Detecting Early Onset Alzheimer's Disease in Innovative Ways
Thanks to new funding, research on biomarkers and blood tests moves forward
The progression and symptoms of early-onset Alzheimer's Disease, typically identified in patients in their 40s or 50s, can vary dramatically depending on the individual. According to the Alzheimer’s Association, “getting an accurate diagnosis of early-onset Alzheimer's can be a long and frustrating process. Symptoms may be incorrectly attributed to stress or there may be conflicting diagnoses from different health care professionals.”
The Alzheimer’s Drug Discovery Foundation (ADDF) is working to eliminate such conflicts through its $50 million Diagnostics Accelerator program. It's aimed at supporting the development of “novel biomarkers" for the early detection of Alzheimer's and related dementias.
"The health of small blood vessels is an increasingly recognized component of dementia and AD."
“We want to accelerate the science,” says Dr. Howard Fillit, founding executive director and chief science officer of ADDF. That means providing funding to support innovative research to quicken the process of developing and implementing clinical trials required for regulatory approval of Alzheimer's diagnostic tools and programs.
The onset of Alzheimer's, in general, is currently diagnosed through: mental and neuropsychological tests performed by primary care doctors and/or neurologists, along with a review of a patient’s medical history; genetic testing that identifies the APOE e4 gene associated with early-onset Alzheimer's; a PET scan or invasive spinal tap that may reveal the presence of amyloid plaques and/or tau tangles in the brain and a CT or MRI that can identify vascular dementia.
All of these solutions are relatively expensive (excluding mental testing), time-consuming, challenging to take advantage of, and, in some cases, not administered properly nor proven to yield 100% valid results in diagnosing Alzheimer's.
“We must now develop inexpensive and noninvasive biomarkers, preferably blood tests, that will help diagnose Alzheimer’s disease and track the effectiveness of treatments,” wrote Fillit in a recent article published in Scientific American.
4 First Round Award Winners
ADDF’s first round of award recipients, announced on May 30, 2019, allocated approximately $3.5 million to two Alzheimer's diagnosis blood tests and two retinal imaging R & D programs. The four — Saliha Mussaoui, Amoneta Diagnostics, based in France; Kaj Blennow, University of Gothenberg, Sweden; Tom MacGillivray, University of Edinburgh, Scotland and Peter van Wijngaarden, the Centre for Eye Research in Australia — were chosen out of 300 applicants from 30 countries.
Creating a Blood Test to Identify Early-Onset Alzheimer's
Amoneta is an affiliate of Firalis, a life sciences biotechnology company created by Dr. Huseyin Firat. Since 2014, Amoneta has conducted research and development for ultimately creating a valid blood test that can identify mild cognitive impairment (MCI) and early-onset Alzheimer's.
The test, called MemoryLINC, is based on finding difficult-to-monitor and characterize lncRNAs (long noncoding ribonucleic acids) in blood panels. These lncRNAs regulate gene expression and diverse biological functions. “It is increasingly recognized that lncRNAs is tightly related to the pathogenesis and prevention and cure of AD (Alzheimer's Disease),” notes a January 2019 study published in Pathology - Research & Practice.
Fillit says Amoneta has data indicating that certain RNAs are elevated in blood samples of people with Alzheimer's that are relevant to learning and memory and the disease itself.
The MemoryLINC Project has reached its final clinical validation phase comprised of 800 subjects at 13 European clinical sites in France, Switzerland, Belgium and Turkey. Firat says “the MemoryLINC study is the most important clinical study ever done in this domain.”
The ADDF funding for Blennow’s project intends to develop brain-specific, tau-related blood tests to identify and monitor neurodegeneration. Tau is a protein contained in nerve cells. It resides in cerebrospinal fluid in the brain and spinal cord and can be gauged through an invasive and highly uncomfortable spinal tap. The aggregation and collapse of tau into tangles that elevate and spread throughout the brain is symptomatic of Alzheimer's.
“Measuring tau in blood can be very useful,” Fillit explains. “But the problem is that tau is present in the blood in such low quantities as it relates to [Alzheimer's] that, so far, we haven’t been able to measure it effectively.” Blennow, however, has discovered how to measure brain-specific tau fragments in blood.
Over the next two years, Blennow’s team will evaluate the presence of different levels of tau in blood samples. Many of these samples will be identified from a Swedish BioFINDER cohort at Lund University, which includes 600 cognitively healthy individuals, 500 patients with subjective cognitive dysfunction or mild cognitive impairment, and 100 patients with Alzheimer's.
“This is an exploratory project aiming to develop a novel analytical method to establish robust blood biomarkers for tau,” Blennow explains.
Looking Behind the Retina
The other two ADDF-funded awardees are conducting research on imaging techniques and processes that can identify the possible unhealthy accumulation of amyloid plaques behind the retina, which is another symptom of Alzheimer's. The Alzheimer’s Association’s “2019 Alzheimer’s Disease Facts and Figures” report noted that recent research has shown that the accumulation of amyloid in the brain “were significantly increased starting 22 years before symptoms were expected to develop.”
In addition to focusing on amyloid buildup, MacGillivray’s project is looking closely at vascular changes in the small blood vessels in the back of the retina, both of which can be seen with Optical Coherence Tomography (OCT) machines that are commonly utilized by ophthalmologists.
MacGillivray says the health of small blood vessels is an increasingly recognized component of dementia and Alzheimer's. “We think we see differences in how wide or how narrow these blood vessels are, and also the number of blood vessels that fill the tissue space," he notes.
“We are seeing potentially a dying lack of blood vessels or a less optimum range of blood vessels delivering oxygen and nutrients to vascular tissue, and this is then replicated in the brain," says MacGillivray. "We have a quick and non-invasive way to see if blood vessels are changing [by utilizing relatively inexpensive OCT imagery scans] and degrading in a detrimental way inside the brain without having to go through expensive techniques such as MRIs and PETS.”
'A Wealth of Information'
“Imagine a world where people who may have memory problems are referred by their primary care doctor to the ophthalmologist around the corner,” Fillit says. The ophthalmologist uses the OCT machine to see if there is an amyloid plaque buildup in the back of the eye. It could tell you whether a person is "cooking" Alzheimer's or not, notes Fillit.
These same principles apply to Wijngaarden’s project, but with different mechanisms and equipment. This one also deals with looking behind the retina for amyloid plaques, but utilizes a sophisticated camera technology, called hyperspectral imaging. That technology can capture images behind the retina revealing different colors of light that correlate to early-onset Alzheimer's based on amyloid plaque buildup.
“We can get a wealth of information about the structure of the back of the eye,” Wijngaarden says.
To support his research and ultimately incorporate it into everyday clinical practice, Wijngaarden has developed a low-cost portable camera for hyperspectral imaging of the retina. It's being tested for use in routine eye exams where the camera will identify amyloid plaque buildup years before a patient might show signs of cognitive decline.
“What we want to do with the digital accelerator is advance these technologies, measuring things like function, cognition and a whole variety of other variables,” Fillit says.
How long will it take for such innovative technologies to possibly get government approval through clinical trials and validation and ultimately reach patients at their next doctor visit? Amoneta estimates that its blood test could be launched for use in clinics in the U.S. and Europe by 2021. The three other awardees all agree that it should take three to five years for their technologies to possibly become common practice in clinics.