Blood Test for Alzheimer's Disease One
Step Closer?

Damian McNamara

June 28, 2019

An accurate, fully automated blood test for Alzheimer's disease (AD) that can be used in primary care settings may be one step closer, results of a large prospective study suggest.

Using a commercially available automated immunoassay, investigators found plasma levels of amyloid proteins Aβ42 and Aβ40 aligned with clinical stage of cognitive impairment and distinguished individuals with mild cognitive impairment (MCI) or AD from their unaffected counterparts.

Dr Sebastian Palmqvist

"This potentially can be a much needed contribution to the otherwise limited diagnostic tools available in primary care," lead author Sebastian Palmqvist, MD, PhD, associate professor of neurology at Lund University and an investigator at the Clinical Memory Research Unit, Skåne University Hospital, Sweden, told Medscape Medical News.

"In the last one to two decades, we have seen major improvements in the diagnostic evaluation at highly specialized centers — using regional MRI measures, cerebrospinal fluid analyses, FDG-PET, amyloid PET, tau PET, etc. But in most cases, primary care centers still use the same tools as 30 years ago," he said.

The study was published online June 24 in JAMA Neurology.

Promise of Greater Accuracy

Previous attempts to identify and develop a blood biomarker for AD have fallen short in replication studies. The most promising candidates to date include tau protein, neurofilament light chain levels, Aβ42 and Aβ40.

However, the recent development of fully automated immunoassays — with improved reliability and precision in testing for AD biomarkers — are offering the hope of greater diagnostic accuracy.  

To determine the precision of this new technology in detecting Aβ42, Aβ40, and tau, the investigators tested one of the commercially available, fully automated systems (Elecsys Immunoassays, Roche Diagnostics) in a cohort of 842 individuals enrolled in the Swedish BioFINDER study.

They also assessed a separate validation cohort of 237 people from a German study. Each group included participants who were cognitively normal or who had MCI or AD dementia.

The researchers found 44% of the overall BioFINDER cohort was positive for amyloid beta. This result included 29% of the cognitively unaffected group, 60% of the MCI patients, and 100% of the 64 individuals diagnosed with AD dementia.

The amyloid-beta 42/40 ratio predicted amyloid beta positivity with an area under the curve (AUC) correlation of 0.77 in a logistic regression analysis. Assessing Aβ42 and Aβ40 markers individually increased the accuracy (AUC, 0.80).

Interestingly, adding tau protein to the plasma assays did not significantly increase the accuracy of predicting amyloid-beta positivity (AUC, 0.81).

Palmqvist said he was "not really" surprised that tau levels added little to the sensitivity. Previous studies on total tau (T-tau) in plasma, the type of tau measured in the present study, "have shown very modest accuracies," he said. "On the other hand, ongoing studies on phosphorylated tau (P-tau) in plasma show very promising results, and we plan to publish this soon."

Adding plasma neurofilament light chain or plasma neurofilament heavy chain levels did not significantly improve the predictability of the assays.

In contrast, adding APOE genotype data to the amyloid-beta individual marker results significantly improved the sensitivity (AUC, 0.85; 95% confidence interval [CI], 0.82 - 0.88; P < .001).

Results were similar in the validation cohort analyses. For example, individual markers Aβ42 and Aβ40 in plasma also predicted amyloid positivity (AUC, 0.86). Addition of tau protein levels actually decreased the sensitivity slightly (AUC, 0.84). Plasma neurofilament light chain, neurofilament heavy chain and APOE status were not available in the validation population.&

In addition to the clinical promise of developing a sensitive blood marker for early detection of AD pathology, the findings could help identify and classify study participants for future AD studies while reducing the need for lumbar punctures or costly imaging.

However, the investigators added a caveat to their findings, noting that the accuracies of "Aβ42 and Aβ40 assays are not sufficient to be used on their own as a clinical test of Aβ positivity."

"Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms," they note.

The investigators are currently conducting a large, prospective study known as ADetect, which aims to determine the accuracy using these immunoassays in primary care settings.

"Within 3 to 4 years we will get the results, and hopefully that will be enough to implement it in clinical practice, perhaps together with other measures such as APOE genotype and brief cognitive tests," Palmqvist said.

"A Solid Foundation"

In an accompanying editorial, Sid E. O'Bryant, PhD, of the Institute for Translational Research at the University of North Texas Health Science Center in Fort Worth, writes that the study provides "preliminary evidence for a test with the specific context of use of screening for amyloid positivity, which the authors suggest may have utility in primary care settings."

"Overall, the performance of the assay was excellent. This study suggests that the field is one step closer to the actual application of blood based biomarkers with specific [use] in AD," he adds.

However, O'Bryant also said the findings "certainly leave room for improvement. The primary concern is the scalability of the methods."

He added that the Aβ42/Aβ40 ratio yielded a sensitivity of 0.70 and specificity of 0.73 when applied to the validation cohort.

"If applied to the expected base rates found in a primary care setting (in other words, 10% to 12%) the negative predictive power would be greater than 0.90; however, the positive predictive power would be 0.22," he writes.

"Overall, the findings of Palmqvist et al are promising and demonstrate that the field is rapidly moving from 'if' blood biomarkers can be used in AD to 'how' they can be used," writes O'Bryant. "This work demonstrates the superiority of automated technologies, and the findings provide a solid foundation on which to build."

The European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Marianne and Marcus Wallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Association, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, and the Swedish federal government under the ALF agreement support work at the authors' research center.

Palmqvist has disclosed no relevant financial relationships. O'Bryant reported grants from the National Institute on Aging during the conduct of the study and personal fees and other support from Roche outside the submitted work; has served on an advisory board for Roche Diagnostics; and is founding scientist of Cx Precision Medicine.

JAMA Neurol. Published online June 24, 2019. Abstract, Editorial

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