Performance of Plasma Biomarkers Combined with Structural MRI to Identify Candidate Participants for Alzheimer's Disease-Modifying Therapy.

BACKGROUND

Recently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer's disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aβ42/Aβ40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy.

OBJECTIVES

To evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI.

DESIGN

A cross-sectional and longitudinal study.

SETTING AND PARTICIPANTS

Data were from the Alzheimer's Disease Neuroimaging Initiative. Participants were aged 55-90 years old with plasma biomarker and structural MRI brain data.

MEASUREMENTS

The optimum cut-off point for plasma Aβ42/Aβ40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis.

RESULTS

A total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aβ42/Aβ40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68-0.77) to detect drug candidate participants at baseline. Combined plasma Aβ42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively).

CONCLUSION

Plasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.

Déclaration de conflit d'intérêts

MM – Dr. Manchumad Manjavong has no conflict of interest to declare. JK – Dr. Jae Myeong Kang has no conflict of interest to declare. AD – Adam Diaz has no conflict of interest to declare. MTA - Dr. Miriam T. Ashford receives funding to her institution from NIH. JE – Joseph Eichenbaum has no conflict of interest to declare. AA – Anna Aaronson has no conflict of interest to declare. MJM – Dr. Melanie J. Miller has no conflict of interest to declare. RSM – Dr. R. Scott Mackin has received research support from The National Institute of Mental Health, the National Institute of Aging, and Johnson and Johnson, during the past 2 years. RT – Dr. Rachana Tank has no conflict of interest to declare. MWW- Dr. Weiner reports grants from National Institutes of Health (NIH), grants from Department of Defense (DOD), grants from Patient-Centered Outcomes Research Institute (PCORI), grants from California Department of Public Health (CDPH), grants from University of Michigan, grants from Siemens, grants from Biogen, grants from Hillblom Foundation, grants from Alzheimer’s Association, grants from The State of California, grants from Johnson & Johnson, grants from Kevin and Connie Shanahan, grants from GE, grants from VUmc, grants from Australian Catholic University (HBI- BHR), grants from The Stroke Foundation, grants from Veterans Administration, personal fees from Acumen Pharmaceutical, personal fees from Cerecin, personal fees from Dolby Family Ventures, personal fees from Eli Lilly, personal fees from Merck Sharp & Dohme Corp., personal fees from National Institute on Aging (NIA), personal fees from Nestle/Nestec, personal fees from PCORI/PPRN, personal fees from Roche, personal fees from University of Southern California (USC), personal fees from NervGen, personal fees from Baird Equity Capital, personal fees from BioClinica, personal fees from Cytox, personal fees from Duke University, personal fees from Eisai, personal fees from FUJIFILM-Toyama Chemical (Japan), personal fees from Garfield Weston, personal fees from Genentech, personal fees from Guidepoint Global, personal fees from Indiana University, personal fees from Japanese Organization for Medical Device Development, Inc. (JOMDD), personal fees from Medscape, personal fees from Peerview Internal Medicine, personal fees from Roche, personal fees from T3D Therapeutics, personal fees from WebMD, personal fees from Vida Ventures, personal fees from The Buck Institute for Research on Aging, personal fees from China Association for Alzheimer’s Disease (CAAD), personal fees from Japan Society for Dementia Research, personal fees from Korean Dementia Society, outside the submitted work; and I hold stocks or options with Alzheon Inc., Alzeca, and Anven. RLN - Dr. Rachel L. Nosheny reports funding from the National Institutes of Health (grants to institution), California Department of Public Health (grants to institution), and Genentech Inc. (grants to institution).