Publications of the Week: Blood biomarkers in the diagnostic workup and treatment of Alzheimer disease

Background: An accurate blood test for Alzheimer disease (AD) has the potential to simplify the diagnostic evaluation and treatment of AD.

Methods: A cohort study was conducted to assess the diagnostic utility of an AD biomarker in 1213 patients with cognitive impairment. For testing, mass spectrometry was used to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non–p-tau217 (expressed as percentage of p-tau217) alone and combined with the amyloid-beta 42 and amyloid-beta 40 (Aß42:Aß40) plasma ratio, referred to as the amyloid probability score 2 (APS2). The primary study outcome was AD pathology based on abnormal cerebrospinal fluid Aß42:Aß40 ratio and p-tau217; the secondary outcome was clinical AD determined either based on a standard evaluation by primary care physicians and dementia specialists (ie, clinical examination, cognitive testing, and a computed tomography [CT] scan) or using the APS2. The positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and diagnostic accuracy values were determined. The biomarker cutoff values were derived from an independent cohort and the blood test was evaluated prospectively in a primary care cohort (n = 208) and a secondary care cohort (n = 398).

Results: The mean age of patients was 74.2 years (52% male); 23% had cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both primary and secondary care assessments, 50% of patients had AD pathology.

When plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%). In the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI: 83%-93%), and the NPV was 87% (95% CI, 82%-93%).

When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%). In the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). In the overall population, the diagnostic accuracy using the APS2 was 90% (95% CI, 88%-92%) and was not different from that using the percentage of p-tau217 alone of 90% (95% CI, 88%-91%).

Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying AD versus 91% (95% CI, 86%-96%) using the APS2, whereas dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) versus 91% (95% CI, 88%-95%) using the APS2.

Conclusions: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD in patients with cognitive symptoms in primary and secondary care using predefined cutoff levels.

McMaster editors’ commentary: This study represents a breakthrough as a diagnostic blood test for AD, with the potential for application in a primary care setting and for facilitating earlier diagnosis and treatment. The main drawback is the method required for blood sample analysis (early blood centrifugation and freezing at -80 degrees Celsius followed by mass spectrometry testing), which is beyond the capacity of most laboratories.