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Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer's disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer's disease co-existent with other pathologies. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) exhibits spatially heterogeneous 3- or 4-repeat tau deposition across participants. Our overall goal was to develop an automated method to quantify the heterogeneous burden of tau deposition into a single number that would be clinically useful. Methods: We used tau PET scans from 3 independent cohorts: the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center (Mayo, n = 1,290), the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 831), and the Open Access Series of Imaging Studies (OASIS-3, n = 430). A machine learning binary classification model was trained on Mayo data and validated on ADNI and OASIS-3 with the goal of predicting visual tau positivity (as determined by 3 raters following Food and Drug Administration criteria for 18 F-flortaucipir). The machine learning model used region-specific SUV ratios scaled to cerebellar crus uptake. We estimated feature contributions based on an artificial intelligence-explainable method (Shapley additive explanations) and formulated a global tau summary measure, Tau Heterogeneity Evaluation in Alzheimer's Disease (THETA) score, using SUV ratios and Shapley additive explanations for each participant. We compared the performance of THETA with that of commonly used meta-regions of interest (ROIs) using the Mini-Mental State Examination, the Clinical Dementia Rating-Sum of Boxes, clinical diagnosis, and histopathologic staging. Results: The model achieved a balanced accuracy of 95% on the Mayo test set and at least 87% on the validation sets. It classified tau-positive and -negative participants with an AUC of 1.00, 0.96, and 0.94 on the Mayo, ADNI, and OASIS-3 cohorts, respectively. Across all cohorts, THETA showed a better correlation with the Mini-Mental State Examination and the Clinical Dementia Rating-Sum of Boxes (ρ ≥ 0.45, P < 0.05) than did meta-ROIs (ρ < 0.44, P < 0.05) and discriminated between participants who were cognitively unimpaired and those who had mild cognitive impairment with an effect size of 10.09, compared with an effect size of 3.08 for meta-ROIs. Conclusion: Our proposed approach identifies positive tau PET scans and provides a quantitative summary measure, THETA, that effectively captures heterogeneous tau deposition observed in AD. The application of THETA for quantifying tau PET in AD exhibits great potential., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials., Competing Interests: V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., Avid Radiopharmaceuticals and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, Avid Radiopharmaceuticals and the NIH (NIA, NCI). D.S.K. serves on a Data Safety Monitoring Board for the DIAN study and for a tau therapeutic for Biogen but receives no personal compensation; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California; has served as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation; and receives funding from the NIH. B.F.B. receives honorarium for SAB activities for the Tau Consortium, is an investigator in clinical trials sponsored by Alector, Biogen, Cognition Therapeutics, EIP Pharma and Transposon and receives funding from the NIH. C.R.J. has no commercial conflicts and receives research support from the NIH, the GHR Foundation and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. R.C.P. consults for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Genentech, Inc.; Eisai, Inc.; and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R 2 PET =0.32 vs R 2 PLASMA =0.32, p difference =0.812) and with progression to mild cognitive impairment (Hazard ratio[HR] PET =1.56[1.43-1.70] vs HR PLASMA =1.63[1.50-1.77], p difference =0.627). Combined plasma and PET models were superior to the single biomarker models (R 2 =0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD., Competing Interests: DECLARATION OF INTERESTS R.O. has received research support from Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. He has given lectures in symposia sponsored by GE Healthcare and serves on advisory boards for Asceneuron and Bristol Myers Squibb. SP has acquired research support (for the institution) from ki elements / ADDF and Avid. In the past 2 years, he has received consultancy/speaker fees from Bioartic, Biogen, Esai, Lilly, and Roche. Research programs of WF have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF is recipient of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003) in the context of Onderzoeksprogramma Dementie, part of the Dutch National Dementia Strategy. TAP-dementia receives co-financing from Avid Radiopharmaceuticals and Amprion. Gieskes-Strijbis fonds also contributes to TAP-dementia. WF has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. WF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. WF is member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. WF is member of the steering committee of PAVE, and Think Brain Health. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. EvdG has performed contract research for Heuron Inc. and Roche. EvdG has a consultancy agreement with IXICO and Life Molecular Imaging for reading PET scans. CET has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had consultancy/speaker contracts for Eli Lilly, Merck, Novo Nordisk, Olink and Roche. SES has served as a consultant to Eisai and Novo Nordisk and has received speaker fees from Eli Lilly and Medscape. She has analyzed biomarker data provided by C2N Diagnostics. JT has served as a consultant for the Neurotorium educational platform and for Alzheon. PR-N has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. CCR has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Enigma/Mellieur Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. RJB laboratory research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation, Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Avid Radiopharmaceuticals, Janssen, Tau Consortium, Novartis, Centene Corporation, Association for Frontotemporal Degeneration, the Cure Alzheimer’s Fund, Coins for Alzheimer’s Research Trust Fund, The Foundation for Barnes-Jewish Hospital, Good Ventures Foundation, DIAN-TU Pharma Consortium, Tau SILK Consortium (AbbVie, Biogen, Eli Lilly, and an anonymous organization), the NfL Consortium (AbbVie, Biogen, Bristol Meyers Squibb, Hoffman La Roche), and the Tracy Family SILQ Center; having equity ownership interest in C2N Diagnostics and receiving income based on technology licensed by Washington University to C2N Diagnostics; and receiving income from C2N Diagnostics for serving on the scientific advisory board. OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. SCJ has served in the past two years on advisory boards for Enigma Biomedical and ALZPath. The other authors report no competing interests.

Background: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals., Methods: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure., Results: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide., Discussion: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Given the prevalence of dementia and the development of pathology-specific disease-modifying therapies, high-value biomarker strategies to inform medical decision-making are critical. In vivo tau-PET is an ideal target as a biomarker for Alzheimer's disease diagnosis and treatment outcome measure. However, tau-PET is not currently widely accessible to patients compared to other neuroimaging methods. In this study, we present a convolutional neural network (CNN) model that imputes tau-PET images from more widely available cross-modality imaging inputs. Participants (n = 1192) with brain T1-weighted MRI (T1w), fluorodeoxyglucose (FDG)-PET, amyloid-PET and tau-PET were included. We found that a CNN model can impute tau-PET images with high accuracy, the highest being for the FDG-based model followed by amyloid-PET and T1w. In testing implications of artificial intelligence-imputed tau-PET, only the FDG-based model showed a significant improvement of performance in classifying tau positivity and diagnostic groups compared to the original input data, suggesting that application of the model could enhance the utility of the metabolic images. The interpretability experiment revealed that the FDG- and T1w-based models utilized the non-local input from physically remote regions of interest to estimate the tau-PET, but this was not the case for the Pittsburgh compound B-based model. This implies that the model can learn the distinct biological relationship between FDG-PET, T1w and tau-PET from the relationship between amyloid-PET and tau-PET. Our study suggests that extending neuroimaging's use with artificial intelligence to predict protein specific pathologies has great potential to inform emerging care models., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers., Methods: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints., Results: Individual timing of plasma p-tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants., Discussion: Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aβ PET was the strongest., Highlights: Plasma p-tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p-tau was associated with Aβ PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aβ PET., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: This study evaluated the performance of the Lumipulse plasma beta-amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid-positron emission tomography (PET)., Methods: Plasma samples from cognitively unimpaired ( N  = 179) and MCI/AD dementia ( N  = 36) individuals were retrospectively evaluated. Plasma Aβ42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP-MS) assay for plasma Aβ42/40 was also evaluated. Amyloid-PET status was the outcome measure., Results: Lumipulse and IP-MS Aβ42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid-PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aβ42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aβ42/40 and pTau181 did not significantly improve performance over Aβ42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71)., Discussion: The Lumipulse Aβ42/40 assay showed similar performance to the IP-MS Aβ42/40 assay for detection of an abnormal amyloid-PET; and both assays performed better than the two p-tau181 immunoassays. The Simoa Aβ42/Aβ40 assay was the least accurate at predicting an abnormal amyloid-PET status., Highlights: Lumipulse plasma Aβ42/Aβ40 AUC for abnormal amyloid-PET detection was 0.81.This performance was comparable to previously reported IP-MS and higher than Simoa.Performance of Alzheimer's disease blood biomarkers varies between assays., Competing Interests: Alicia Algeciras‐Schimnich has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics and Siemens Healthineers. Daniel J. Figdore reports no disclosures. Heather J. Wiste reports no disclosures. Joshua A. Bornhorst has participated on an advisory board for Sunbird Bio and received an honorarium from Roche Diagnostics. Randall J. Bateman has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb, and Novartis. Washington University and Randall J. Bateman have equity ownership interest in C2N Diagnostics and receive income based on technology (stable isotope labeling kinetics, blood plasma assay, and methods of diagnosing AD with phosphorylation changes) licensed by Washington University to C2N Diagnostics. Randall J. Bateman receives income from C2N Diagnostics for serving on the scientific advisory board. Randall J. Bateman serves on the Roche Gantenerumab Steering Committee as an unpaid member. Yan Li reports no disclosures. Jonathan Graff‐Radford receives funding from the NIH. He is an investigator in clinical trials sponsored by Biogen, Eisai and the University of Southern California. David S. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for lecanemab on December 2, 2022, but received no compensation. He receives funding from the NIH. Prashanthi Vemuri receives funding from the NIH. Val J. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Eisai, Inc., AVID Radiopharmaceuticals, Eli Lilly and Company, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). Clifford R. Jack receives funding from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Ronald C. Petersen has consulted for Roche, Inc.; Genentech, Inc.; Eli Lilly, Inc.; Nestle, Inc. and Eisai, Inc.; a DSMB for Genentech, Inc. and receives royalties from Oxford University Press for Mild Cognitive Impairment and from UpToDate. His research funding is from NIH/NIA. Author disclosures are available in the Supporting Information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Whether a relationship exists between cerebrovascular disease and Alzheimer's disease has been a source of controversy. Evaluation of the temporal progression of imaging biomarkers of these disease processes may inform mechanistic associations. We investigate the relationship of disease trajectories of cerebrovascular disease (white matter hyperintensity, WMH, and fractional anisotropy, FA) and Alzheimer's disease (amyloid and tau PET) biomarkers in 2406 Mayo Clinic Study of Aging and Mayo Alzheimer's Disease Research Center participants using accelerated failure time models. The model assumes a common pattern of progression for each biomarker that is shifted earlier or later in time for each individual and represented by a per participant age adjustment. An individual's amyloid and tau PET adjustments show very weak temporal association with WMH and FA adjustments (R = -0.07 to 0.07); early/late amyloid or tau timing explains <1% of the variation in WMH and FA adjustment. Earlier onset of amyloid is associated with earlier onset of tau (R = 0.57, R 2  = 32%). These findings support a strong mechanistic relationship between amyloid and tau aggregation, but not between WMH or FA and amyloid or tau PET., (© 2023. The Author(s).)

Staging the severity of Alzheimer's disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (n = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center; had a concurrent amyloid PET, tau PET and blood draw; and met clinical criteria for cognitively unimpaired (n = 864), mild cognitive impairment (n = 148) or Alzheimer's clinical syndrome with dementia (n = 124). The latter two groups were combined into a cognitively impaired group (n = 272). We used multinomial regression models to estimate discrimination [concordance (C) statistics] among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6) and a combined amyloid and tau PET stage (none/low versus intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ1-42 and Aβ1-40 (analysed as the Aβ42/Aβ40 ratio), glial fibrillary acidic protein and neurofilament light chain were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (n = 355) of cognitively unimpaired participants using the Lilly Meso Scale Discovery assay. Models with all Quanterix plasma analytes along with risk factors (age, sex and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78-0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72-0.85 versus C = 0.73-0.86). Discriminating a PET proxy of intermediate/high from none/low Alzheimer's disease neuropathological change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 versus 0.87 for unimpaired and C = 0.91 versus 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high versus intermediate amyloid (C = 0.85 versus 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 versus 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high versus none/low neuropathological change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes., Methods: We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated., Results: The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R 2  = 0.31) and 59% in plasma p-tau217 (Adj. R 2  = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm 2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm 2 was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R 2  = 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously., Conclusions: Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration., (© 2022. The Author(s).)

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A + ) and tau PET-positive (T + ) in the medial temporal lobe (A + T MTL + ) and/or in the temporal neocortex (A + T NEO-T + ) and compared them with A + T - and A - T - groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A + T NEO-T + (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A + T MTL + (HR = 14.6, 95% CI = 8.1-26.4) and A + T - (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A - T - (reference) group. Both A + T MTL + (HR = 6.0, 95% CI = 3.4-10.6) and A + T NEO-T + (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A + T - group. Linear mixed-effect models indicated that the A + T NEO-T + (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A + T MTL + (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A + T - (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A - T - (reference) group (all P < 0.001). Both A + T NEO-T + (P < 0.001) and A + T MTL + (P = 0.002) groups also progressed faster than the A + T - group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance., (© 2022. The Author(s).)

We evaluated the relationship between baseline CSF p-tau181 and the rate of tau PET change in the temporal meta-ROI and entorhinal cortex (ERC) and how it varied by amyloid level (CSF Aβ42 or amyloid PET) among 143 individuals from the Mayo Clinic Study of Aging and Mayo Alzheimer Disease Research Center. Higher CSF p-tau181, lower CSF Aβ42, and higher amyloid PET levels were associated with faster rates of tau PET change in both the temporal meta-ROI and ERC. In the temporal meta-ROI, longitudinal tau PET accumulation occurred primarily in participants with abnormal biomarker levels and a diagnosis of dementia, which supports the hypothesis that tau aggregation begins later in the disease process. Compared to the temporal meta-ROI, the ERC showed greater change in tau PET in non-demented participants but less change in later disease stages, supporting ERC as a more sensitive marker of early tau PET changes but with less dynamic range over the disease spectrum. We found both amyloid and CSF p-tau181 were associated with rates of tau PET change but there were some differences in associations by region, amyloid biomarker, and disease stage., (Copyright © 2022. Published by Elsevier Inc.)

Background: Localized regions of left-right image intensity asymmetry (LRIA) were incidentally observed on T 2 -weighted (T 2 -w) and T 1 -weighted (T 1 -w) diagnostic magnetic resonance imaging (MRI) images. Suspicion of herpes encephalitis resulted in unnecessary follow-up imaging. A nonbiological imaging artifact that can lead to diagnostic uncertainty was identified., Purpose: To investigate whether systematic LRIA exist for a range of scanner models and to determine if LRIA can introduce diagnostic uncertainty., Study Type: A retrospective study using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data base., Subjects: One thousand seven hundred fifty-three (median age: 72, males/females: 878/875) unique participants with longitudinal data were included., Field Strength: 3T., Sequences: T 1 -w three-dimensional inversion-recovery spoiled gradient-echo (IR-SPGR) or magnetization-prepared rapid gradient-echo (MP-RAGE) and T 2 -w fluid-attenuated inversion recovery (FLAIR) long tau fast spin echo inversion recovery (LT-FSE-IR). Only General Electric, Philips, and Siemens' product sequences were used., Assessment: LRIA was calculated as the left-right percent difference with respect to the mean intensity from automated anatomical atlas segmented regions. Three neuroradiologists with 37 (**), 32 (**), and 3 (**) years of experience rated the clinical impact of 30 T 2 -w three-dimensional FLAIR exams with LRIA to determine the diagnostic uncertainty. Statistical comparisons between retrospective intensity normalized T 1 m and original T 1 -w images were made., Statistical Tests: For each image type, a linear mixed effects model was fit using LRIA scores from all scanners, regions, and participants as the outcome and age and sex as predictors. Statistical significance was defined as having a P-value <0.05., Results: LRIA scores were significantly different from zero on most scanners. All clinicians were uncertain or recommended definite diagnostic follow-up in 62.5% of cases with LRIA >10%. Individuals with acute brain pathology or focal neurologic deficits are not enrolled in ADNI; therefore, focal signal abnormalities were considered false positives., Data Conclusion: LRIA is system specific, systematic, creates diagnostic uncertainty, and impacts IR-SPGR, MP-RAGE, and LT-FSE-IR product sequences., Level of Evidence: 2 Technical Efficacy Stage: 3., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers., Methods: Cut points for Elecsys amyloid beta 42 (Aβ42), total tau (t-tau), hyperphosphorylated tau (p-tau), and t-tau/Aβ42 and p-tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants., Results: The t-tau/Aβ42 and p-tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)-based cut points were 0.26 (0.24-0.27) for t-tau/Aβ42 and 0.023 (0.020-0.025) for p-tau/Aβ42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA)., Conclusion: CSF t-tau/Aβ42 and p-tau/Aβ42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: This study established the psychometric properties and preliminary validity of the Stricker Learning Span (SLS), a novel computer adaptive word list memory test designed for remote assessment and optimized for smartphone use., Methods: Women enrolled in the Mayo Clinic Specialized Center of Research Excellence (SCORE) were recruited via e-mail or phone to complete two remote cognitive testing sessions. Convergent validity was assessed through correlation with previously administered in-person neuropsychological tests (n = 96, ages 55-79) and criterion validity through associations with magnetic resonance imaging measures of neurodegeneration sensitive to Alzheimer's disease (n = 47)., Results: SLS performance significantly correlated with the Auditory Verbal Learning Test and measures of neurodegeneration (temporal meta-regions of interest and entorhinal cortical thickness, adjusting for age and education). Test-retest reliabilities across two sessions were 0.71-0.76 (two-way mixed intraclass correlation coefficients)., Discussion: The SLS is a valid and reliable self-administered memory test that shows promise for remote assessment of aging and neurodegenerative disorders., Competing Interests: NHS, KK, and MMMi serve as consultants to Biogen, and MMMi serves as a consultant to the Brain Protection Company, outside the scope of this work. KK receives research support from Avid and Eli Lilly, outside the scope of this work. CRJ serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. CRJ receives research support from NIH, the GHR Foundation, and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. JH is a paid consultant for Lundbeck, Biogen, Roche, and Takeda, outside the scope of this work. A Mayo Clinic invention disclosure has been submitted for the Stricker Learning Span and the Mayo Test Drive platform (NHS, JLS). AJK, JRG, JAF, JH, CGS, NT, HJW, CRJ, KK, and MMM have no disclosures related to the content of this submission., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Dementia and mortality rates rise inexorably with age and consequently interact. However, because of the major logistical difficulties in accounting for both outcomes in a defined population, very little work has examined how risk factors and biomarkers for incident dementia are influenced by competing mortality. The objective of this study was to examine long-term associations between amyloid PET, APOE ɛ4, sex, education and cardiovascular/metabolic conditions, and hazard and absolute risk of dementia and mortality in individuals without dementia at enrolment. Participants were enrolled in the Mayo Clinic Study of Aging, a population-based study of cognitive ageing in Olmsted County, MN, USA. All were without dementia and were age 55-92 years at enrolment and were followed longitudinally. Predictor variables were amyloid PET, APOE ɛ4 status, sex, education, cardiovascular/metabolic conditions and age. The main outcomes were incident dementia and mortality. Multivariable, multi-state models were used to estimate mortality and incident dementia rates and absolute risk of dementia and mortality by predictor variable group. Of the 4984 participants in the study, 4336 (87%) were cognitively unimpaired and 648 (13%) had mild cognitive impairment at enrolment. The median age at enrolment was 75 years; 2463 (49%) were women. The median follow-up time was 9.4 years (7.5 years after PET). High versus normal amyloid (hazard ratio 2.11, 95% confidence interval 1.43-2.79), APOE ɛ4 (women: hazard ratio 2.24, 95% confidence interval 1.80-2.77; men: hazard ratio 1.37, 95% confidence interval 1.09-1.71), older age and two additional cardiovascular/metabolic conditions (hazard ratio 1.37, 95% confidence interval 1.22-1.53) were associated with the increased hazard of dementia (all P  < 0.001). Among APOE ɛ4 carriers with elevated amyloid, remaining lifetime risk of dementia at age 65 years was greater in women [74% (95% confidence interval 65-84%) high and 58% (95% confidence interval 52-65%) moderate amyloid], than men [62% (95% confidence interval 52-73%) high and 44% (95% confidence interval 35-53%) moderate amyloid]. Overall, the hazard and absolute risk of dementia varied considerably by predictor group. The absolute risk of dementia associated with predictors characteristic of Alzheimer's disease was greater in women than men while at the same time the combination of APOE ɛ4 non-carrier with normal amyloid was more protective in women than men. This set of findings may be attributed in part to different biological effects and in part to lower mortality rates in women., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Do MRI-based metrics of a CSF-dynamics disorder, disproportionately enlarged subarachnoid-space hydrocephalus (DESH), correlate with discordant amyloid biomarkers (low CSF β-amyloid 1-42, normal Aβ-PET scan)? Individuals ≥50 years from the Mayo Clinic Study of Aging, with MRI, 11C-Pittsburgh compound B (Aβ) PET scans, and CSF phosphorylated-tau protein and Aβ42, were categorized into 4 groups: normal and/or abnormal by CSF β-amyloid 1-42 and Aβ amyloid PET. Within groups, we noted MRI patterns of CSF-dynamics disorders and Aβ-PET accumulation-change rate. One-hundred participants (21%) in the abnormal-CSF and/or normal-PET group had highest DESH-pattern scores and lowest CSF-phosphorylated-tau levels. Among normal amyloid-PET individuals, a 1-unit DESH-pattern score increase correlated with 30%-greater odds of abnormal amyloid CSF after age, and sex adjustment. Mean rate over time of amyloid-PET accumulation in abnormal-CSF and/or normal-PET individuals approximated individuals with normal amyloid values. Adjusting for phosphorylated-tau, abnormal CSF-amyloid and/or normal amyloid-PET individuals had higher mean amyloid-PET accumulation rates than normal individuals. CSF dynamics disorders confound β-amyloid and phosphorylated-tau CSF-biomarker interpretation., (Copyright © 2021. Published by Elsevier Inc.)

Background: To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid., Methods: The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months., Results: Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1)., Interpretation: The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145-1156., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials., Competing Interests: Declaration of Competing Interest C.R.J. serves on an independent data monitoring board for Roche and has consulted for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. D.T.J. receives funding from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. D.S.K. served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety Monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock, and Alzeca Biosciences but receives no personal compensation. He receives research support from the NIH. R.C.P. has consulted for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Eisai, Inc. and is on a Data and Safety Monitoring Committee for Genentech, Inc. He receives research support from the National Institute on Aging, the GHR Foundation, and the Alzheimer's Association. J.G-R. receives research support from the NIH. C.G.S. receives research support from the NIH. M.L.S. has owned shares of the following medical related stocks, unrelated to the current work: Align Technology, Inc., LHC Group, Inc., Mesa Laboratories, Inc., Natus Medical Incorporated, Varex Imaging Corporation, CRISPR Therapeutics, Gilead Sciences, Inc., Globus Medical Inc., Inovio Biomedical Corp., Ionis Pharmaceuticals, Johnson & Johnson, Medtronic, Inc., Parexel International Corporation. P.M.C., J.L.G., H.J.W., and S.D.W. report no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Recent advances in automated face recognition algorithms have increased the risk that de-identified research MRI scans may be re-identifiable by matching them to identified photographs using face recognition. A variety of software exist to de-face (remove faces from) MRI, but their ability to prevent face recognition has never been measured and their image modifications can alter automated brain measurements. In this study, we compared three popular de-facing techniques and introduce our mri&#95;reface technique designed to minimize effects on brain measurements by replacing the face with a population average, rather than removing it. For each technique, we measured 1) how well it prevented automated face recognition (i.e. effects on exceptionally-motivated individuals) and 2) how it altered brain measurements from SPM12, FreeSurfer, and FSL (i.e. effects on the average user of de-identified data). Before de-facing, 97% of scans from a sample of 157 volunteers were correctly matched to photographs using automated face recognition. After de-facing with popular software, 28-38% of scans still retained enough data for successful automated face matching. Our proposed mri&#95;reface had similar performance with the best existing method (fsl&#95;deface) at preventing face recognition (28-30%) and it had the smallest effects on brain measurements in more pipelines than any other, but these differences were modest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM., Competing Interests: Declaration of Competing Interest B.B.B. has served as an investigator for a clinical trial sponsored for Biogen. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr Lewy Body Dementia Program, and the Little Family Foundation, C.R.J. serves on an independent data monitoring board for Roche and has consulted for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. D.T.J. receives funding from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. K.K. serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc.; receives research support from Avid Radioparmaceuticals and Eli Lilly, and receives funding from NIH and Alzheimer's Drug Discovery Foundation. D.S.K. served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation. He receives research support from the NIH. V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). M.M.M. receives support from the NIH, unrestricted research grants from Biogen, and consults for Brain Protection Company. R.C.P. has consulted for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Eisai, Inc. and is on a Data and Safety Monitoring Committee for Genentech, Inc. He receives research support from the National Institute on Aging, the GHR Foundation and the Alzheimer's Association. C.G.S. and J.G-R. receive research support from the NIH. M.L.S. has owned shares of the following medical related stocks, unrelated to the current work: Align Technology, Inc., LHC Group, Inc., Mesa Laboratories, Inc., Natus Medical Incorporated, Varex Imaging Corporation, CRISPR Therapeutics, Gilead Sciences, Inc., Globus Medical Inc., Inovio Biomedical Corp., Ionis Pharmaceuticals, Johnson & Johnson, Medtronic, Inc., Parexel International Corporation. P.M.C., H.J.W., S.D.W., H.B., T.M.T., J.L.G., report no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: We studied interrelationships between CSF biomarkers and associations with APOE ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota., Methods: We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of APOE ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population., Results: Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, APOE ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, APOE ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk., Conclusion: We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins., (© 2020 American Academy of Neurology.)

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-β and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A+T-), or high amyloid and high tau (A+T+). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A+T- (28%), and A+T+ (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A+T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A+T+ quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: A National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms., Objectives: To estimate the sex- and age-specific prevalence of 3 imaging biomarker-based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease., Design, Setting, and Participants: The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019., Main Outcomes and Measures: The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease)., Results: The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P < .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P < .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women., Conclusions and Relevance: Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.

Objective: To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults., Methods: Tau- and amyloid-PET were performed in 579 CU participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49., Results: Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory z scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+., Conclusions: Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal., (© 2019 American Academy of Neurology.)

Importance: A National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers., Objective: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information., Design, Setting, and Participants: Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018., Exposures: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles., Main Outcomes and Measures: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only., Results: Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier., Conclusions and Relevance: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.

See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.

See Gordon (doi:10.1093/brain/awy052) for a scientific commentary on this article.Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis may account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating > 0) with amnestic presentations ≥ 75 years who had MRI and PET imaging with 18F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18F-FDG-PET were screened and those with TDP-43-negative Alzheimer's disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer's disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and may serve as a biomarker for hippocampal sclerosis.

Objective: To describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research., Methods: Eight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status., Results: All participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR <1.33)., Conclusions: The participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD., (© 2018 American Academy of Neurology.)

See Herholz (doi:10.1093/brain/awx340) for a scientific commentary on this article.Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (≥50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30-49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Functionally related brain regions are selectively vulnerable to Alzheimer's disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer's disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer's disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer's disease dementia, we found several distinct spatial patterns of tau deposition, including 'Braak-like' and 'non-Braak-like', across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with 'non-Braak-like' patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer's disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer's disease., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older., Methods: All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50-89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A-) or abnormal (A+) amyloid using amyloid PET, normal (T-) or abnormal (T+) tau using tau PET, and normal (N-) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging., Findings: The numbers of participants in each profile group were 165 A-T-N-, 35 A-T+N-, 63 A-T-N+, 19 A-T+N+, 44 A+T-N-, 25 A+T+N-, 35 A+T-N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55-64) in A-T-N- and 57 years (54-64) in A-T+N- to a median 80 years (75-84) in A+T-N+ and 79 years (73-87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A- group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N-, A+T-N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A-T+N-, A-T-N+, and A-T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A-T-N- prevalence declined and A+T+N+ and A-T+N+ prevalence increased. In both men and women, A-T-N- was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities., Interpretation: Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired., Funding: National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness., Methods: We examined five methods for determining cut points., Results: The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal., Discussion: In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)