Tag Archives: Amyloid

Aducanumab, an antibody developed by the University of Zurich, has been shown to trigger a meaningful reduction of harmful beta-amyloid plaques in patients with early-stage Alzheimer’s disease. These protein deposits in the brain are a classic sign of Alzheimer’s disease and contribute to the progressive degeneration of brain cells. The researchers furthermore demonstrated in an early-stage clinical study that, after one year of treatment with Aducanumab, cognitive decline could be significantly slowed in antibody-treated patients as opposed to the placebo group.

Although the causes of Alzheimer’s disease are still unknown, it is clear that the disease commences with progressive amyloid deposition in the brains of affected persons between ten and fifteen years before the emergence of initial clinical symptoms such as memory loss. Researchers have now been able to show that Aducanumab, a human monoclonal antibody, selectively binds brain amyloid plaques, thus enabling microglial cells to remove the plaques. A one-year treatment with the antibody, as part of a phase Ib study, resulted in almost complete clearance of the brain amyloid plaques in the study group patients. The results, which were realized by researchers at UZH together with the biotech company “Biogen” and the UZH spin-off “Neurimmune,” have been published in Nature.

Reduction of brain amyloid plaque is dependent on treatment duration and dosage

“The results of this clinical study make us optimistic that we can potentially make a great step forward in treating Alzheimer’s disease,” says Roger M. Nitsch, professor at the Institute for Regenerative Medicine at UZH. “The effect of the antibody is very impressive. And the outcome is dependent on the dosage and length of treatment.” After one year of treatment, practically no beta-amyloid plaques could be detected in the patients who received the highest dose of the antibody.

The antibody was developed with the help of a technology platform from “Neurimmune.” Using blood collected from elderly persons aged up to one hundred and demonstrating no cognitive impairment, the researchers isolated precisely those immune cells whose antibodies are able to identify toxic beta-amyloid plaques but not the amyloid precursor protein that is present throughout the human body and that presumably plays an important role in the growth of nerve cells. The good safety profile of Aducanumab in patients may well be attributed to the antibody’s specific capacity to bond with the abnormally folded beta-amyloid protein fragment as well as the fact that the antibody is of human origin.

Investigational treatment also curbs cognitive decline

165 patients with early-stage Alzheimer’s disease were treated in the phase 1b clinical trial. Although not initially planned as a primary study objective, the good results encouraged researchers to additionally investigate how the treatment affected the symptoms of disease. This was evaluated via standardized questionnaires to assess the cognitive abilities and everyday activities of the patients. “Aducanumab also showed positive effects on clinical symptoms,” is how Nitsch sums up the findings. “While patients in the placebo group exhibited significant cognitive decline, cognitive ability remained distinctly more stable in patients receiving the antibody.”

Some of the trial participants temporarily suffered from amyloid-related imaging abnormality (ARIA), an adverse effect that can be detected via magnetic resonance imaging. In a minority of cases, this was accompanied by temporary mild to moderate headaches. The UZH researchers believe that ARIA is a measurable biological effect of amyloid clearance.

The promising effects of Aducanumab are currently being investigated in two large phase-three clinical studies to further evaluate safety and efficacy. Involving over 300 centers in 20 countries throughout North America, Europe, and Asia, these studies are evaluating the effectiveness and safety of the antibody on a total of 2,700 patients with early-stage Alzheimer’s disease.

Paper: “The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease”
Reprinted from materials provided by the University of Zurich.

 

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer’s disease at age 65 than the rest of the population. Now, researchers have identified a connection between ApoE4 and protein build-up associated with Alzheimer’s that provides a possible biochemical explanation for how extra ApoE4 causes the disease.

Their findings, which appear in the Journal of the American Chemical Society, underscore the importance of looking at genes and proteins not classically associated with Alzheimer’s to make progress in understanding the disease.

Late-onset Alzheimer’s disease — the subset of the disorder occurring in people age 65 and over — affects more than 5 million Americans, and is characterized by progressive memory loss and dementia. Scientists have put forth a variety of hypotheses on its causes, including the accumulation of protein clusters called beta-amyloid plaques and tau tangles in the brain.

Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer’s disease. Previous reports have suggested that ApoE4 may affect how the brain clears out beta-amyloid, but what was happening at the molecular level wasn’t clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown.

To find the protein responsible for degrading ApoE4, the researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1).

When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells — and more of the breakdown products of the protein.

But it’s not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer’s in people with ApoE4. The researchers also found that ApoE4 — because it binds so well to HtrA1 — keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer’s.

The results need be tested and confirmed in animal studies before researchers can be sure that HtrA1 is the link between ApoE4 and Alzheimer’s in humans. But if they hold true, they could point toward a better understanding of the disease and potential new treatment strategies.

Paper: “HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective”
Reprinted from materials provided by the Salk Institute.

Scientific Reports“The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease” has been published in Scientific Reports. This research was supported in part by JPND through the BiomarkAPD project, selected under the 2011 biomarkers call.

For years, neuroscientists have puzzled over how two abnormal proteins, called amyloid and tau, accumulate in the brain and damage it in Alzheimer’s disease (AD). Which one is the driving force behind dementia? The answer: both of them, according to a new study.

In the journal Molecular Psychiatry, researchers report for the first time evidence that the interaction between amyloid and tau proteins drives brain damage in cognitively intact individuals.

”We specifically found that both proteins mutually enhance their individual toxic effects and cause a brain dysfunction considered to be a signature of AD. This finding challenges previous polarized theories that a single protein abnormality was the major driving force of disease progression,” explained the study’s leader, Dr. Pedro Rosa-Neto, a clinician scientist at the Douglas Mental Health University Institute and assistant professor of Neurology, Neurosurgery and Psychiatry at McGill University.
This research also points toward new potential therapeutic strategies to mitigate the progression of AD.

”Until now, therapeutic clinical trials have targeted a single pathological process. Our result paves the way for new therapeutic strategies for prevention or stabilization of AD. For example, combination therapies should be used simultaneously against both amyloid and tau protein accumulation”, says Dr. Tharick A. Pascoal, the study’s first author.

The researchers analyzed the performances of 120 cognitively intact individuals over two years (equal gender distribution; average age 75). By measuring amyloid levels using PET scans and tau proteins through cerebrospinal fluid analysis, the researchers were able to identify the patients at risk for brain damage associated with AD.

Source: Reprinted from materials provided by the McGill University.

Paper: “Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease

Two studies in the May 19 issue of JAMA analyze the prevalence of the plaque amyloid among adults of varying ages, with and without dementia, and its association with cognitive impairment.

The earliest recognizable pathological event in Alzheimer’s Disease (AD) is cerebral amyloid-beta aggregation (protein fragments that clump together to form plaque).This pathology may be present up to 20 years before the onset of dementia.

Therefore, estimates of the prevalence of amyloid pathology in persons without dementia are needed to better understand the development of AD and to facilitate the design of AD prevention studies. Initiation of treatment for AD in the pre-dementia phase, when neuronal damage is still limited, may be crucial to have clinical benefit.

Led by Pieter Jelle Visser at VU University Medical Center in Amsterdam and Maastricht University, The Netherlands, these two studies compiled amyloid PET and cerebrospinal fluid (CSF) biomarker data from thousands of participants, and represent the largest data sets to date on how commonly amyloid builds up in people’s brains.

One meta-analysis looked at the prevalence of amyloid in cognitively normal people, and concluded that amyloid creeps into the brain 20 to 30 years before dementia can be diagnosed. This was particularly true for people who carry an ApoE4 allele; indeed, they developed amyloid at a younger age.

In the second study, the researchers compared amyloid prevalence among people clinically diagnosed with AD or other dementias, including dementia with Lewy bodies, frontotemporal dementia, and corticobasal syndrome. They found that the prevalence of brain amyloid in people diagnosed with most non-AD dementias was higher with increasing age. They concluded that older people may be likelier to have multiple pathologies, or to have been misdiagnosed. The data may help researchers set inclusion criteria for clinical trials, or make better diagnoses.

“The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD,” the researchers wrote. “Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”

However, the authors point out that follow-up studies need to be conducted since not all people with amyloid pathology develop dementia in their lifetime, and not all people with a clinical diagnosis of Alzheimer’s dementia have amyloid pathology.

“Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state,” they wrote. “Our prevalence rates can be used as an inexpensive and noninvasive approach to select persons at risk for amyloid positivity.”