Qualifying patients for treatment with anti-amyloid monoclonal antibody treatment includes making a specific diagnosis of Alzheimer's disease and demonstrating the presence of amyloid-beta, which now requires a cerebrospinal fluid (CSF) analysis or PET scan to assess.
Blood-based biomarkers have shown considerable promise for taking on these and other functions in both clinical and research settings.
In Alzheimer's drug trials, blood markers already are integrated into research protocols as screening tools and exploratory outcomes, as with the (Leqembi) and the study of investigational donanemab.
"We're seeing a lot of remarkable data starting to come out from these large-scale phase III clinical trials that are incorporating plasma tests," said Rebecca Edelmayer, PhD, of the Alzheimer's Association in Chicago.
However, significant uncertainty about blood biomarkers for clinical use remains. To date, no blood biomarker test for Alzheimer's disease has been approved as an in vitro diagnostic tool by the FDA.
Some laboratory-developed tests (LDTs) have demonstrated they can help clinicians reduce the need for confirmatory CSF or PET testing. Other LDTs say they can help identify Alzheimer's risk, and some have been marketed directly to patients.
Regardless of who requests a blood test -- patient or clinician -- the tests should be used in a setting where clinicians have experience in diagnosing memory disorders, Edelmayer pointed out.
"These tests should not be a stand-alone test," she said. "They should be used in the context of clinical care, both for the importance of being able to disclose and understand the information, and then to understand what the next steps might be."
Blood biomarkers may play several clinical roles, noted Howard Fillit, MD, of the Alzheimer's Drug Discovery Foundation in New York City, a co-author of the 2022 Clinical Trials on Alzheimer's Disease (CTAD) on blood biomarkers.
Patient and family motives for Alzheimer's testing are important to understand, Fillit pointed out. "We have to educate doctors on how to talk about these tests, their benefits, their restrictions, what the value is, and what counseling the doctor will give the patient," he said.
Will FDA Oversight Change?
The FDA actively oversees in vitro diagnostic tests made in outside laboratories by test manufacturers, but without FDA oversight.
LDTs are made and run within a single laboratory which are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). Currently, LDTs are regulated by the Centers for Medicare & Medicaid Services (CMS), which does not require tests to show clinical validity.
Last year, the FDA proposed new rules to phase out this approach. In January 2024, the FDA and CMS expressed of the analytical and clinical validity of LDTs.
"What FDA wants to do is raise the bar for the use of blood biomarkers in practice," Fillit said. In vitro classification may ultimately be the goal for these tests, he noted, and whether the LDT category will be eliminated is unknown.
While it's not clear whether the current LDTs will work well in monitoring Alzheimer's disease, "the characteristics of some blood biomarkers are so good in terms of accuracy, sensitivity, and specificity that I think they will sooner or later replace the requirement for a brain scan and will be used to determine eligibility of patients for first-generation monoclonal antibodies," Fillit said.
The Alzheimer's Association has encouraged blood test makers to pursue an FDA pathway to show clinical validation and utility. "There is certainly a level of trust that is incurred when there is FDA approval of tests of this nature," Edelmayer said.
"I also think that clinical guidelines will be important because this is what clinicians will use to inform how they do clinical care," she noted. "We will need both to recognize that the tests may not be appropriate in all clinical settings and for all reasons."
Next Steps
In 2022, the Alzheimer's Association issued for blood biomarkers for Alzheimer's disease.
The guidance recommended cautious use of blood biomarkers in specialized memory clinics to diagnose patients with cognitive symptoms, which should be confirmed when possible with CSF or PET. It also stated that additional data are needed before blood-based biomarkers can be used as stand-alone diagnostic Alzheimer's markers, or before considering using them in primary care.
"When that was published, we recognized that we're moving at a very, very fast pace in blood biomarker research for Alzheimer's disease," Edelmayer said.
An update to the 2022 recommendations will be presented at the 2024 Alzheimer's Association International Conference in July, she added. New guidelines to define how blood tests should be used in clinic settings and a systematic review should be published by the end of the year.
Biomarkers may have a broader goal in Alzheimer's disease, Fillit observed: they could foster precision medicine by including measures of inflammation, epigenetics, and other variables.
"That world is a few more years away," he said. "But I think that's the future: recognition that Alzheimer's is a complex, multifactorial disease. The current drugs, the monoclonal antibodies, slow it down by 30% or so. We need to get to 100%."
Disclosures
Edelmayer had no disclosures.
Fillit reported receiving royalties from the Icahn School of Medicine at Mount Sinai. In the past 3 years, he has consulted with Alector, Otsuka Lundbeck, LifeWorx, and The Key, and has served as an unpaid consultant for Eli Lilly.