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Fully Automated Plasma Beta-Amyloid Immunoassays Predict Amyloid Pathology Defined by Amyloid PET

Kazuto Yamashita¹, Masao Miura¹, Shunsuke Watanabe¹, Kengo Ishiki¹, Yuji Arimatsu², Yasuhiro Irino¹, Toshiko Kubo³, Kei Hagino², Kota Nagai⁴, David Verbel⁵, Akihiko Koyama⁶, Shobha Dhadda⁷, Hayato Niiro⁸, Shigeki Iwanaga¹, Toshiyuki Sato¹, Tomokazu Yoshida⁹, Atsushi Iwata¹⁰

Accumulation of β-amyloid peptide (Aβ) (amyloid pathology) in the brain is a hallmark of Alzheimer’s disease (AD). Several clinical trials on disease-modifying therapies (DMTs) targeting Aβ have been conducted. The US Food and Drug Administration has recently granted accelerated approval for an anti-amyloid antibody for early AD. Given this background, there is an increasing need for simple, cost-effective diagnostic methods of detecting amyloid pathology in the brain.

Our group previously reported that amyloid PET status was correlated with Aβ_1-42/ Aβ_1-40 ratio in plasma (hereafter, “plasma Aβ ratio”) and that amyloid pathology in the brain could potentially be predicted using blood biomarkers.^*1 Our research has focused on the plasma Aβ ratio using clinical specimens. In this presentation, we conducted a clinical evaluation of the plasma Aβ ratio measured using the HISCL Automated Immunoassay System (Sysmex) in comparison with amyloid PET status determined by the Centiloid method^*2 in 180 patients (Discovery Study) and 191 patients (Validation Study) clinically diagnosed with mild AD or mild cognitive impairment.

(Results)

• In the Discovery Study, the plasma Aβ ratio was significantly lower in the Amyloid PET positive group as compared to the negative group and it predicted amyloid PET status with high accuracy: sensitivity 97.5%, specificity 80.8%, AUC = 0.93 (0.90 – 0.97).
• In the Discovery Study, the plasma Aβ ratio and Centiloid unit (CL) were significantly correlated with a Spearman rank correlation coefficient^*3 of -0.75 (P<0.001), and this indicates that our assay could be indicative of the amount of Aβ accumulation in the brain. Also, we observed inconsistency in several patients, who had a positive plasma Aβ ratio and a negative CL. This inconsistency has also been found in other studies and it was reported that it represented an increased risk of conversion to PET positive as compared to Aβ ratio negative subjects.^*4 Our results suggest that the plasma Aβ ratio measured using the HISCL Automated Immunoassay System could potentially indicate presence of amyloid pathology in the brain at an earlier stage when it was not detectable by PET.

Since measurement of plasma Aβ_1-42 and Aβ_1-40 in the HISCL is fully automated immunoassay that is less invasive and more accessible, it may contribute to the diagnosis of AD in routine clinical practice. We believe that the plasma Aβ can contribute to early diagnosis, of AD, treatment selection and monitoring of treatment effect.