More Evidence Suggests That Viruses Play a Role in Alzheimer’s

Viruses have been considered a controversial risk factor for Alzheimer’s for decades. It is a contentious hypothesis regarding the disease, frequently brushed aside by specialists as a dubious offshoot of accepted knowledge.

However, research continued to establish whether they have a role in the development of Alzheimer’s. Two recent studies have lent some support to this controversial idea.

Involvement of Herpes Virus in Alzheimer’s

In 2018, a team, including eminent Alzheimer’s researchers who had previously questioned this idea, conducted a study that supported the claim of the involvement of viruses in Alzheimer’s. The study, published in the journal Neuron, provides compelling evidence that viruses, notably two forms of herpes (HHV-6A and HHV-7) that most individuals contract as babies and which subsequently go latent for years, may have a role in Alzheimer’s disease.

According to the study, viruses interact with genes associated with Alzheimer’s and may influence how the disease manifests itself and advances. The researchers discovered much more viral genetic material in Alzheimer’s-affected brains than in healthy ones. In addition, viral RNA levels in Alzheimer’s brains were higher than in the brains of healthy individuals for both HHV-6A and HHV-7, and they correlated with the severity of clinical symptoms. HHV-6A is a late-life virus that typically causes no symptoms. More than 80% of newborns have HHV-7 infection, which frequently results in a rash.

They discovered numerous interactions, indicating that the viruses might turn on and off genes relevant to Alzheimer’s. The researchers bred mice lacking one molecule that herpes appeared to deplete to determine if those interactions mattered. Indeed, more amyloid plaques appeared in the mice.

The authors clearly stated that they had not discovered that these viruses directly cause Alzheimer’s. However, their research, coupled with another soon-to-be-published study, reveals that viruses could trigger an immunological response that might accelerate the accumulation of amyloid, a protein in human brains that aggregates into the unmistakable plaques of Alzheimer’s.

The Role of Herpes and Varicella Zoster Viruses

Another recent study published in the Journal of Alzheimer’s disease has further strengthened the notion that viruses may play a role in Alzheimer’s development. The study showed how the Herpes Simplex Virus (HSV-1) could interact with the related varicella zoster virus (VZV), which causes chickenpox and shingles, to trigger the early stages of dementia. In the early 1990s, Ruth Itzhaki (one of the study’s researchers) initially demonstrated that HSV-1 is dormant in the brains of many older individuals.

Researchers discovered that VZV might activate HSV-1 in the brain, causing an accumulation of tau and amyloid proteins and a loss of neuronal function—markers of Alzheimer’s disease—in a three-dimensional neural tissue culture model of the brain developed at Tufts. VZV didn’t do anything on its own.

One of the authors, Dana Cairns, stated that although they found a connection between VZV and HSV-1 activation, other inflammatory brain events (like head trauma) may potentially awaken HSV-1 and cause Alzheimer’s.

Researchers are trying to gather more concrete evidence concerning the involvement of HSV-1 in Alzheimer’s via clinical trials at Columbia University and the New York State Psychiatric Institute. They have given the participants in the early stages of the illness having an HSV-1 infection either valacyclovir, an antiviral medication, or a placebo. The trial is to be completed in December 2023.

Impact of Covid-19 on the Alzheimer’s Research

As more evidence mounts that Sars-Cov-2, the virus that causes Covid, can harm the brain in some people, interest in the connections between viruses and dementia has also grown due to the Covid-19 pandemic.

Researchers at Oxford University extensively studied and reported the chronic neurological and psychological effects of Sars-Cov-2. They examined the electronic health data of 1.25 million Covid patients and a control group of patients with comparable respiratory illnesses. In the following two years, 4.5% of Covid patients 65 or older acquired dementia, compared to 3.3% of the control group.

However, the research had limitations since the first case of Covid was recorded less than three years ago, and the researchers did not have enough time to follow up to understand the implications of Covid for people who may develop dementia in the future. The initial neural triggers that cause Alzheimer’s symptoms can take longer to manifest.

Itzhaki believes that by reactivating latent HSV-1 in the brain, Sars-Cov-2, like VZV, raises the risk of Alzheimer’s. ApoE4 gene carriers seem to be especially susceptible. To investigate it, Neurologists from 25 countries have set up a worldwide collaboration: The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of Sars-Cov-2 Infection.

Sources

  1. Readhead, B., Haure-Mirande, J.V., Funk, C.C., Richards, M.A., Shannon, P., Haroutunian, V., Sano, M., Liang, W.S., Beckmann, N.D., Price, N.D. and Reiman, E.M., 2018. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron, 99(1), pp.64-82. https://www.cell.com/neuron/fulltext/S0896-6273(18)30421-5?_.
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A Setback: Potential Alzheimer’s Drug Fails Roche Trial

Alzheimers

The failure of a test medicine to reduce the Alzheimer’s course in international clinical trials has dealt another blow to hopes for a cure for the disease. The possible drug gantenerumab by Roche failed to slow clinical decline in patients with early Alzheimer’s in two phase-III trials.

On November 14th, 2022, the Swiss pharmaceutical company Roche stated that the twin trials that examined the effect of the drug gantenerumab on memory, problem-solving, and other cognitive skills in persons with early-stage Alzheimer’s exhibited no obvious advantage.

The disappointment came amid emerging indications that antibodies directed against beta-amyloid may one day successfully treat this memory-robbing neurodegenerative illness. After a US-Japanese partnership between Biogen and Eisai disclosed in September that a comparable medicine, lecanemab, reduced cognitive decline in patients, making it the first shown to do so, experts had hoped for encouraging results from Roche’s Graduate I and II clinical trials.

The Gantenerumab Trial

Gantenerumab is an antibody treatment that binds to clumps of amyloid beta proteins in the brain and removes the plaques. Although aberrant protein aggregates might play a significant part in Alzheimer’s, many patients are likely to have various disease processes at work in their brains.

About 1,000 volunteers in each of Roche’s two similar phase-3 studies of gantenerumab received an injection of the medication or a placebo every two weeks. For more than two years, the subjects underwent tests to track their deterioration in cognitive function.

Although individuals who received the medication experienced a relative fall in the clinical decline of 8% in the Graduate 1 and 6% in the Graduate 2 trials, the company stated the results were not statistically significant.
Early in 2014, Roche began their first phase 3 trial of gantenerumab. However, it was discontinued early at the end of the year when an interim analysis revealed the intervention was ineffective. Many researchers were shocked by the company’s decision to try again with greater doses of the antibody in two further trials that enrolled approximately 2000 individuals with moderate cognitive impairment or mild dementia attributable to Alzheimer’s across 30 nations.

What were the results of the trial?

In those studies, gantenerumab injections, which target a different portion of the amyloid protein than other antibodies, only slightly reduced cognitive decline compared to placebo. Roche admitted that this difference was not statistically significant. The company also stated that the treatment’s removal of beta-amyloid was lower than predicted. That may make it difficult to determine whether the research supports or refutes the widely held but increasingly challenged theory that beta-amyloid directly damages neurons, causing Alzheimer’s.

The company also pointed out that in the pooled gantenerumab-treated arms of the two trials, the prevalence rate of amyloid-related imaging abnormalities (ARIA), brain swelling, and fluid buildup frequently seen with this class of antibodies was 25%. This figure was significantly higher than the reported incidence for lecanemab.

According to the firm, most ARIA cases were minor and did not require doctors to stop treating patients. The number of cases of the more serious “hemorrhagic” variant, which involves bleeding in the brain, was not disclosed by Roche. However, it claimed they were balanced across the placebo and gantenerumab groups.

Based on earlier results, many scientists and biotech analysts thought that gantenerumab had little chance of being effective in the two trials. Even proponents of the amyloid theory had little hope.

Roche shutters most Alzheimer’s drug trials after failure

After disclosing the primary results on November 14th, Roche was to give more details on the clinical trial at an Alzheimer’s meeting in San Francisco on November 30th.

The company revealed on November 30th that it is ending most of its clinical trials for gantenerumab, an experimental treatment for Alzheimer’s, because, in two sizable, late-stage studies, it did not stop the spread of the debilitating condition.

According to a presentation, gantenerumab, administered by injection, only demonstrated amyloid clearance in 28% of patients in the Graduate I trial and 25% in the Graduate II trial after two years, which is half of what the firm predicted. In comparison, lecanemab eliminated amyloid in 68% of trial participants after 18 months.
There are a variety of potential reasons why Roche’s medicine may have failed, including variations in chemistry, dose, and the method it was provided by injection as opposed to infusion, according to the chief science officer at the Alzheimer’s Drug Discovery Foundation, Dr. Howard Fillit. However, it is evident that the drug’s apparent inability to eliminate amyloid deposits from the brain played a part.

To deliver more medication to the brain, Roche is still testing trontinemab (a different form of gantenerumab), which can transport the drug across the blood-brain barrier. This barrier is a set of protective blood vessels that blocks the entry of chemicals from the bloodstream into the brain.

Sources

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  2. Roche Alzheimer’s antibody fails to slow cognitive decline in major test. Science. https://www.science.org/content/article/roche-alzheimer-s-antibody-fails-slow-cognitive-decline-major-test?cookieSet=1. Accessed: 6.12.2022. 
  3. Roche’s Alzheimer’s drug fails to meet goal in long awaited trial. Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/roche-says-phase-iii-trial-alzheimers-trial-drug-fails-2022-11-14/. Accessed: 6.12.2022.  
  4. Roche shutters most trials of Alzheimer’s drug after failed trials. Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/roche-shutters-most-trials-alzheimers-drug-after-failed-trials-2022-12-01/. Accessed: 6.12.2022. 

Surprising New Theory Explains What Might Cause Alzheimer’s

One of the most investigated questions in Alzheimer’s research is its cause. The accepted theory for more than a century was that amyloid plaque formation in the brain resulted in the disease. However, a recent study has challenged this prevailing hypothesis, claiming that the disease results due to a decline in levels of a specific protein.

The Prevailing Theory: Amyloid Beta Plaques Cause Alzheimer’s

In 1906, Alois Alzheimer, a neuroanatomist and psychiatrist, reported a severe disease process of the cerebral cortex. The case subject was a 50-year-old woman who suffered from delusions, memory loss, aggression, hallucinations, and confusion some of the symptoms of Alzheimer’s. After her death, an autopsy showed distinctive plaques on her brain. These plaques were clumps of amyloid-beta protein, which is still considered the cause of Alzheimer’s disease.

The amyloid beta peptide is a naturally occurring protein derived from amyloid precursor protein (APP) in our brains that forms throughout life. According to the widely-accepted theory, it accumulates as amyloid plaques in the brain that are the markers of Alzheimer’s and the culprit involved in initiating the pathological cascade of the disease.

The basement membranes of the artery and capillary walls along the interstitial fluid drainage pathway are the routes for the elimination of Aβ. It is considered the perivascular lymphatic drainage pathway for the brain. However, as arteries in the brain age, they become stiff, thus, failing the perivascular elimination of Aβ. As a result, the protein accumulates in blood vessel walls as brain parenchymal plaques.

The Recent Research Findings: What Might Cause Alzheimer’s

The researchers have highlighted two main issues in the commonly accepted theory. First, it does not explain why the subjects have developed plaques in their brain without showing any neurological symptoms, such as memory loss. Second, it does not explain the reason for the failure of clinical trials for drugs that reduce these plaques (with one exception).

The initial soluble form of the protein responsible for carrying out crucial tasks in the brain degrades and is lost when amyloid-beta starts to build up as insoluble clumps (plaques). Research has revealed that decreased levels of this soluble protein called amyloid-beta 42 result in causing patients having worse clinical outcomes.

In the recent research published in the Journal of Alzheimer’s Disease, the question for investigation is whether it is the remaining amount of amyloid-beta 42 or the number of plaques in the brain which has a more significant role in Alzheimer’s disease progression.

The researchers hypothesized that plaques are simply the result of lower quantities of soluble amyloid-beta in the brain. These levels decline due to normal protein transforming into aberrant amyloid plaques in the presence of biological, metabolic, or viral stress.

The study team looked at the amyloid-beta levels in a group of people with rare inherited gene mutations that foretold an overabundance of amyloid plaques in the brain, thought to increase their risk of Alzheimer’s.

After an average of three years of follow-up, the researchers discovered that participants with high amyloid-beta 42 levels in their cerebrospinal fluid were protected and retained their cognitive abilities throughout the study regardless of the number of plaques in their brains.

It is also worth noting that in some uncommon, inherited forms of Alzheimer’s, such as those caused by the Osaka gene mutation or the Arctic mutation, people can acquire dementia with low levels of amyloid-beta 42 and no apparent plaques. It shows that low amyloid-beta 42 levels may be the source of their dementia rather than plaques.

Lecanemab – A Drug That Increases The Amyloid-beta 42 Levels

Based on the belief that Alzheimer’s patients will form fewer plaques if the protein levels decline, some researchers created medications to reduce the amount of amyloid-beta 42. Unfortunately, these drugs frequently made the patient’s condition worse.

A recent trial has reported an antibody drug, lecanemab, to have a significant effect in decreasing cognitive decline. The drug has exhibited an increase in the levels of amyloid-beta 42 in the CSF. This research also supports the hypothesis that a rise in the normal amyloid protein can be helpful.

However, further research in this field will bring more to light. The researchers believe that future trials should focus on amyloid-beta 42 levels and if it is helpful to boost and restore them to normal levels rather than targeting them for eradication. “Protein analogs” or proteins that resemble amyloid-beta 42 but do not clump together as much as their natural counterparts can help achieve this goal.

Research is still underway to clearly understand the cause of Alzheimer’s. However, if future trials focus on the active protein replacement approach, they might uncover a promising new treatment for protein aggregation diseases, such as Alzheimer’s, motor neuron disease, and Parkinson’s.

Tips for Enjoyable Holidays for Caregivers of Alzheimer’s Patients

The holiday season can be a difficult time for families with Alzheimer’s. Even though it is typically a time for celebration, they may feel a sense of loss for how things used to be.

The holidays may also mean more responsibility and work for caregivers. They will have to consider the needs of their loved one with Alzheimer’s when decorating for the holidays and hosting gatherings.

Caregivers can discover meaningful ways to enjoy holidays by adapting their expectations and changing some traditions. The following tips may help them make the holiday season enjoyable for their loved ones.

Create a peaceful and safe environment

It is crucial to make preparations to ensure a calm and safe space for the person with Alzheimer’s. The following tips can help in this regard:

  • Avoid potential hazards. Replace burning candles with electric candles. Do not let candles burn unattended if you light them. Avoid delicate ornaments or ornaments that could be mistaken for food, like fake fruit. Fix the Christmas tree to a wall if you have one.
  • Avoid using blinking lights or huge decorative displays, which can be confusing. Also, avoid decorations that create clutter or necessitate rearranging a room familiar to the person.
  • Play the person’s favorite music. Consider holiday music that is familiar or enjoyable for them. Adjust the volume to be calming rather than distressing.

Adapt holiday activities

The following tips can help you make the holidays for your loved one with Alzheimer’s more enjoyable:

  • Make holiday preparations together, such as baking cookies, opening holiday cards, and making simple decorations. Concentrate on the task at hand rather than the consequence.
  • Organize a small gathering and keep the celebrations calm and relaxed.
  • Arrange a gathering at the optimal time of day for the person with Alzheimer’s. Maintain daily routines as much as feasible to avoid disturbances.
  • If you have guests, ensure a quiet area where the person with Alzheimer’s may spend some time alone and relax.
  • Make plans for meaningful holiday activities. You may read a favorite holiday story, browse through photo albums, watch a movie, or sing songs.
  • Make your excursions brief. If you are going to a Christmas party, make your visit brief and be ready to depart early if necessary. Be sure there is a place for the person with Alzheimer’s to take a break and rest.

Preparing Visitors

It is crucial to let the guests know about the person’s behavioral changes before their visit. The following tips can help:

  • Update and inform visitors beforehand of any modifications to behavior or memory from their previous visit. People may be better prepared for changes in appearance if you provide a recent photo.
  • Offer communication tips to the guests and suggest that they listen patiently to the person. Ask them to refrain from correcting mistakes, criticizing repetitive comments, and interrupting.
  • Inform your guests in advance of the activities you have planned or suggest something they might bring, for instance, a photo album.

Celebrating the holiday at a care facility

If a member of your family is in a nursing home or other type of care facility, consider the following:

  • Try celebrating in the most familiar environment. Holding a little family celebration within the facility could be a good idea because a change in the atmosphere might be upsetting. You could participate in the festivities scheduled for the residents of the facility.
  • Minimize the number of visitors. Make arrangements for a few family members to visit on different days. A large group could be intimidating for a person with Alzheimer’s.

Caregivers, remember! Simplifying celebrations, planning ahead of time, and establishing boundaries can help reduce stress and create an enjoyable holiday experience for you and the person with Alzheimer’s.