Subtle decline in cognition predicts progression to Alzheimer's pathology

February 14, 2020

Science Daily/University of California - San Diego

Researchers report that abnormal levels of beta-amyloid plaques in brain predict cognitive decline and higher risk of developing Alzheimer's disease, but also that cognitive performance predicts progression from normal to abnormal levels of beta-amyloid.

Alzheimer's disease (AD) is progressive, but slow to develop -- or at least to reveal itself. In a new study, published online February 14, 2020 in the journal Biological Psychiatry, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, report that early, subtle differences in cognitive performance, such as fewer words recalled on a memory test, are a sign that harmful proteins are accumulating in the brain, even if levels of those proteins do not yet qualify as dangerous.

Pathologically, AD is primarily characterized by the accumulation of protein plaques called β-amyloid (Aβ), which gradually accumulate in the brain, disrupting cell function and eventually killing affected neurons. A second type of protein, called tau, also accumulates abnormally inside neurons, damaging functions.

In the progression of AD, Aβ levels build in the brain, but the process leading to abnormally high levels is typically long. It is often years or decades before consequential symptoms of severe cognitive impairment appear. A new framework from the National Institute on Aging and Alzheimer's Association defines the first stage of AD to be individuals with abnormal levels of Aβ who are still cognitively normal.

"Although AD pathology, and Aβ in particular, appear long before severe cognitive deficits appear," said first author Jeremy A. Elman, PhD, assistant professor in the Department of Psychiatry at UC San Diego School of Medicine, "recent evidence suggests more subtle cognitive changes may appear earlier in the disease than commonly appreciated."

Elman and colleagues, including senior author William S. Kremen, PhD, professor of psychiatry at UC San Diego School of Medicine, sought to determine whether poor cognitive performance, however subtle, might be a predictor that current Aβ-negative levels (accumulations below the threshold for AD diagnosis) were likely to become Aβ-positive.

"Once a person reaches the point of being Aβ-positive, it means that there is already substantial underlying pathology," said Kremen. "It would be advantageous to identify at-risk individuals before they develop substantial amyloid burden to improve treatment efficacy and slow progression to AD dementia."

The researchers conducted a pair of non-invasive cognitive tests on 292 participants in the Alzheimer's Disease Neuroimaging Initiative, an ongoing study to assess whether the use of medical imaging, biological markers and clinical assessments can be combined to measure the progression of cognitive decline and early AD.

All of the participants were Aβ-negative at baseline testing and displayed no dementia; 40 participants would progress to Aβ-positivity during the study and follow-up period.

The scientists found that participants who tested with lower baseline cognition were at significantly higher risk of progressing to Aβ-positivity. That is, low test scores indicating poorer cognitive function suggested amyloid plaque levels that, while not yet considered to be problematic, were likely rising and would ultimately reach the threshold definition of AD.

"We found that subthreshold levels of baseline Aβ were predictive of future accumulation, adding to evidence that even low levels of Aβ are clinically relevant, but that cognitive performance was still significantly predictive even after controlling for this pathology," said Elman.

The findings, wrote the researchers, suggest that low-cost, non-invasive cognitive testing is useful for identifying persons who may be at risk for developing AD, making them ideal candidates for therapeutic intervention and clinical trials.

https://www.sciencedaily.com/releases/2020/02/200214134653.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