Using Blood Diagnostics to Detect Risk of Alzheimer’s Disease

May 16, 2022 - Alzheimer’s disease (AD) is the most common form of dementia, affecting 5.8 million people in the United States. In the past, a definitive AD diagnosis could only be made during an autopsy, making it difficult for neurologists to distinguish patients with mild cognitive impairment (MCI) due to normal aging from those with an increased risk of AD or another neurodegenerative disorder. Today, doctors use numerous tools and methods to determine if an individual is at risk of developing AD, including blood diagnostics.

Michael Racke, MD, a neurologist specializing in neuroimmunology, knows a great deal about diagnosing and treating brain disorders, including AD. As the medical director of Neurology at Quest Diagnostics, Racke has firsthand experience with one of the first nationally available Clinical Laboratory Improvement Amendments (CLIA)-certified blood tests — AD-Detect, Amyloid Beta 42/40 Ratio, Plasma (AD-Detect) — developed to aid in the detection of AD risk in adults exhibiting signs of mild cognitive impairment (MCI) or dementia, Racke explained in an interview with LifeSciencesIntelligence.

AD is characterized by two protein aggregations in the brain: intraneuronal tau protein and extracellular amyloid beta (Aβ). AD-Detect measures the amyloid beta ratio of two blood-based biomarkers, beta amyloid 42 (Aβ42) and beta amyloid (Aβ40), for early detection of AD in blood plasma using liquid chromatography–tandem mass spectrometry (LC–MS/MS). This analysis-based assay provides a more straightforward option than positron emission tomography (PET) imaging and a less invasive procedure than cerebrospinal fluid (CSF) sampling, Racke noted.

“With these longitudinal studies, the idea is that we anticipate that we’ll be able to show what happens to the Aβ42/40 ratio over time,” Racke said. A decrease in the Aβ42/40 ratio is a strong AD marker, he added.

Additionally, biomarker analysis of CSF and neuroimaging techniques such as PET can recognize the disease in patients before initial symptoms begin. However, these invasive and expensive tests are not part of routine care for the millions suffering from this AD, Racke noted.

Racke explained that physicians can also look at a wide range of established AD risk factors, such as CSF, age, medical history, genetics, environment, and lifestyle, to determine if a patient has an increased risk.

“Last summer, the first treatment for the pathogenesis of Alzheimer’s was approved, aducanumab. And we knew we were going to be approving the first big-time blood test for Alzheimer’s disease,” Racke stated

Aducanumab is an amyloid-beta-directed monoclonal antibody that targets aggregated forms of amyloid beta found in the brains of people with Alzheimer’s disease to reduce buildup. In June 2021, Biogen’s aducanumab (Aduhelm) became the first FDA-approved treatment for Alzheimer’s disease despite years of speculation regarding its murky clinical benefits and astronomical price.

“Right now, we spend $7 trillion to care for people in the United States who have Alzheimer’s disease. And if we could do something to push back the diagnosis and identify who needs care, that alone could save the system lots of money,” said Racke.

In 2022, all forms of dementia (AD, vascular, Lewy body, frontotemporal, and mixed dementias) will cost the United States healthcare system close to $321 billion. And by 2050, these costs could balloon to nearly $1 trillion.

Compared to the price tag of aducanumab — $56,000 per year before being cut down to $28,000 — AD-Detect is a much more affordable method of diagnosing AD, Racke explained.

“Right now, a lot depends on a patient’s insurance. The out-of-pocket cost for this, without insurance, would be $500. But we anticipate that most patients will have some level of coverage. Obviously, it depends on the individual’s plan and the responsibility of that plan for coverage,” he clarified.

Time is another essential factor. “Even if you look at aducanumab, it’s very clear you’ve got to treat early,” Racke said. “By the time a patient has moderate dementia, a scan would show that a lot of their brain would be gone,” he continued.

Research shows that amyloid can be deposited in the brain years before PET scans can detect it.

“And that’s even probably 10–20 years before someone’s symptomatic,” Racke noted. “For example, to be eligible for the aducanumab trial, a patient must be PET-positive, meaning that they had a scan that showed amyloid deposition in the brain and already had some evidence of cognitive dysfunction, even if it was mild,” he continued.

Simply put, damage to the brain begins long before memory and other cognitive impairments appear. During this preclinical stage of AD, individuals can be symptom-free while substantial changes occur in the brain. For most people, late-onset symptoms first appear around 65, while early-onset AD can appear anywhere between 30 and 65.

Racke and company recently surveyed the attitudes of US physicians and adults on the current and future landscape of dementia and AD testing, evaluation, care, and treatment.

“In the survey, doctors said that they start evaluating people for Alzheimer’s disease around age 66, but patients said they wanted to be evaluated by age 57,” Racke recalled.

Because this blood test can be collected in primary care settings or one of the more than 2,200 national patient service centers Quest operates, this risk assessment analysis could begin a new era of AD diagnosis.

“After a few tests, if one sees the ratio continue to go down, that would be somebody who would be referred to a neurologist Alzheimer’s disease research center for clinical trial evaluation,” he asserted.

Quest-AD identifies pharma biomarker-ready cohorts and helps fill clinical trials with patients who are cognitively normal and present a normal PET scan but are determined to be at risk for AD, Racke clarified. The degradation could be identified much earlier in the process and allow for intervention before too much damage is done.

While some say a cure for AD is impossible, Racke believes the treatment of AD can only go as far as our current understanding of science. “I would argue that a lot depends on our level of understanding medicine,” he expressed.

“We’re not going to cure the disease right now, but if we can take out the amyloid before it starts causing permanent damage, then we could potentially treat patients before they lose the neuron and the synapses that result in impaired cognition.”

While some researchers believe other disease markers such as tau could prove more promising when incorporated into blood tests for Alzheimer’s, Racke described the A/T/N framework frequently used in clinical trials, where A stands for amyloid, T stands for tau, and N stands for neurodegeneration. Additionally, Racke noted that biomarker tests for pTau-181 and pTau-217 already exist.

However, since monitoring the A/T/N framework is not the only option in diagnosing AD risk, the underlying cause of MCI or dementia should be analyzed in conjunction with medical and family history, nutritional deficiency biomarkers, neuroimaging, and neurological and neuropsychological examination for a comprehensive review.

Racke noted that the new standard of care will likely begin earlier in life, with primary care physicians being the initial point of AD screening. “It’s going to turn healthcare a little bit on its head because we don’t typically do that. People usually wait until they are symptomatic before they are treated,” he concluded.