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

Risk and progression of Alzheimer's disease differs by sex

July 16, 2019

Science Daily/Vanderbilt University Medical Center

The abnormal accumulation of proteins in the brain is a biological marker for Alzheimer's disease, but the ways in which these proteins spread may help explain why the prevalence of Alzheimer's is higher in women than in men.

A recent study by researchers from the Center for Cognitive Medicine (CCI) at Vanderbilt University Medical Center identified differences in the spread of a protein called tau -- which is linked to cognitive impairment -- between men and women, with women showing a larger brain-wide accumulation of tau than men due to an accelerated brain-wide spread.

The findings were presented at the Alzheimer's Association International Conference July 14-18 in Los Angeles.

Accumulating evidence suggests that tau spreads through brain tissue like an infection, traveling from neuron to neuron and turning other proteins into abnormal tangles, subsequently killing brain cells. Using data from positron emission tomography (PET) scans of healthy individuals and patients with mild cognitive impairment who were enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, CCI researchers constructed in vivo networks modeling tau spread using graph theory analysis.

"It's kind of like reconstructing a crime scene after a crime. You weren't there when it happened, but you can determine where an intruder entered a house and what room they entered next," said Sepi Shokouhi, PhD, assistant professor of Psychiatry and Behavioral Sciences and lead investigator for the study. "The graph analysis does something similar to show how tau spreads from one region to another."

The results of the analysis showed the architecture of tau networks is different in men and women, with women having a larger number of "bridging regions" that connect various communities in the brain. This difference may allow tau to spread more easily between regions, boosting the speed at which it accumulates and putting women at greater risk for developing Alzheimer's disease.

If proven, an accelerated spread of tau in women may indicate a need for sex-specific approaches for the prevention of Alzheimer's disease, including earlier therapies, lifestyle interventions and/or cognitive remediation. More studies are needed to validate the accelerated tau spread model in women.

"Understanding how different biological processes influence our memory is a really important topic. Sex-specific differences in the brain's pathological, neuroanatomical and functional organization may map into differences at a neurobehavioral and cognitive level, thus explaining differences in the prevalence of neurodegenerative disorders and helping us develop appropriate treatments," said Shokouhi.

https://www.sciencedaily.com/releases/2019/07/190716124853.htm

Exercise offers protection against Alzheimer's

July 16, 2019

Science Daily/Massachusetts General Hospital

Higher levels of daily physical activity may protect against the cognitive decline and neurodegeneration (brain tissue loss) from Alzheimer's disease (AD) that alters the lives of many older people, researchers from Massachusetts General Hospital (MGH) have found. In a paper in JAMA Neurology, the team also reported that lowering vascular risk factors may offer additional protection against Alzheimer's and delay progression of the devastating disease. The findings from this study will be presented at the Alzheimer's Association International Conference (AAIC) in Los Angeles by the first author of the study, Jennifer Rabin, PhD, now at the University of Toronto, Sunnybrook Research Institute.

"One of the most striking findings from our study was that greater physical activity not only appeared to have positive effects on slowing cognitive decline, but also on slowing the rate of brain tissue loss over time in normal people who had high levels of amyloid plaque in the brain," says Jasmeer Chhatwal, MD, PhD of the MGH Department of Neurology, and corresponding author of the study. The report suggests that physical activity might reduce b-amyloid (Ab)-related cortical thinning and preserve gray matter structure in regions of the brain that have been implicated in episodic memory loss and Alzheimer's-related neurodegeneration.

The pathophysiological process of AD begins decades before clinical symptoms emerge and is characterized by early accumulation of b-amyloid protein. The MGH study is among the first to demonstrate the protective effects of physical activity and vascular risk management in the "preclinical stage" of Alzheimer's disease, while there is an opportunity to intervene prior to the onset of substantial neuronal loss and clinical impairment. "Because there are currently no disease-modifying therapies for Alzheimer's disease, there is a critical need to identify potential risk-altering factors that might delay progression of the disease," says Chhatwal.

The Harvard Aging Brain Study at MGH assessed physical activity in its participants -- 182 normal older adults, including those with elevated b-amyloid who were judged at high-risk of cognitive decline -- through hip-mounted pedometers which counted the number of steps walked during the course of the day.

"Beneficial effects were seen at even modest levels of physical activity, but were most prominent at around 8,900 steps, which is only slightly less than the 10,000 many of us strive to achieve daily," notes co-author Reisa Sperling, MD, director of the Center for Alzheimer's Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital and co-principal investigator of the Harvard Aging Brain Study.

Interventional approaches that target vascular risk factors along with physical exercise have added beneficial properties, she adds, since both operate independently. Vascular risk factors measured by the researchers were drawn from the Framingham Cardiovascular Disease Risk Score Calculator, and include age, sex, weight, smoking/non-smoking, blood pressure, and whether people are on treatment for hypertension.

Through ongoing studies MGH is working to characterize other forms of physical activity and lifestyle changes that may help retard the progress of Alzheimer's disease. "Beta amyloid and tau protein build-up certainly set the stage for cognitive impairment in later age, but we shouldn't forget that there are steps we can take now to reduce the risk going forward -- even in people with build-up of these proteins," says Chhatwal. "Alzheimer's disease and the emergence of cognitive decline is multifactorial and demands a multifactorial approach if we hope to change its trajectory."

https://www.sciencedaily.com/releases/2019/07/190716193543.htm