Changes in the Diagnostic Process of Alzheimer Disease: A New Era of Blood-Based Approaches

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While specialists still debate the diagnostics of impaired cognition, the identification of patients at the earliest stages is beginning to be met through new biomarkers and available assays.

Alzheimer disease (AD) is defined by the presence of amyloid plaques and tangles in the brain leading to progressive memory loss and an inability to carry out daily function. In 2020, as many as 5.8 million Americans were living with AD, with this number projected to nearly triple by 2060.1 As society continues to age, AD poses as a serious challenge for the medical community and neurologists specifically.

What was once seen as a disease that began with old age, advances in research have shown that AD is a continuous process that starts in the brain several years prior to the onset of symptoms. Because of this, the approach to diagnosis has changed and will continue to change over time. Now, patients who show the earliest signs of cognitive decline are followed up for additional screening, with a combination of biomarkers and imaging techniques to confirm the presence of amyloid-ß (Aß) and tau, the 2 major hallmarks of the disease.

Changes in the Diagnostic Process of Alzheimer Disease: A New Era of Blood-Based Approaches

FDA-Approved Biofluid Markers

In 2011, the National Institute on Aging and Alzheimer’s Association (NIA-AA) proposed diagnostic guidelines for AD, including the pre-symptomatic and symptomatic stages of the disease.2 Years later, the group updated the framework to biologically define AD through validated biomarkers that include Aß and phosphorylated-tau (p-tau) PET; the cerebrospinal fluid (CSF) concentration of Aß42; the CSF Aß42/40 ratio; the CSF concentrations of total tau (t-tau) and p-tau181.3

Michael Alosco, PhD, director of Boston University’s Alzheimer’s Disease Research Center Clinical Core

Michael Alosco, PhD

“The framework of how we diagnose Alzheimer disease has shifted. We’ve moved towards a framework of diagnosing it by its underlying biology instead of the signs and symptoms,” Michael Alosco, PhD, director of Boston University’s Alzheimer’s Disease Research Center Clinical Core, told NeurologyLive®. "It places more emphasis on biomarkers to detect whether or not the disease is present in the brain. Using biomarkers plus signs and symptoms is the best way to get a specific, accurate diagnosis."

Alosco, who also serves as an associate professor of neurology at Boston University Chobanian & Avedisian School of Medicine, added, "we’re not at the place where we’re clinically taking blood samples and making diagnoses, but we’re very close. The first step is characterizing the person’s signs and symptoms, and then nailing down etiology using our biomarkers."

A year after the 2011 NIA-AA guidelines, the US Food and Drug Administration (FDA) approved Eli Lilly’s florbetapir F18 (Amyvid) as the first diagnostic agent to image AD-related Aß neuritic plaques in the living brain.4 Prior to the approval, the only way to confirm diagnosis of these plaques was from post-mortem biopsies. Florbetapir is an 18F-labeled ligand that, in nonclinical studies, has shown to bind to Aß aggregates in postmortem sections of human brains and in brain homogenates.

Martin Sadowski, MD, PhD

Martin Sadowski, MD, PhD

"Blood-based biomarkers are very versatile, they can provide a lot of information, and they’re cheap and ready to use," Martin Sadowski, MD, a professor of neurology, psychiatry, and pharmacology at the NYU Grossman School of Medicine, told NeurologyLive. "They can tell us where the patient is, what stage they are in, and the level of complexity in the brain. They tell us whether the patient has beta-amyloid, tau, active neuroinflammation, active neural degeneration, etc."

In 2020, the FDA approved Tauvid (flortaucipir F18) for intravenous injection, becoming the first approved drug used to help image tau in AD.5 Intended for those being evaluated for AD, the tool is indicated for PET imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles, a primary marker of AD. After Tauvid is administered intravenously, it binds to site in the brain associated with this tau protein misfolding.

Over the past year, there have been a number of other notable approaches to enter the field. Roche’s CSF Elecsys assays, which include the beta-amyloid1-42 CSF II (Abeta42) and t-tau assay, received 510(k) clearance in June of this year.6 These assays are designed to detect AD pathology in earlier stages of the disease and are intended to be used with other clinical diagnostic evaluations.

The approval of such assays came less than a year after the FDA cleared Roche’s Abeta42 and ptau181 assays. According to Roche, the assays “achieve 90% concordance” with amyloid PET scans.7

Lynn Bekris, MD

Lynn Bekris, MD

“The blood tests are offering a prescreening tool for ruling out symptomatic individuals with a low likelihood of Aß pathology,” Lynn Bekris, MD, said. “This approach makes it possible to avoid unnecessary CSF amyloid testing, therefore reducing costs and the burden associated with these more invasive and costly examinations.”

Bekris, an associate staff and associate professor at Cleveland Clinic, believes that the most useful markers in clinics right now are CSF p-tau and Aß42, which she noted “are the most robust markers of the disease.”

AD-Detect, another diagnostic screening test that evaluates the ratio of Aß42 and Aß40 in plasma, became available to physicians in May 2022.8 Patients may supply a blood specimen at 1 of over 2000 Quest Diagnostic patient service centers nationwide for testing.

From Diagnosis to Treatment

While specialists still debate whether mild cognitive impairment (MCI) is truly a diagnosis, what is acknowledged is that people with MCI have a risk state that could in the future develop into dementia or AD. Thus, the identification of patients at the earliest stages, otherwise known as the prodromal phase, is critical.

With the FDA’s approval of lecanemab (Leqembi; Eisai), an antiamyloid therapy, earlier this year, eligible individuals must be able to confirm a presence of Aß in the brain to receive treatment. Going forward, many in the field believe this will be the standard for any approved medication.

For years, patients would pay out of pocket costs for PET imaging; however, earlier this year, the Centers for Medicare and Medicaid Services (CMS) announced they will cover the imaging tool in cases for patients for a follow-up of potential AD diagnosis.9 In its decision memo, the agency noted that appropriate patient selection is "key to ensuring benefits outweigh harms of newly developed drugs targeting amyloid." This decision may prove to be critical in the coming years as society continues to age and more patients present to clinics with cognitive and executive issues.

As the field enters a new era of novel treatments, there will be an increased emphasis on the efficiencies of the healthcare system, and how to provide these therapies to those in need. "We still don’t know the optimal way for a prescreening process that is going to work in the primary care setting," Bekris said. "We won’t know how precise some of these blood-based biomarkers are, and the field is interested in pinning down the best correlated tau biomarkers. There’s a lot of work being done on tau in blood right now, but those have not been FDA-approved. They’re really in the research arena right now."

Emerging Concepts and Approaches to Aid in the Diagnosis of AD

Several in the field expect a number of blood- and imaging-based techniques to emerge over the coming years. The use of artificial intelligence (AI), a hot topic across not just neurology but all medicine, has begun to gain ground in this field.

Pixyl.Neuro, an AI-generated medical technology designed to improve detection and accelerate MRI reading time, was FDA-cleared earlier this year.10 Using proprietary AI algorithms combined with Pixyl’s computing infrastructure, the software enables quick analysis in less than 5 minutes.

Numerous types of machine learning, a branch of AI, have also begun to make headway in research settings. A published study using a machine learning model developed by researchers at Duke Health showed an ability to differentiate normal cognition from MCI using retinal images.11 Once considered a phenomenon, retinal imaging has shown to be an innovative and promising method to aid in the diagnosis of AD. RetiSpec, a medical imaging company, has developed a hyperspectral imaging technology that evaluates changes in the retina for early and accurate detection of AD markers.12

RetiSpec is designed to look at the distinctive signs of AD, as well as Parkinson disease (PD), vascular dementia, and amyotrophic lateral sclerosis, which all share some overlapping pathologies. "We increasingly see how mixed pathologies are to blame for a lot of the symptoms," Alosco said. "It’s not just 1 or 2 proteins. [We need] to get better techniques for evaluating some of these other pathologies where we don’t have good biomarkers. For example, looking at α-synuclein, looking at biomarkers for chronic traumatic encephalopathy. How can we develop these other biomarkers so that we can differentiate the diseases and hone in on the one or multiple [pathologies] that are present is where we’re going to see a lot of improvement."

α-synuclein has been widely discussed as a prominent biomarker for not only AD, but other neurodegenerative disorders. Alterations in α-synuclein dosage have led to familial PD, and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies, and multiple system atrophy. Importantly, α-synuclein regulates the fibrilization of both Aß and tau, 2 of the most key proteins in AD pathophysiology.13

Amprion’s SYNTap biomarker test, which became commercially available in 2021, represents the only seed amplification assay to help in the diagnosis of synucleinopathies such as PD, DLB, and AD.14 In clinical settings, the test has shown that approximately one-third of patients with AD have a second parallel disease that is driven by the misfolded α-synuclein. These patients, all of whom can now be more easily detected, tend to have more rapidly progressive symptoms, and may respond differently to treatment than patients with just AD, rather than a mixed dementia.

"There are biomarkers of the immune response to amyloid and tau that some people are investigating, including my lab," Bekris said. "The research community is also observing differences in amyloid and tau biomarkers by comorbidities, such as kidney disease, which can impact the levels observed in plasma or CSF. There are some differences in amyloid and tau measures in biofluids, by race and by sex—although more by sex—that still have to be better pinned down. We don’t really know why these differences are happening, so we need to characterize it and use more cohorts to try to understand that a little better."

In addition to blood-based biomarker approaches, several in the field are dedicating efforts towards improving and expanding the imaging techniques available in clinic. F-PI-2620 and MK6240, second-generation tau tracers designed to detect the neurofibrillary tangles of AD, have begun to emerge in research settings.15,16

"These are designed to have a little bit better imaging properties and less off-target binding,” Alosco added. "Those are being shown to be increasingly useful for Alzheimer disease, but also for other forms of dementias."

Alosco also believes there will be an increased effort towards understanding and diagnosing vascular dementia and the vascular aspects of AD. The vascular theory that AD is treatable based on the brain’s continuing need for cerebral blood flow (CBF) especially in the presence of advancing age.17 Previous research has shown that a decrease in CBF that can occur as a function of normal aging phenomena, less blood results in decreased mitochondria, decreased ATP, and a decrease in neuronal activity, which could potentially lead to AD. Arterial spin labeling, an MRI technique that enables the measurement of brain perfusion noninvasively at the tissue level, has been increasingly used to assess CBF in research settings.18

"Exactly what comes first is unclear, but I think I some of these more vascular imaging techniques will have important value in this field," Alosco continued. "Whether or not it’s going to specifically talk to you about the presence of Alzheimer disease is unclear, but at least in terms of getting a sense of other types of pathologies that might count for symptoms will be interesting."

References
1. Alzheimer’s Disease and Related Dementias. Centers for Disease Control and Prevention. Updated October 26, 2020. Accessed December 6, 2023. https://www.cdc.gov/aging/aginginfo/alzheimers.html
2. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National institute on Aging Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263-269. doi:10.1016/j.jalz.2011.03.005
3. Jack CR, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dementia. 2018;14(4):535–562. doi:10.1016/j.jalz.2018.02.018
4. FDA approves Amyvid (Florbetapir F18 injection) for use in patients being evaluated
for Alzheimer’s disease and other causes of cognitive decline. News release. Eli Lilly. April 9, 2012. Accessed December 6, 2023. https://www.prnewswire.com/news-releases/fda-approves-amyvid-florbetapir-f-18-injection-for-use-in-patients-being-evaluated-for-alzheimers-disease-and-other-causes-of-cognitive-decline-146638165.html
5. FDA Approves first drug to image tau pathology in patients being evaluated for Alzheimer’s disease. News release. FDA. May 28, 2020. Accessed December 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-image-tau-pathology-patients-being-evaluated-alzheimers-disease
6. Roche receives FDA clearance for additional Alzheimer’s disease cerebrospinal fluid (CSF) assays, supporting timely diagnosis and treatment decision-making. News release. June 27, 2023. Accessed June 27, 2023. https://www.prnewswire.com/news-releases/roche-receives-fda-clearance-for-additional-alzheimers-disease-cerebrospinal-fluid-csf-assays-supporting-timely-diagnosis-and-treatment-decision-making-301863708.html
7. Roche Alzheimer’s disease Cerebrospinal Fluid (CSF) assays receive FDA clearance, supporting more accurate and timely diagnosis. News release. Roche. July 19, 2022. Accessed December 6, 2023. https://diagnostics.roche.com/us/en/news-listing/2022/roche-alzheimers-disease-cerebrospinal-fluid-assays-receive-fda-clearance.html
8. Quest introduces first-to-market consumer-initiated blood test for Alzheimer’s disease risk assessment on questhealth.com. News release. Quest Diagnostics. July 31, 2023. https://newsroom.questdiagnostics.com/2023-07-31-Quest-Introduces-First-To-Market-Consumer-Initiated-Blood-Test-for-Alzheimers-Disease-Risk-Assessment-on-questhealth-com
9. Beta amyloid positron emission tomography in dementia and neurodegenerative disease. Medicare Coverage Database. October 13, 2023. Accessed December 6, 2023. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=308
10. Pixyl receives FDA clearance for AI-powered brain MRI software Pixyl.Neuro. News release. Pixyl. November 20, 2023. Accessed December 6, 2023. https://www.prnewswire.com/news-releases/pixyl-receives-fda-clearance-for-ai-powered-brain-mri-software-pixylneuro-301992829.html
11. Wisely CE, Richardson A, Henao R, et al. A convolutional neural network using multimodal retinal imaging for differentiation of mild cognitive impairment from normal cognition. Ophthalmolo Sci. Published June 25, 2023. DOI: https://doi.org/10.1016/j.xops.2023.100355
12. RetiSpec. Accessed December 6, 2023. https://www.retispec.com/solution
13. Wong YC, Koranic D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med . 2017;23(2):1-13. Doi:10.1038/nm.4269
14. Launch of SYNTap test. News release. Amprion. October 5, 2021. Accessed December 6, 2023https://ampriondx.com/news/launch-of-syntap-test/
15. Mueller A, Bullish S, Barret O, et al. Tau PET imaging with F-PI-2620 in patients with Alzheimer disease and health cohorts: a first-in-humans study. J Nucl Med. 2020;61(6):911-919. doi:10.2967/jnumed.119.236224
16. Malarte ML, Nordberg A, Lemoine L. Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer’s disease cases. Eur J Nucl Med Mol Imaging. 2021;48(4):1093-1102. doi:10.1007/s00259-020-05035-y
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