Education may be protective for people with gene for familial early onset Alzheimer's
August 5, 2020
Science Daily/American Academy of Neurology
Even for people who carry the gene for early onset Alzheimer's disease, more years of education may slow the development of beta-amyloid plaques in the brain that are associated with the disease, according to a new study published in the August 5, 2020, online issue of Neurology®, the medical journal of the American Academy of Neurology.
About 1-6% of people with Alzheimer's disease have rare genes that cause the disease in everyone who has them. This is called familial Alzheimer's disease. It leads to an early onset of the disease, when people are in their 30s to 50s.
"Because we've assumed that the effects of these genes can't be changed, very little research has been done on whether we can modify the trajectory of the disease," said study author Sylvia Villeneuve, PhD, of the McGill University in Montreal, Canada. "It's exciting to see that education may play a role in delaying the start of this devastating disease, which affects people during the prime of life."
Most people diagnosed with Alzheimer's have the sporadic form of the disease, which is thought to be caused by a combination of both environmental and genetic factors, including a gene variant called APOE ?4, or apolipoprotein E ?4. Having this gene variant is known to increase the development of amyloid plaques in the brain, even though it does not guarantee that the person will develop symptoms of Alzheimer's disease.
The study involved two groups: one group of 106 people with an average age of 67 who had a parent diagnosed with the sporadic form of Alzheimer's disease, of whom 39% had the APOE ?4 gene variant; and another group of 117 people with an average age of 35 who had the gene mutations linked to familial early onset Alzheimer's disease, of whom 31% also had the APOE ?4 gene variant. Each group had an average 15 years of education. None of the participants showed symptoms of the disease at the start of the study.
Participants had brain scans to determine levels of amyloid plaques.
Researchers found that in the people with familial early onset Alzheimer's, increasing levels of education were associated with lower levels of amyloid plaques in the brain. The strength of the association between education and plaque levels was similar to the strength of this same association in people at risk of sporadic Alzheimer's disease.
In both groups, people with less than 10 years of education had about twice the amount of amyloid plaques when compared to people with more than 16 years of education.
"While it has been believed that people with familial Alzheimer's disease, with its strong genetic causes, may have few ways to slow development of the disease, our study shows that education may be somewhat protective, perhaps promoting brain resistance against these plaques, just as it has been shown to be in people with unknown causes of the disease," said Villeneuve.
A limitation of the study was that most participants were white, so results may not be the same for all people. Also, the quality of education may be affected by other factors like socioeconomic status, so future studies should look more closely at other factors in addition to years of education to determine whether other environmental factors may be at play to explain these study results.
https://www.sciencedaily.com/releases/2020/08/200805160829.htm
Possible Alzheimer's breakthrough suggested
January 22, 2020
Science Daily/Case Western Reserve University
Researchers at the Case Western University School of Medicine say they have identified a previously unknown gene and associated protein which could potentially be suppressed to slow the advance of Alzheimer's disease.
"Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimer's disease (AD)," said Xinglong Wang, an associate professor of pathology at the School of Medicine. "We also see this as a potential novel therapeutic target for this devastating disease."
Wang said proving the latter assertion, which has not yet been tested in humans, would require additional research to corroborate the function of the protein they have dubbed "aggregatin." Eventually, that would someday mean clinical trials with Alzheimer's patients, he said.
"This protein characteristically accumulates, or aggregates, within the center of plaque in AD patients, like the yolk of an egg -- which is part of the reason we named it "aggregatin," Wang said.
A research team led by Wang and Xiaofeng Zhu, a professor of Population and Quantitative Health Sciences at the School of Medicine, has filed for a patent through the university's Office of Research and Technology Management for "novel Alzheimer's disease treatments and diagnosis based on this and related study," Wang said.
"We're very excited about this because our study is likely the first systematic work combining the identification from a genome-wide association study of high dimensional brain-imaging data and experimental validation so perfectly in Alzheimer's disease," Zhu said.
Their research was published this month by the scientific journal Nature Communications and supported by grants from the National Institutes of Health (NIH) and the Alzheimer's Association. Genomic and brain imaging data was obtained from the Alzheimer's Disease Neuroimaging Initiative, which is supported by the NIH.
Alzheimer's Disease affects millions
More than 5.7 million Americans have Alzheimer's disease, which is the primary cause of dementia and sixth-leading cause of death in the United States. That population is predicted to reach 14 million by the year 2050, according to the Alzheimer's Association.
The relationship between Alzheimer's (and subsequent brain atrophy) and amyloid plaques -- the hard accumulations of beta amyloid proteins that clump together between the nerve cells (neurons) in the brains of Alzheimer's patients -- has been well-established among researchers.
Less understood is precisely how that amyloid-beta actually leads to plaque formation -- and where this new work appears to have broken new ground, Wang said.
Further, while there has been much research into what genes might influence whether or not someone gets Alzheimer's, there is less understanding of genes that might be linked to the progression of the disease, meaning the formation of plaque and subsequent atrophy in the brain.
The role of 'aggregatin' protein
In the new work, the researchers began by correlating roughly a million genetic markers (called single-nucleotide polymorphisms, or SNPs) with brain images. They were able to identify a specific SNP in the FAM222, a gene linked to different patterns of regional brain atrophy.
Further experiments then suggested that the protein encoded by gene FAM222A is not only associated with AD patient-related beta-amyloid plaques and regional brain atrophy, but that "aggregatin" attaches to amyloid beta peptide -- the major component of plaque and facilitates the plaque formation.
So when researchers injected mouse models with the "aggregatin" protein (made from the FAM222A gene), plaque (amyloid deposits) formation accelerated in the brain, resulting in more neuroinflammation and cognitive dysfunction. This happened, they report, because the protein was found to bind directly the amyloid beta peptide, thus facilitating the aggregation and placque formation, Wang said.
Conversely, when they suppressed the protein, the plaques were reduced and neuroinflammation and cognitive impairment alleviated.
Their findings indicate that reducing levels of this protein and inhibition of its interaction with amyloid beta peptide could potentially be therapeutic -- not necessarily to prevent Alzheimer's but to slow its progression.
https://www.sciencedaily.com/releases/2020/01/200122080532.htm
Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue
Tau PET brain imaging could launch precision medicine era for Alzheimer's disease
January 1, 2020
Science Daily/University of California - San Francisco
The results support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.
Brain imaging of pathological tau-protein "tangles" reliably predicts the location of future brain atrophy in Alzheimer's patients a year or more in advance, according to a new study by scientists at the UC San Francisco Memory and Aging Center. In contrast, the location of amyloid "plaques," which have been the focus of Alzheimer's research and drug development for decades, was found to be of little utility in predicting how damage would unfold as the disease progressed.
The results, published January 1, 2020 in Science Translational Medicine, support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.
"The match between the spread of tau and what happened to the brain in the following year was really striking," said neurologist Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professor in Memory and Aging and leader of the PET imaging program at the UCSF Memory and Aging Center. "Tau PET imaging predicted not only how much atrophy we would see, but also where it would happen. These predictions were much more powerful than anything we've been able to do with other imaging tools, and add to evidence that tau is a major driver of the disease."
Interest in Tau Growing as Amyloid-Based Therapies Stumble
Alzheimer's researchers have long debated the relative importance of amyloid plaques and tau tangles -- two kinds of misfolded protein clusters seen in postmortem studies of patients' brains, both first identified by Alois Alzheimer in the early 20th century. For decades, the "amyloid camp" has dominated, leading to multiple high-profile efforts to slow Alzheimer's with amyloid-targeting drugs, all with disappointing or mixed results.
Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of the disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).
"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease," explained Renaud La Joie, PhD, a postdoctoral researcher in Rabinovici's In Vivo Molecular Neuroimaging Lab, and lead author of the new study. "Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."
Tau PET Scans Predict Locations of Future Brain Atrophy in Individual Patients
Despite early misgivings that tau might be impossible to measure in the living brain, scientists recently developed an injectable molecule called flortaucipir -- currently under review by the FDA -- which binds to misfolded tau in the brain and emits a mild radioactive signal that can be picked up by PET scans.
Rabinovici and collaborator William Jagust, MD, of UC Berkeley and Lawrence Berkeley National Laboratory, have been among the first to adopt tau PET imaging to study the distribution of tau tangles in the normally aging brain and in a smaller cross-sectional study of Alzheimer's patients. Their new study represents the first attempt to test whether tau levels in Alzheimer's patients can predict future brain degeneration.
La Joie recruited 32 participants with early clinical stage Alzheimer's disease through the UCSF Memory and Aging Center, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.
The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration.
"Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease," La Joie said.
Notably, PET scans revealed that younger study participants had higher overall levels of tau in their brains, as well as a stronger link between baseline tau and subsequent brain atrophy, compared to older participants. This suggests that other factors -- likely other abnormal proteins or vascular injuries -- may play a larger role in late-onset Alzheimer's, the researchers say.
Ability to Predict Brain Atrophy a 'Valuable Precision Medicine Tool'
The results add to hopes that tau-targeting drugs currently under study at the UCSF Memory and Aging Center and elsewhere may provide clinical benefits to patients by blocking this key driver of neurodegeneration in the disease. At the same time, the ability to use tau PET to predict later brain degeneration could enable more personalized dementia care and speed ongoing clinical trials, the authors say.
"One of the first things people want to know when they hear a diagnosis of Alzheimer's disease is simply what the future holds for themselves or their loved ones. Will it be a long fading of memory, or a quick decline into dementia? How long will the patient be able to live independently? Will they lose the ability to speak or get around on their own? These are questions we can't currently answer, except in the most general terms," Rabinovici said. "Now, for the first time, this tool could let us give patients a sense of what to expect by revealing the biological process underlying their disease."
Rabinovici and his team also anticipate that the ability to predict future brain atrophy based on tau PET imaging will allow Alzheimer's clinical trials to quickly assess whether an experimental treatment can alter the specific trajectory predicted for an individual patient, which is currently impossible due to the wide variability in how the disease progresses from individual to individual. Such insights could make it possible to adjust dosage or switch to a different experimental compound if the first treatment is not affecting tau levels or altering a patient's predicted trajectory of brain atrophy.
"Tau PET could be an extremely valuable precision medicine tool for future clinical trials," Rabinovici said. "The ability to sensitively track tau accumulation in living patients would for the first time let clinical researchers seek out treatments that can slow down or even prevent the specific pattern of brain atrophy predicted for each patient."
https://www.sciencedaily.com/releases/2020/01/200101144012.htm
Possible dementia vaccine closer after mice studies
Human trials tipped within two years
December 31, 2019
Science Daily/Flinders University
A vaccine to ward off dementia may proceed to clinical trials after successful animal testing. The research is looking to develop effective immunotherapy via a dual vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease. It is showing success in begenic mice models, supports progression to human trials in years to come.
A preventive treatment for dementia may proceed to clinical trials after successful animal testing.
The US-led research is looking to develop effective immunotherapy via a new vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease.
Recent success in bigenic mice models supports progression to human trials in years to come, the researchers say.
A new paper in the journal Alzheimer's Research & Therapy paves the way for more work in 2020, with medical researchers at the Institute for Molecular Medicine and University of California, Irvine (UCI) working with a successful vaccine formulated on adjuvant developed by Flinders University Professor Nikolai Petrovsky in South Australia.
The latest research aims to come up with a new treatment to remove accumulated beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline in Alzheimer's disease.
Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting about 5.7 million people in the US. Major challenges in AD include the lack of effective treatments, reliable biomarkers, or preventive strategies.
Professor of the Institute for Molecular Medicine Anahit Ghochikyan and colleagues, Associate Professors Hvat Davtyan and Mathew Blurton-Jones from UCI, and other co-authors tested the universal MultiTEP platform-based vaccines formulated in the adjuvant developed at Professor Petrovsky's Australian lab.
The possible new therapies were tested in bigenic mice with mix Aβ and tau pathologies.
"Taken together, these findings warrant further development of this dual vaccination strategy based on the MultiTEP technology for ultimate testing in human Alzheimer's disease," the lead authors Professor Ghochikyan and Blurton-Jones conclude.
Professor Petrovsky says the Advax adjuvant method is a pivotal system to help take the combination MultiTEP-based Aβ/tau vaccines therapy, as well as separate vaccines targeting these pathological molecules, to clinical trials -- perhaps within two years.
"Our approach is looking to cover all bases and get past previous roadblocks in finding a therapy to slow the accumulation of Aβ/tau molecules and delay AD progression in a the rising number of people around the world," says Professor Petrovsky, who will work in the US for the next three months.
Several promising drug candidates have failed in clinical trials so the search for new preventions or therapies continues.
A recent report on human monoclonal antibody, aducanumab, showed that high dose of this antibody reduced clinical decline in patients with early AD as measured by primary and secondary endpoints.
However, it is obvious that it could not be used as a preventive measure in healthy subjects due to the need for frequent (monthly) administration of high concentrations of immunotherapeutic.
Professor Ghochikyan says there is a pressing need to keep searching for new preventive vaccine to delay AD and slow down progression of this devastating disease.
The new combined vaccination approach could potentially be used to induce strong immune responses to both of the hallmark pathologies of AD in a broad population base of vaccinated subjects with high MHC (major histocompatibility complex) class II gene polymorphisms, the new paper concludes.
https://www.sciencedaily.com/releases/2019/12/191231111835.htm