23 Aug 2022

Part 3 of 3

An abundance of blood-based biomarker findings were on display at the Alzheimer’s Association International Conference, held July 31-August 4 in San Diego. Scientists presented findings directly comparing the top markers to each other in different cohorts, revealing a slew of markers that detect amyloid plaques in the brain and predict cognitive decline (see Part 2 of this series). With tests coming onto the scene, scientists are starting to grapple with the problems that remain to be solved before they can be used broadly in clinical practice, let alone in primary care settings without the help of memory specialists. Researchers at the meeting charted a path toward implementation, articulated the questions for this next phase, and proposed studies needed to answer them. One focus: initial data on how different comorbidities might tweak readings of some biomarkers.

Roadmap to Primary Care
Charlotte Teunissen of Amsterdam University Medical Center laid out a path of studies needed to develop Alzheimer's disease blood biomarkers, from initial preclinical exploration to routine use (see Part 1). It includes five phases, each requiring completion of studies in ever-more-heterogenous, diverse populations. The final phase concerns the ultimate, and most far-off, goal: to ready blood tests for routine use not only in specialist memory clinics, but also in primary care.

Douglas Galasko, University of California, San Diego, zeroed in on that phase. For starters, the role of primary care doctors in diagnosing and treating neurodegenerative disorders varies markedly by country. Some, such as England, France, and Spain, have established memory clinics all over the country; in others, including Australia, Belgium, Finland, Denmark, and Canada, primary care doctors manage Alzheimer's care with support from specialists. In the U.S., the balance between primary care and specialist care varies by state and health plan, Galasko said. This is to say nothing of the situation in most developing countries, where dementia specialists are few and far between. 

Regardless of the structure of the healthcare system in which they work, physicians ordering a blood biomarker test will need to have a firm grasp of what the biomarker is measuring. They need training in what different results may and may not mean for an individual given their overall health, age, sex, and ApoE status, and in how to accurately communicate these nuances to the patient.

“This is not some simple, check-off-a-box blood test,” Galasko said. “One may need to discuss the test, its context, and possible outcomes with a patient before ordering it.” Once the results are in, an in-depth conversation about interpretation, prognosis, and potential treatment options will need to occur, Galasko said. As of now, such analysis and discussion are beyond the scope of most busy primary care doctors, and even some dementia specialists, Galasko said.

How can physicians help their patients decide if biomarker testing is right for them? Several groups are working on developing tools for physicians and patients to aid in decision-making. One is the Advisory Group on Risk Evidence Education for Dementia (AGREEDementia), an NIA-coordinated working group that previously developed a decision aid for people with MCI who were considering undergoing amyloid-PET. The group is now putting together a decision aid for blood biomarkers.

Biomarker scientists at AAIC broadly agreed that blood tests are best interpreted in the context of a cognitive assessment. The trouble with that? Cognitive tests often fall by the wayside in primary care, Galasko said. Many primary care doctors lack the time or expertise to test cognition consistently. Case in point: Although cognition is included in annual Medicare wellness exams in the U.S., doctors only need ask the patient in front of them about their cognition, rather than actually test it, to check this box.

“Cognition should be considered a vital sign,” Galasko told Alzforum. To take pressure off primary care doctors, the field could agree on digital tests, whose development has accelerated in recent years. A patient could take a brief cognitive test on a smartphone or tablet, either at home or in the waiting room prior to their annual wellness check, Galasko suggested. This would remove the burden from primary care doctors, standardize cognitive tests, and aid in decisions to order biomarker tests and interpret their results.

Work is already underway to figure out how best to combine quick cognitive tests with blood biomarkers in primary care. Oskar Hansson of Lund University described an ongoing prospective study that aims to derive easy-to-use algorithms based on combinations of blood biomarker assays and brief cognitive tests to improve the diagnosis and prognosis of AD in primary care (see image below). Thus far, it has enrolled 300 of what are to be 800 participants from 25 primary care centers across Sweden with subjective cognitive complaints, MCI, or mild dementia. Nurses at the primary care clinics collect blood and oversee cognitive tests that run on smartphones, iPads, and paper. To establish a reference standard of diagnostic accuracy, all participants in this study will also undergo the kind of extensive, specialized memory clinic work-up that is familiar to Alzforum readers—neuropsychological testing, CSF sampling, and PET. The winning mixture of blood biomarkers and primary care-level cognitive tests that best matches the memory clinic findings will then be considered for broader deployment in primary care.

Blood Tests in Primary Care. To move blood biomarkers from research cohorts into primary care, researchers are testing various combinations of blood biomarkers and brief cognitive tests in 25 primary care clinics in Sweden. [Courtesy of Oskar Hansson, Lund University, Sweden.]

Contending with Comorbidities
Even with a winning combination of cognitive tests and blood biomarkers in hand, physicians remain uncertain about the influence of genetics, race/ethnicity, and comorbidities on the test. Most blood-biomarker studies have been conducted in research cohorts that included predominantly white participants. A notable exception are the cohorts at Washington University, St. Louis. A recent study led by Suzanne Schindler there found that while plasma Aβ42/40 had comparable predictive value in African Americans and Caucasians in that cohort, plasma p-tau181 performed worse in African Americans (Apr 2022 news on Schindler et al., 2022).

The authors speculated that these differences likely reflect differences in underlying medical comorbidities and social determinants of health. For example, they noted that African Americans in the study had higher rates of hypertension and diabetes than their Caucasian counterparts. This jibes with recent studies reporting that heart and kidney disease influence biomarker levels (Syrjanen et al., 2022).

At AAIC, researchers dug more deeply into the potential influence of comorbidities on biomarker levels. Michelle Mielke, who is now at Wake Forest University in Winston-Salem, North Carolina, reported that among 1,329 participants in the Mayo Clinic Study of Aging, the effect of chronic kidney disease rivaled that of amyloid status on a person's level of plasma p-tau181 and p-tau217 (Mielke et al., 2022). Stroke and myocardial infarction were each associated with higher p-tau levels as well, whereas higher body-mass index (BMI) lowered the measured p-tau value. In her AAIC talk, Mielke described an example of one participant who had minimal AD pathology upon autopsy, despite having the highest plasma concentration of p-tau217 in the entire cohort. Mielke discovered that this participant also had sky-high serum creatinine levels, indicative of poor kidney function. “As a result of having chronic kidney disease, this person would have been a false positive,” Mielke said.

Mielke further reported that including people with myocardial infarction, stroke, or kidney disease in the cohort widened the normal range for these biomarkers, such that the cut point of abnormality for p-tau181 decreased from 1.75 to 1.5 pg/mL once these people were excluded. This effect was smaller for p-tau217, where it inched the cut point down from 0.26 to 0.25. Such findings suggest that, at the group level, such comorbidities have minimal influence on plasma p-tau217’s predictive power for amyloid. However, for an individual person with one of these comorbidities, researchers will need to figure out whether adjustments are needed to avoid misdiagnosing them.

Of the participants in the Mayo Clinic cohort, 95 percent are non-Hispanic white, so Mielke was unable to investigate the relationship between race, ethnicity, comorbidities, and biomarkers. She did note that African Americans have a higher prevalence of all the comorbidities that also increase biomarker levels, which could lead to disproportionate misdiagnoses in this group. Mielke highlighted a recent study in Mexican Americans, which reported that dyslipidemia, hypertension, and diabetes bumped up their AD plasma biomarker levels (O’Bryant et al., 2022).

Hansson also reported findings about how comorbidities might degrade the accuracy of plasma biomarkers. In the Swedish BioFINDER-1 and BioFINDER-2 cohort studies, the Lund team investigated whether potential confounds such as kidney function or BMI influenced the associations between individual plasma biomarkers and their CSF counterparts, or the ability of the plasma markers to predict a person's progression to dementia. Their finding? Creatinine levels correlated with higher plasma concentrations of NfL, GFAP and, to a lesser extent, p-tau181 and p-tau217.

As in the Mayo cohort, BMI had the opposite association in BioFINDER, probably reflecting the diluting effect of a larger blood volume. Importantly, however, when the researchers adjusted for creatinine or BMI in their models, they saw that these factors did not influence how well a given blood marker correlated with its counterpart in CSF, nor a blood marker's ability to predict subsequent dementia. Hansson concluded that while creatinine and BMI do hold sway over levels of certain plasma biomarkers, they are not clinically relevant confounds for most people.

In a comment to Alzforum, Mielke cautioned against using the term “confounder” to describe physiological factors that can affect the interpretation of the blood biomarkers. “In public health, a confounder is something associated with both the risk factor and outcome, and can be adjusted for,” Mielke wrote. “Chronic kidney disease is not associated with amyloid pathology, but [is associated] with neurodegeneration and vascular pathology. Therefore, we cannot simply ‘adjust’ for kidney disease or other factors shown to affect the blood biomarkers due to physiological reasons.”

Hansson said that how comorbidities influence the predictive value of blood biomarkers relates not only to the prevalence of these comorbidities in the population at hand, but also to how strongly the disease raises the biomarker concentration.

For example, in cognitively normal people, p-tau217 shoots up by 80-350 percent in those with brain amyloid, depending on the study. Among people with cognitive symptoms, p-tau217 is typically up a whopping three- to sevenfold in people with plaques. In the latter group, the influences of kidney dysfunction or high BMI are unlikely to cause a problem, Hansson said, adding, “But they might be a problem in population screening of cognitively normal individuals, especially in populations where kidney problems and very high BMI are common.” This was the situation with the Mayo Clinic cohort, in which most participants were cognitively unimpaired, and the incidence of comorbidities was higher than in the BioFINDER cohort.

Future prospective studies in ever more diverse cohorts will be needed to understand how comorbidities disproportionately affect biomarker effectiveness in different populations.—Jessica Shugart

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References

News Citations

1. Alzheimer's Blood Tests Have Arrived; Road to Broad Use Still Stretches On 23 Aug 2022
2. Diversity: FDA Guidance and New Data on Incidence/Biomarkers by Race 29 Apr 2022

Paper Citations

1. Schindler SE, Karikari TK, Ashton NJ, Henson RL, Yarasheski KE, West T, Meyer MR, Kirmess KM, Li Y, Saef B, Moulder KL, Bradford D, Fagan AM, Gordon BA, Benzinger TL, Balls-Berry J, Bateman RJ, Xiong C, Zetterberg H, Blennow K, Morris JC. Effect of Race on Prediction of Brain Amyloidosis by Plasma Aβ42/Aβ40, Phosphorylated Tau, and Neurofilament Light. Neurology. 2022 Jul 19;99(3):e245-e257. Epub 2022 Apr 21 PubMed.
2. Syrjanen JA, Campbell MR, Algeciras-Schimnich A, Vemuri P, Graff-Radford J, Machulda MM, Bu G, Knopman DS, Jack CR Jr, Petersen RC, Mielke MM. Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities. Alzheimers Dement. 2021 Sep 27; PubMed.
3. Mielke MM, Dage JL, Frank RD, Algeciras-Schimnich A, Knopman DS, Lowe VJ, Bu G, Vemuri P, Graff-Radford J, Jack CR Jr, Petersen RC. Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med. 2022 Jul;28(7):1398-1405. Epub 2022 May 26 PubMed. Correction.
4. O'Bryant SE, Petersen M, Hall J, Johnson LA, HABS-HD Study Team. Medical comorbidities and ethnicity impact plasma Alzheimer's disease biomarkers: Important considerations for clinical trials and practice. Alzheimers Dement. 2022 Mar 2; PubMed.

Other Citations

1. Part 2

External Citations

1. AGREEDementia

Further Reading

No Available Further Reading