Li homes in on predictive biomarkers for dementia
Dementia is the loss of cognitive functioning—the ability to think, remember, or reason—to such an extent that it interferes with a person's daily life and activities. That’s how dementia is described by the National Institute of Neurological Disorders and Stroke. Alzheimer’s Disease is the most common form of dementia, afflicting more than seven million Americans.
Most Americans know someone who has been diagnosed with dementia. More will as the population ages.
A recent study showed that the risk of developing dementia at any time after age 55 among Americans is 42 percent, more than double what was thought. That study, “Lifetime risk and projected burden of dementia,” was based on participants selected from the ongoing Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Launched in 1987, ARIC-NCS has closely tracked the vascular health and cognitive function of nearly 16,000 participants as they age. The cohort is drawn from four U.S. communities including Minneapolis.
LMP associate professor Danni Li knows the ARIC cohort well. Her research uses data from ARIC and other studies to show how diet, exercise, and frailty influence cognitive decline. LMP’s Advanced Research and Diagnostic Laboratory (ARDL), where Li applies ultra-sensitive immunoassays such as Single Molecular Array (Simoa) to the discovery of biomarkers for diagnosis including for Alzheimer’s disease and Amyotrophic Lateral Sclerosis (ALS), has served as a central biochemical testing laboratory for multi-center ARIC clinical trials over many years.
Besides the immunoassay, mass spectrometry (MS) is the gold standard technique for identifying biomarkers in cerebrospinal fluid (CSF) that can lead to early diagnosis of Alzheimer’s Disease, although PET (positron emission tomography) scans are also used. Once identified, these biomarkers are being incorporated into immunoassays that sample blood plasma to detect risk, forgoing the spinal tap need to obtain CSF for MS analysis. Immunoassays are also easier to automate than MS, which requires extensive sample preparation, Li said in an interview.
“From the perspective of doing large-scale testing, I think immunoassays definitely have a lot of advantages,” she said. “All these methods have their pros and cons. Not all immunoassays or mass spec perform equally well, but immunoassays have the advantage of being easier to automate.”
Li said Alzheimer’s Disease is biologically established as associated with beta-amyloid (ß-Amyloid) aggregation or plaques followed by phosphorylation of tau. Phosphorylated tau 217 (p-tau217) is emerging as the leading biomarker for detecting Alzheimer's disease and related dementias.
The tau protein is essential for healthy neurons. When it is damaged through excessive phosphorylation -- the addition of a phosphoryl group of phosphorous and oxygen atoms to tau – neurofibrillary tangles develop, and the neuron is impaired. p-tau217 is one of more than 80 p-tau variants but one with superior predictive power.
The U.S. Food and Drug Administration (FDA) has granted its Breakthrough Device Designation to p-tau217 blood tests for Alzheimer’s Disease. On May 16th, the FDA approved the first in vitro (outside the body) diagnostic device that tests blood to aid in diagnosing Alzheimer’s disease. "The Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio is for the early detection of amyloid plaques associated with Alzheimer’s disease in adult patients, aged 55 years and older, exhibiting signs and symptoms of the disease," according to an FDA news release.
In an April substack posting "The breakthrough blood test for Alzheimer's Disease," the noted cardiologist, scientist and author Eric Topol observes: “The p-Tau217 biomarker is one of the most exciting advances in neurology for decades, giving us a new opportunity to accurately predict and potentially prevent (or at least substantially delay) MCI and Alzheimer’s.” MCI, mild cognitive impairment, typically precedes Alzheimer’s Disease by years, sometimes decades.
Li agrees that p-tau217 is emerging as the most predictive of the several Alzheimer’s biomarkers she has worked with. She and LMP professor Bharat Thyagarajan have introduced and applied a p-tau217 immunoassay at ARDL, which Thyagarajan directs.
The Alzheimer’s Association recently released the results of a national survey of 1,700 adults showing that nearly 8 in 10 respondents said they would want to know if they had Alzheimer's before they developed symptoms. Last year, the Lancet’s standing commission on dementia prevention, intervention, and care reported that modifying 14 risk factors “might prevent or delay half of dementia cases.” In addition, the FDA has approved two new drugs that slow the buildup of beta-amyloid plaques in the brain, which are associated with dementia.
Is mass screening of the general population with the p-tau217 test on the horizon? Topol is opposed, writing in his new book Super Agers that “my view in the face of the raging debate is that this test should not be done routinely in people who are cognitively intact, nor should it be used to assign a diagnosis of pre-Alzheimer’s. That is not warranted or appropriate based on what we know.”
While there is a lot of interest in p-tau217 for screening, Thyagarajan said, “I think the big population-based studies are not showing the same assay performance that was seen in highly controlled clinical studies.” He said he can see the test being used in a “narrow clinic setting for diagnosing people with symptoms but not for screening asymptomatic patients anytime in the near future.”
Meanwhile, Li is forging ahead. “When it comes to my research, a lot of the grants I’m part of involve measuring plasma biomarkers using ARDL’s Simoa assays and Quanterix instruments,” she said. “We work on the role of exercise in clinical trials, looking at how plasma biomarkers respond in Alzheimer Disease patients. We are also interested in how lipoproteins that carry cholesterol through the bloodstream change in terms of disease pathology and cognitive function – both in the blood and the CSF.”
In addition to ARDL’s instruments, Li also makes use of the Mass Spec Core Facility in the CCRB Building, “which is a wonderful resource. The fee for using those instruments is very reasonable.”
Source for image at the top of the page: National Institute on Aging: NIA.NIH.GOV
