Simple Blood Test Highly Accurate in Detecting Alzheimer's Biomarker

ST. LOUIS — A highly accurate blood test detects amyloid, a key biomarker of Alzheimer's disease (AD), potentially eliminating the need for a lumbar puncture, new research suggests.

The study shows "that plasma Aβ42/Aβ40 accurately identifies individuals with brain amyloidosis, whether they are cognitively normal or cognitively impaired," study investigator Suzanne Schindler, MD, PhD, assistant professor of neurology, Washington University School of Medicine, St Louis, Missouri, told Medscape Medical News.

These most recent findings, presented here at ANA 2019: 144th Annual Meeting of the American Neurological Association, add to those recently published online in Neurology by the same research group.

Early Detection Critical

The ability to detect amyloidosis as early as possible is critical. Amyloid plaques are deposited in the brain up to 20 years prior to the onset of AD symptoms. However, once the symptoms emerge, the damage is irreversible and potential treatments may not be effective.

"We think that most drug trials for Alzheimer's disease have failed because they have started treatment too late. The major utility of [plasma amyloid detection] would be in identifying people early for drug trials," Schindler said.

However, a challenge is that amyloid plaques, in addition to intraneuronal neurofibrillary tau tangles, the other key neuropathological hallmark of AD, are typically assessed using cerebrospinal fluid (CSF).

The procedure requires a lumbar puncture along with positron emission tomography (PET) scans, which are costly, use radiation, and require time and coordination, Schindler noted.

With recent evidence indicating that the ratio of plasma levels of amyloid proteins Aβ42 and Aβ40 could represent a blood-based biomarker of AD, investigators used a high precision immunoprecipitation mass spectrometry assay (IP-MS, C2N Diagnostics) to evaluate plasma levels in 158 study participants.

They also evaluated CSF samples from the individuals, all of whom were at risk for AD and enrolled in longitudinal studies of memory and aging at Washington University.

Most participants had normal cognition, with 94% showing a clinical dementia rating of 0. Blood samples were obtained within 18 months of an amyloid PET scan.

"Quite Spectacular"

Researchers found a robust association between the plasma Aβ42/Aβ40 ratio and positivity of amyloidosis confirmed on PET imaging (area under the curve [AUC], 0.88; 95% CI, 0.82 - 0.93).

"This ratio really discriminated well between people who were PET-positive and PET-negative, with an AUC of 88% — which is quite spectacular for a blood test," Schindler said.

The plasma ratio also had high correspondence with the CSF ratio of phosphorylated tau181 and Aβ42 (AUC, 0.85; 95% CI, 0.79 - 0.92), also well-established biomarkers of Alzheimer's brain pathology.

When combined with the other high risk factors of older age and APOE genotype positivity, the plasma Aβ42/Aβ40 ratio showed an even higher association with amyloid PET (AUC, 0.94; 95% CI, 0.90 - 0.97).

Importantly, even when the amyloid PET scan at baseline was negative, a positive plasma amyloid ratio (Aβ42/Aβ40 < 0.1218) significantly predicted a subsequent conversion to a PET-positive scan within an average of 3.9 years (P = .01).

"When patients have a negative PET scan but a positive blood test, one might typically think that the blood test was a false positive, but we found when we scanned these individuals later, at an average of about 4 years later, they had about a 15-fold higher risk for becoming amyloid PET positive compared to those with a negative result on the blood test," Schindler said.

In other words, "this wasn't a failure of the blood test" she explained. "In fact, the blood test was detecting the brain changes of Alzheimer's disease before the PET scan, or at least before the threshold used for the amyloid PET scan."

Though the commercial availability of the assay could be several years in the future, a blood test for brain amyloidosis could eventually have benefits not just in clinical trials but also in the clinical setting for identifying a cause of cognitive impairment.

For example, it is sometimes unclear in a memory clinic whether the cause of a patient's cognitive impairment is related to AD or other causes, such as medications, mood disorders, or sleep apnea, Schindler said.

Other Tests in Development

Other immunoassays have also been evaluated to detect plasma amyloid. As reported by Medscape Medical News, a recent study included a large cohort of over 800 participants from the Swedish BioFINDER trial, and a German study included 200 more participants.

However, those results fell short of the new IP-MS findings, with the Aβ42/Aβ40 ratio predicting amyloid-beta positivity with a lower AUC correlation (0.77 vs 0.88, respectively).

Similar to the IP-MS assay, the older assay also had improved sensitivity when combined with APOE genotype data (AUC, 0.85; P < .001).

Still, the two assays use very different techniques, and the predictive accuracy was improved with the IP-MS assay for the covariate-corrected prediction models (ROC AUC, 0.85 [Elecsys] vs 0.94 [IP-MS]).

"In clinical use, there is a significant gap between performance on the assays — essentially 85% accurate versus 94% accurate," Schindler said.

She noted that the IP-MS assay itself has since been validated in the Swedish BioFinder cohort and shown to have high accuracy (0.90), as well as the Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohort (AUC, 0.93) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (AUC, 0.87), for a combined AUC of 0.90.

"We think this rate is very good considering the different cohorts and combination of multiple protocols for collecting blood and multiple tracers," Schindler said.

Variability Eliminated

Commenting on the findings for Medscape Medical News, Costantino Iadecola, MD, professor of neurology and director and chair of the Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, New York City, noted that previous efforts at detecting plasma amyloid using enzyme-linked immunosorbent assays (ELISA) were challenged by poor variability and lack of precision. However, the focus on the Aβ42/Aβ40 ratio helps rule out many factors.

"By using the Aβ42/Aβ40 ratio, you get around the impurity of the disease and really can eliminate that variability. The data show it is highly sensitive and accurate, so it's much better than ELISA," said Iadecola, who was not involved with the research.

He noted that, going forward, the findings will be beneficial for selecting patients for clinical trials.

"I think it's really going to help, and hopefully we will be able to use it in the community and make it a tool available for physicians to screen the general population," Iadecola said.

Schindler and Iadecola have reported no relevant financial relationships. The IP-MS assay is being commercialized by two of the coauthors. Other investigator disclosures are listed in the earlier article.

ANA 2019. Presented October 13, 2019. Abstract S148.

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