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IntroductionWe describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids.MethodsReview publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1-42, t-tau, and p-tau181 data.ResultsCSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies.DiscussionFurther studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.

Objective: To determine if plasma tau phosphorylated at threonine 181 (p‐tau181) distinguishes pathology‐confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p‐tau181 predicts cognitive and functional decline, and to validate findings in an external cohort. Methods: Thirty‐one neuropathology‐confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini‐Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N = 70), MCI (N = 75), and AD dementia (N = 50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p‐tau181 was measured using the Quanterix SiMoA HD‐X platform. Results: Plasma p‐tau181 differentiated pathology‐confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p‐Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p‐tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia. Interpretation: Plasma p‐tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p‐tau181 are associated with faster cognitive and functional decline. [ABSTRACT FROM AUTHOR]

Introduction: Pre‐analytical sample handling might affect the results of Alzheimer's disease blood‐based biomarkers. We empirically tested variations of common blood collection and handling procedures. Methods: We created sample sets that address the effect of blood collection tube type, and of ethylene diamine tetraacetic acid plasma delayed centrifugation, centrifugation temperature, aliquot volume, delayed storage, and freeze–thawing. We measured amyloid beta (Aβ)42 and 40 peptides with six assays, and Aβ oligomerization‐tendency (OAβ), amyloid precursor protein (APP)699‐711, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), total tau (t‐tau), and phosphorylated tau181. Results: Collection tube type resulted in different values of all assessed markers. Delayed plasma centrifugation and storage affected Aβ and t‐tau; t‐tau was additionally affected by centrifugation temperature. The other markers were resistant to handling variations. Discussion: We constructed a standardized operating procedure for plasma handling, to facilitate introduction of blood‐based biomarkers into the research and clinical settings. [ABSTRACT FROM AUTHOR]

Objective: Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p‐tau‐181p, or Aβ levels after non‐cardiac, non‐neurologic surgery in older adults. Methods: Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6‐week postoperative testing and were included in the analysis. Results: There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: −1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p‐tau‐181p or Aβ over this period. There was no change in cognitive index (mean [95% CI] 0.040 [−0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (−0.346 [−0.523, −0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6‐week postoperative changes in cognition and CSF tau, p‐tau‐181p, or Aβ42 changes over this interval (p > 0.05 for each). Interpretation: Neurocognitive changes after non‐cardiac, non‐neurologic surgery in the majority of cognitively healthy, community‐dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aβ, tau or p‐tau‐181p levels or the p‐tau‐181p/Aβ or tau/Aβ ratios). Trial Registration: clinicaltrials.gov (NCT01993836). [ABSTRACT FROM AUTHOR]

Postoperative delirium is the most common postsurgical complication in older adults and is associated with an increased risk of long-term cognitive decline and Alzheimer's disease (AD) and related dementias (ADRD). However, the neurological basis of this increased risk-whether postoperative delirium unmasks latent preoperative pathology or leads to AD-relevant pathology after perioperative brain injury-remains unclear. Recent advancements in neuroimaging techniques now enable the detection of subtle brain features or damage that may underlie clinical symptoms. Among these, Neurite Orientation Dispersion and Density Imaging (NODDI) can help identify microstructural brain damage, even in the absence of visible macro-anatomical abnormalities. To investigate potential brain microstructural abnormalities associated with postoperative delirium and cognitive function, we analyzed pre- and post-operative diffusion MRI data from 111 patients aged ≥60 years who underwent non-cardiac/non-intracranial surgery. Specifically, we investigated preoperative variation in diffusion metrics within the posterior cingulate cortex (PCC), a region in which prior work has identified glucose metabolism alterations in the delirious brain, and a key region in the early accumulation of amyloid beta (Aβ) in preclinical AD. We also examined the relationship of preoperative PCC NODDI abnormalities with preoperative cognitive function. Compared to patients who did not develop postoperative delirium (n=99), we found increased free water (FISO) and neurite density index (NDI) and decreased orientation dispersion index (ODI) in the dorsal PCC before surgery among those who later developed postoperative delirium (n=12). These FISO differences before surgery remained present at six weeks postoperatively, while these NDI and ODI differences did not. Preoperative dorsal PCC NDI and ODI values were also positively associated with preoperative attention/concentration performance, independent of age, education level, and global brain atrophy. Yet, these diffusion metrics were not correlated with cerebrospinal fluid Aβ positivity or levels. These results suggest that preoperative latent brain abnormalities within the dorsal PCC may underlie susceptibility to postoperative delirium, independent of AD-related (i.e., Aβ) neuropathology. Furthermore, these preoperative microstructural differences in the dorsal PCC were linked to preoperative deficits in attention/concentration, a core feature of postoperative delirium. Our findings highlight microstructural vulnerability within the PCC, a key region of the default mode network, as a neuroanatomic locus that can help explain the link between preoperative attention/concentration deficits and increased postoperative delirium risk among vulnerable older surgical patients., Competing Interests: Competing interests MB has received material support (i.e. EEG monitors) for a postoperative recovery study in older adults from Masimo, unrelated to this manuscript. MB and JB have also received legal consulting fees related to postoperative neurocognitive function in older adults. JB acknowledges receiving funding from Claret Medical, Inc. and CardioGard, Inc., both unrelated to this manuscript. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). The other authors have no relevant conflicts to disclose.

Introduction: Pre-analytical sample handling might affect the results of Alzheimer's disease blood-based biomarkers. We empirically tested variations of common blood collection and handling procedures., Methods: We created sample sets that address the effect of blood collection tube type, and of ethylene diamine tetraacetic acid plasma delayed centrifugation, centrifugation temperature, aliquot volume, delayed storage, and freeze-thawing. We measured amyloid beta (Aβ)42 and 40 peptides with six assays, and Aβ oligomerization-tendency (OAβ), amyloid precursor protein (APP) 699-711 , glial fibrillary acidic protein (GFAP), neurofilament light (NfL), total tau (t-tau), and phosphorylated tau181., Results: Collection tube type resulted in different values of all assessed markers. Delayed plasma centrifugation and storage affected Aβ and t-tau; t-tau was additionally affected by centrifugation temperature. The other markers were resistant to handling variations., Discussion: We constructed a standardized operating procedure for plasma handling, to facilitate introduction of blood-based biomarkers into the research and clinical settings., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Blood-based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure Aβ and how they compare among centers and assays., Methods: Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass-spectrometric methods were used to measure plasma Aβ concentrations., Results: Correlations were weak for Aβ42 while Aβ40 correlations were stronger. The ratio Aβ42/Aβ40 did not improve the correlations and showed weak correlations., Discussion: The poor correlations for Aβ42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre-analytical sample handling and specificity, and cross-reactivity of different antibodies. Different methods might also measure different pools of plasma Aβ42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study., Competing Interests: OH has acquired research support (for the institution) from Avid Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau, and Roche. SP is a full‐time employee of Roche Diagnostics GmbH and holds shares in Roche. TB is a full‐time employee of and owns stock in F. Hoffmann‐La Roche Ltd. KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served on scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx. JLD is an employee and stockholder of Eli Lilly and Company. ELECSYS is a trademark of Roche. E Stoops and KM are full‐time paid employees of ADx NeuroSciences. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly and Company); has consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly; given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen; and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. RJB cofounded C2N Diagnostics. Washington University and Dr. Bateman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co‐inventor, has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition.” He has received consultant fees from Roche, C2N Diagnostics, Genentech, AbbVie, Pfizer, Boehringer‐Ingelheim, Eisai, AC Immune, Janssen, and Merck. He serves as principal investigator of the DIAN‐TU, which is supported by the Alzheimer's Association, GHR Foundation, Eisai, an anonymous organization ,and the DIAN‐TU Pharma Consortium. HV is a founder of Biomarkable and a co‐founder of ADx NeuroSciences. RY and NK are full‐time employees of Shimadzu Corporation. NK holds stock in Shimadzu Corporation and has received payment for manuscript writing from Rinshohoushasen. CET has a collaboration contract with ADx Neurosciences and Quanterix; performed contract research or received grants from AC‐Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon; received honoraria from Medidact Neurologie. LMS has received honorarium from Biogen for teaching. LS and JA have submitted patents for “Methods for quantification of amyloid beta peptides in plasma by mass spectrometry.” AN received honoraria from The Educational Program for Dementia Experts in Hokuriku (NINPRO), The Japan Society for the Promotion of Science (JSPS), Translational Research Center for Medical Innovation (TRI), Eisai Co. Ltd. SY is an employee and shareholder of MagQu Co., Ltd. KGM, VO, and JB have submitted patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” and may receive royalties based on blood plasma assay technology licensed to C2N Diagnostics. ES has received payment (to institution) from Roche Diagnostics for medical writing., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)