Alzheimer’s Disease (AD) is the most common form of dementia in adults 65 years and older. AD is associated with amyloid plaques containing amyloid-β peptides of 40 and 42 peptides (Aβ40 and Aβ42). Currently Aβ42, total Tau (tTau) and phosphorylated Tau 181 (pTau) are well-established biomarkers of AD, but they require invasive or expensive tests with limited availability. These investigators have developed a blood test that uses highly specific antibodies followed by mass spectrometry to measure the ratio of Aβ42/Aβ40 and compared these results with amyloid PET scans and cerebrospinal fluid pTau/Aβ42 measures in the same subjects. They present data indicating that the Aβ42/Aβ40 ratio, especially in combination with APOE ε4 genotype, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis who are at risk for developing AD dementia. Furthermore, individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to become amyloid PET-positive. This may provide an important tool for selecting appropriate subjects for participation in clinical trials aimed at AD prevention.
Full abstract, to be presented at the American Neurological Association 2019 Annual Meeting (October 13-15 in St. Louis):
Plasma Aβ42/Aβ40 Measured with a High Precision Assay Predicts Current and Future Brain Amyloidosis
Suzanne E. Schindler, MD, PhD, James G. Bollinger, PhD, Vitaliy Ovod, MS, Kwasi G. Mawuenyega, PhD, Yan Li, PhD, Brian A. Gordon, PhD, David M. Holtzman, MD, John C. Morris, MD, Tammie L.S. Benzinger, MD, PhD, Chengjie Xiong, PhD, Anne M. Fagan, PhD, Randall J. Bateman, MD. Washington University, St. Louis, MO, USA.
Introduction: Alzheimer disease (AD) is the most common cause of dementia in adults older than age 65 years. The two key neuropathological hallmarks of AD are extracellular amyloid plaques comprised of amyloid β-peptides (Aβ) including lengths of 42 and 40 amino acids (Aβ42 and Aβ40, respectively) and intraneuronal neurofibrillary tangles comprised of tau. Cerebrospinal fluid (CSF) levels of Aβ42, total tau (tTau), and phosphorylated tau181 (pTau) are well established biomarkers of AD brain pathology, but their assessment requires a lumbar puncture. Amyloid PET scans are also well validated, but use radiation, are costly and have limited availability. Recent AD drug trials have used CSF biomarkers and/or amyloid PET to screen potential participants for brain amyloidosis. A blood-based biomarker would enable more rapid and inexpensive screening of potential participants, particularly for prevention trials where rates of negative amyloid PET scans are high. Methods: Using a high precision immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within eighteen months of an amyloid PET scan. Results: Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (ROC AUC 0.88, 95% confidence intervals [CI] 0.82-0.93) and CSF pTau181/Aβ42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma Aβ42/Aβ40, age and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90-0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p=0.01). Additional results from other international studies will be presented. Conclusions: Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.
All abstracts from ANA2019 will be available under embargo starting October 4. Contact Katherine Pflaumer ([email protected]) for full meeting abstracts, and for call-in information for the ANA2019 Media Roundtable (Oct. 15, 11 a.m. US Central).
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American Neurological Association Annual Meeting, October 13-15, 2019