-- FROM THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE 2019 

Significant advances in the global search for blood test technologies for 
Alzheimer's disease and other dementias were reported at the Alzheimer's 
Association International Conference ( 
https://c212.net/c/link/?t=0&l=en&o=2524018-1&h=2836536051&u=https%3A%2F%2Fwww.alz.org%2Faaic%2Foverview.asp&a=Alzheimer%27s+Association+International+Conference 
) (AAIC) 2019 in Los Angeles. 

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A new report at AAIC 2019 describes methods for measuring abnormal versions of 
amyloid protein, which is the building block of one of the hallmark brain 
lesions of Alzheimer's disease, in blood and correlating it with established 
Alzheimer's markers. Two additional reports describe new blood-based methods 
for assessing alpha synuclein, which contributes to the brain changes of 
Parkinson's disease and Dementia with Lewy Bodies, and neurofilament light, 
which may turn out to be the most reliable indicator of general brain cell 
damage.

Currently, the brain changes that occur before Alzheimer's dementia symptoms 
appear can only be reliably assessed by positron-emission tomography (PET) 
scans, and from measuring amyloid and tau proteins in spinal fluid. These 
methods are expensive and, in the case of a spinal tap, invasive. And, too 
often, they are unavailable, not covered by insurance or difficult to access.

There is a global "race" to uncover and develop new screening and diagnostic 
tools for Alzheimer's disease, such as a blood test. 

"There is a great need for simple, reliable, inexpensive, non-invasive and 
easily available diagnostic tools for Alzheimer's," said Maria C. Carrillo, 
PhD, Alzheimer's Association chief science officer. "Families facing 
Alzheimer's now and in the future would benefit greatly from simple and widely 
accessible diagnostic tools that enable accurate diagnosis, earlier in the 
disease process, allowing for important care and planning."

"These new testing technologies, which are currently under development by 
industry and academic researchers, could also potentially be used to track the 
impact of therapies in clinical trials," Carrillo added. 

How Does Plasma Amyloid Compare with Other Alzheimer's Biomarkers?
In a study published in Nature in January 2018, Akinori Nakamura, MD, PhD, of 
the National Center for Geriatrics and Gerontology, Obu, Japan and colleagues 
described a potential blood biomarker of amyloid-beta which they suggested 
might allow identification of people likely to develop Alzheimer's dementia in 
the future. The technology measures plasma levels of amyloid-related peptides 
(AB1-42, AB1-40, and APP669-711), and the biomarker is generated by combining 
the ratios of the peptides (APP669-711/AB1-42 and AB1-40/AB1-42).

At AAIC 2019, Nakamura and colleagues reported results of a study aimed at 
analyzing the plasma biomarker in comparison to brain amyloid PET scans 
(reflecting AB deposition), structural MRI (reflecting brain atrophy), FDG-PET 
(reflecting glucose hypometabolism) and behavioral tests (MMSE/reflecting 
cognitive decline). They analyzed 201 samples (70 cognitively normal, 46 MCI, 
61 Alzheimer's, and 24 non-Alzheimer's dementia) from three different 
institutes in Japan. 

The composite blood biomarker values were significantly correlated with amyloid 
PET values (p<0.001), MRI (p<0.001), FDG-PET (p<0.002), and MMSE (p<0.001).

"We found that the plasma biomarker can detect earlier stages of amyloid 
deposition, even before dementia symptoms are apparent," Nakamura said. "Our 
results suggest that the plasma biomarker may be useful in screening people who 
are at risk for Alzheimer's. This can facilitate clinical trials for 
Alzheimer's therapies, and also accelerate studies to investigate the effects 
of non-drug interventions, risk management, and lifestyles on Alzheimer's 
progression."

Alpha Synuclein (a Lewy Body Marker), Amyloid and Tau in Red Blood Cells
A common feature of many degenerative brain diseases is accumulation of 
"misfolded proteins," including a-synuclein (a-syn), amyloid-beta (AB) and tau, 
in both the brain and peripheral fluids. Recently, the physical interaction of 
a-syn with amyloid and tau has been suggested to be involved in the cause and 
progression of these diseases. 

Abnormal versions of amyloid and tau protein are the main building blocks of 
the hallmark brain lesions of Alzheimer's disease, though they also appear in 
other conditions. a-syn is a major constituent of Lewy bodies, protein clumps 
that are the hallmark of Parkinson's disease and Dementia with Lewy Bodies. 

Filippo Baldacci, MD, of the Department of Clinical and Experimental Medicine, 
University of Pisa, Italy, and the Institute of Memory and Alzheimer's Disease 
(IM2A), Department of Neurology, Pitié-Salpêtrière Hospital in Paris, and 
colleagues sought to discover whether concentrations of a-syn and its 
combinations with amyloid and tau (a-syn/AB and a-syn/tau) in red blood cells 
can accurately discriminate people with Alzheimer's from healthy individuals.

Levels of a-syn, a-syn/AB and a-syn/tau were analyzed in 39 people with 
early-stage Alzheimer's and 39 age-matched healthy controls. Alzheimer's 
patients received a biomarker-based diagnosis (CSF AB and CSF total-tau and/or 
phospho-tau; alternatively, a positive brain amyloid PET scan).

The researchers found that people with Alzheimer's in the study had lower 
concentrations of a-syn, a-syn/AB and a-syn/tau in red blood cells (RBC) than 
controls. RBC a-syn/AB and RBC a-syn/tau discriminated people with Alzheimer's 
from healthy controls with "fair accuracy" (AUROC=0.76, 0.72, respectively). 
RBC a-syn was less accurate (AUROC=0.63). 

"Our results showed that people with Alzheimer's had much lower concentrations 
of a-synuclein and its combinations with amyloid and tau in their red blood 
cells, compared to healthy individuals," Baldacci said. "With further research 
and confirmation, this may prove to be a good tool to identify people with 
Alzheimer's. We have experiments in progress now to verify its ability to 
discriminate Alzheimer's from other brain diseases, such as Lewy body dementia 
or Parkinson's dementia."

"Red blood cells may represent workable and relevant models of 
neurodegeneration since they are likely to be involved in the accumulation and 
clearance of the misfolded proteins," Baldacci added.

Plasma Neurofilament Light Distinguishes Multiple Diseases from Healthy Controls
Neurofilament light (NfL), also known as neurofilament light chain, is being 
actively investigated as a biological marker for neurodegeneration in 
cerebrospinal fluid and plasma in a variety of neurological disorders, 
including Alzheimer's disease and other dementias.

Abdul Hye, PhD, of the Institute of Psychiatry, Psychology & Neuroscience, 
King's College London (KCL) says, "Although blood NfL differences between 
aged-matched controls and disease patients are widely accepted, there has so 
far been limited research into how concentrations of NfL differ across 
neurodegenerative disorders."

As reported at AAIC 2019, Hye and colleagues at KCL, Lund University and 
University of Gothenburg led a multi-center international study to compare the 
levels of blood NfL across multiple neurodegenerative/neurological conditions. 
In the study, the original group (n=1,465; BioFINDER from Lund University) and 
a second independent cohort (n=852; KCL), included people with mild cognitive 
impairment (MCI), Alzheimer's disease, frontotemporal dementia (FTD), dementia 
with Lewy bodies (DLB), Parkinson's disease (PD), primary tauopathies and 
healthy elderly controls. In addition, several other conditions such as 
vascular dementia, Down syndrome (DS), amyotrophic lateral sclerosis (ALS), 
multiple sclerosis (MS) and clinical depression were included. 

The researchers found that NfL was significantly increased in eight 
neurodegenerative conditions including Alzheimer's, FTD, DLB, corticobasal 
syndrome (CBS), ALS and Down syndrome with dementia (DS-D), compared to the 
control group. Similar results were observed for both study groups. They 
subsequently generated an NfL concentration cut-off point (in the BioFINDER 
study group) to attempt to distinguish what was considered normal and abnormal; 
this was then tested in the KCL cohort.

The scientists found that only 2% of the healthy controls had abnormal NfL 
levels, which strengthened the choice of cut-off point. The cut-off point 
identified these groups as those in the study with the highest NfL 
concentrations: ALS (82%), DS-D (100%), CBS (53-67%) and FTD (40-63%). In both 
study groups, only between 16-20% of people with Alzheimer's would cross the 
threshold of abnormal NfL. The researchers say they have replicated this 
Alzheimer's finding in the Alzheimer's Disease Neuroimaging Initiative data.

"For the first time we have shown that NfL on its own is able to distinguish 
several neurodegenerative conditions when compared to healthy controls," Hye 
said. "These results hold promise for the use of NfL as a diagnostic tool and 
in clinical trials."

"Though, as previously seen in other studies, NfL is not specific for any 
condition, with validation it could be valuable as a relatively inexpensive and 
fast test for accumulating neurodegeneration in the brain," Hye added.

About the Alzheimer's Association International Conference (AAIC)
The Alzheimer's Association International Conference (AAIC) is the world's 
largest gathering of researchers from around the world focused on Alzheimer's 
and other dementias. As a part of the Alzheimer's Association's research 
program, AAIC serves as a catalyst for generating new knowledge about dementia 
and fostering a vital, collegial research community.
AAIC 2019 home page: www.alz.org/aaic/

AAIC 2019 newsroom: www.alz.org/aaic/pressroom.asp

About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in 
Alzheimer's care, support and research. Our mission is to eliminate Alzheimer's 
disease through the advancement of research, to provide and enhance care and 
support for all affected, and to reduce the risk of dementia through the 
promotion of brain health. Our vision is a world without Alzheimer's. Visit 
alz.org or call 800.272.3900.

    -- Akinori Nakamura, MD, PhD, et al. What Kind of Information Does the 
       Plasma Amyloid-B Biomarker Tell Us? (Funder(s): Japan Agency for 
       Medical Research and Development) 
    -- Filippo Baldacci, MD, et al. Potential Diagnostic Value of Red Blood 
       Cells a-Synuclein Heteroaggregates in Alzheimer's Disease. (Funder(s): 
       PRA Health Sciences, Inc.) 
    -- Abdul Hye, PhD, et al. Plasma Neurofilament Light a Pan-
       Neurodegenerative Marker. (Funder(s): National Institute for Health 
       Research (NIHR); European Research Council; Swedish Research Council; 
       Knut and Alice Wallenberg Foundation; Marianne and Marcus Wallenberg 
       Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; 
       Parkinson Foundation of Sweden; Skane University Hospital Foundation; 
       Swedish federal government.)

SOURCE  Alzheimer's Association

CONTACT: Alzheimer's Association Media Line, +1.312.335.4078, media@alz.org; 
AAIC 2019 Press Office, +1.213.743.6202, aaicmedia@alz.org