Month: December 2022

Lead is known to harm children’s developing brains, and a recent study indicates that the consequences might last into old age. According to the study, lead exposure throughout childhood may result in lower cognitive abilities later in life, implying that people may develop dementia symptoms sooner.

Although scientists have long known that lead exposure causes poor cognitive and educational performance in children and adults, only a few studies have looked into the long-term effects.

The recent study, one of the first to look into the long-term effects of lead poisoning, shows that countries may witness a spike in the number of people seeking dementia care as individuals who were exposed to high amounts of lead as children grow older. Researchers discovered that among over 1,100 older Americans, individuals who grew up in cities with lead-contaminated drinking water performed worse on memory and cognitive abilities tests. Lead is a naturally occurring element that, if accumulated in the blood, can have serious health consequences. Children under six years of age are especially susceptible, as lead can harm their developing brains and create learning or behavioral issues. However, the impact of lead exposure during childhood on the aging brain is not well understood.

Once inside the body, extra lead is stored in the bones, where it “stays quietly,” according to the researchers. However, decades after the initial exposure, age-related bone loss or fractures can let some of this element into circulation.

The Research Findings

The research involved 1,089 senior citizens from the United States who participated in a long-running health study between 1998 and 2016. Warren and his team used 1940 census data with information from the US-based Health and Retirement Study (HRS), a long-term study that has tracked the mental health of thousands of adults over several decades, to determine where these people resided as kids. As a proxy for excessive lead exposure, they also plotted the locations of towns and cities with lead pipes and acidic or alkaline water.

The study, published in Science Advances, found that individuals who grew up in cities with lead-contaminated water had lower baseline cognitive functioning at age 72 than those who did not. Cognitive functioning is their capacity to learn, process information, and reason. The age difference was almost eight years.

Warren stated that the majority of people frequently consider lead to be an old issue. We tend to think of this as a problem that we have fixed because we got rid of lead paint and leaded gasoline, and we’re doing all we can to clean up the water. Unfortunately, the long-term effects of all that lead exposure might not become apparent for several decades. According to Warren, although exposure to lead in childhood does not guarantee that a person will develop dementia, it does indicate that they will likely start much lower on the cognitive impairment scale and may reach troublesome levels earlier.

The good news is that there was no difference in the pace of cognitive deterioration between the two groups. It may be because their cognition testing was done after any lead exposure-related brain damage had already occurred.

The results only demonstrated a connection between lead exposure throughout childhood and cognition in adulthood. They did not show the cause and effect. Warren, however, pointed out that early exposure could have long-term impacts in several ways, including indirect ones. Children with high blood lead levels, for instance, frequently struggle academically and behaviorally, and they are less likely than their classmates to complete high school or pursue further education. Slower mental deterioration in old age might be associated with lower academic achievement and less lifelong mental stimulation, such as cognitively demanding work.

More research is urgently needed to clearly understand the long-term effects of lead exposure throughout childhood on brain aging and to discover practical methods to lessen lead’s long-term effects.

Reference

1. Lee, H., Lee, M.W., Warren, J.R. and Ferrie, J., 2022. Childhood lead exposure is associated with lower cognitive functioning at older ages. Science Advances, 8(45), p.eabn5164. https://www.science.org/doi/10.1126/sciadv.abn5164.

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?_.
2. Cairns, D.M., Itzhaki, R.F. and Kaplan, D.L., 2022. Potential Involvement of Varicella zoster virus in Alzheimer’s disease via reactivation of quiescent Herpes simplex virus type 1. Journal of Alzheimer’s Disease, (Preprint), pp.1-12. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad220287.
3. Taquet, M., Sillett, R., Zhu, L., Mendel, J., Camplisson, I., Dercon, Q. and Harrison, P.J., 2022. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. The Lancet Psychiatry, 9(10), pp.815-827. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext.
4. https://www.alz.org/research/for_researchers/partnerships/sars-cov2-global-brain-study

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

1. Disappointment after potential Alzheimer’s drug fails trial. The Guardian. https://www.theguardian.com/society/2022/nov/14/disappointment-after-potential-alzheimers-drug-fails-roche-trial-gantenerumab. Accessed: 6.12.2022.
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.