies further research is needed before anyone can claim that this therapy works.

According to the results of two recent small trials published in the journal PLoS One, an Alzheimer’s treatment is under development at MIT that alters patients’ brain waves using light and sound may be a safe approach to boost memory while preventing brain abnormalities associated with the disease.

These investigations are far too small to demonstrate the efficacy of the therapy. However, a much larger study is already underway to test this treatment option and might be completed by May 2025.

Brain Waves 101

About 86 billion neurons make up our brains, and these cells interact with one another using brief electrical pulses. When several neurons are activated, the pulses can synchronize and repeat in a systematic pattern, resulting in a rhythm known as a brain wave.

The brain generates five types of brain waves, classified based on their frequencies or how many times the cycle repeats every second. The frequency of delta waves is the lowest (0.5-4 Hertz), while the frequency of gamma waves is the highest (32–100 Hz).

Although our brains can produce more than one form of brain wave at a time, the dominant type is typically associated with alertness. For example, delta waves may predominate when you sleep, while gamma waves may predominate when you concentrate very hard.

What’s the idea behind the research?

Researchers have previously noted that those who have Alzheimer’s may have weaker and less synchronized gamma waves than those who do not. In a series of earlier investigations, scientists from MIT showed that exposing animals to 40 Hz clicking sounds or flickering lights could boost the strength and synchronization of these waves in Alzheimer’s mice models.

Together with their boosted gamma waves, the mice also appeared to have a range of benefits, such as memory enhancements, delayed neuronal degeneration, and decreased levels of proteins linked to Alzheimer’s in the brain compared to controls.

The researchers think this is because more powerful and in-sync gamma waves strengthen the neural connection, enlarge waste-clearing arteries, and improve immune cell responsiveness in the brain.

Evaluating the Safety and Effectiveness

The MIT researchers have completed two short clinical trials to see how the 40-Hz light and sound treatment, known as “Gamma ENtrainment Using Sensory stimuli” (GENUS), impacts people.

Two early-stage clinical studies evaluating the safety and effectiveness of 40-hertz sensory stimulation for Alzheimer’s treatment have found that the potential therapy was well-tolerated, had no notable adverse effects, and was associated with some considerable neurological and behavioral advantages in a small cohort of patients.

In a phase 1 trial, 43 participants, including 16 people with early-stage Alzheimer’s and two persons with epilepsy who were about to have brain surgery, received the 40-Hz GENUS treatment for a few minutes.

The team used scalp electrodes to track the activity of the participants’ frontal and occipital lobes before, during, and after the sensory stimulation. Activity in deeper brain areas that were reachable during surgery was evaluated in epilepsy patients.

According to the results, the strength of gamma waves in all brain areas seemed to rise throughout therapy, and gamma wave synchronization in the frontal and occipital lobes also increased. Sleepiness was the most often reported adverse event, and no other serious adverse events.

Home Therapy

In a phase 2a trial, the team provided GENUS devices to 15 individuals with early-stage Alzheimer’s to be used at home for an hour each day for at least three months. Each comprised a light panel linked to a speaker and video cameras to watch device usage.

They then randomly divided the participants into two groups and exposed eight of them to sound and light of 40 Hz frequency via the GENUS apparatus. White noise and steady light served as a sham treatment for the other seven.
At the start and end of the study, the subjects underwent cognitive testing, EEG recordings, and MRIs to quantify brain volume. Both groups’ users utilized the gadget around 90% of the time as instructed and reported no severe adverse effects.

The treatment group had a much greater connection between the areas of the brain associated with cognition and visual processing than the control group. They also fared much better on a memory assessment that challenged them to match faces with names.

Two metrics linked to Alzheimer’s progression — reduced hippocampal volume and raised ventricle volume — worsened in control participants but did not alter significantly in the treatment group. Yet, with only a few individuals in each group, it is hard to be confident in these results.

What’s Next?

While these trials imply that 40-Hz GENUS is safe and beneficial for Alzheimer’s patients, the sample sizes are far too limited to prove that sensory stimulation works.

Cognito Therapeutics, an MIT spinoff formed by senior author Li-Huei Tsai and co-author Ed Boyden, has already initiated a phase 3 trial in which they will randomly assign 500 persons with Alzheimer’s to receive daily 40-Hz auditory and visual stimulation or placebo treatment for 9 to 12 months.

If this more extensive experiment, dubbed HOPE, can demonstrate the treatment’s success, it could one day provide individuals with Alzheimer’s with a safer strategy to tackle the illness that does not put them in danger of grave side effects that some medications can cause.


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