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Introduction: MicroRNAs are short non-coding RNAs that control proteostasis at the systems level and are emerging as potential prognostic and diagnostic biomarkers for Alzheimer's disease (AD)., Methods: We performed small RNA sequencing on plasma samples from 847 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants., Results: We identified microRNA signatures that correlate with AD diagnoses and help predict the conversion from mild cognitive impairment (MCI) to AD., Discussion: Our data demonstrate that plasma microRNA signatures can be used to not only diagnose MCI, but also, critically, predict the conversion from MCI to AD. Moreover, combined with neuropsychological testing, plasma microRNAome evaluation helps predict MCI to AD conversion. These findings are of considerable public interest because they provide a path toward reducing indiscriminate utilization of costly and invasive testing by defining the at-risk segment of the aging population., Highlights: We provide the first analysis of the plasma microRNAome for the ADNI study. The levels of several microRNAs can be used as biomarkers for the prediction of conversion from MCI to AD. Adding the evaluation of plasma microRNA levels to neuropsychological testing in a clinical setting increases the accuracy of MCI to AD conversion prediction., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: MicroRNAs (miRNAs) play important roles in gene expression regulation and Alzheimer's disease (AD) pathogenesis., Methods: We investigated the association between baseline plasma miRNAs and central AD biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 803): amyloid, tau, and neurodegeneration (A/T/N). Differentially expressed miRNAs and their targets were identified, followed by pathway enrichment analysis. Machine learning approaches were applied to investigate the role of miRNAs as blood biomarkers., Results: We identified nine, two, and eight miRNAs significantly associated with A/T/N positivity, respectively. We identified 271 genes targeted by amyloid-related miRNAs with estrogen signaling receptor-mediated signaling among the enriched pathways. Additionally, 220 genes targeted by neurodegeneration-related miRNAs showed enrichment in pathways including the insulin growth factor 1 pathway. The classification performance of demographic information for A/T/N positivity was increased up to 9% with the inclusion of miRNAs., Discussion: Plasma miRNAs were associated with central A/T/N biomarkers, highlighting their potential as blood biomarkers., Highlights: We performed association analysis of microRNAs (miRNAs) with amyloid/tau/neurodegeneration (A/T/N) biomarker positivity. We identified dysregulated miRNAs for A/T/N biomarker positivity. We identified Alzheimer's disease biomarker-specific/common pathways related to miRNAs. miRNAs improved the classification for A/T/N positivity by up to 9%. Our study highlights the potential of miRNAs as blood biomarkers., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease., Methods: A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-., Results: SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline., Discussion: These results highlight the interplay between amyloid and α-syn and their association with disease progression., Highlights: Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4)., Methods: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs., Results: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level., Discussion: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges., Highlights: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimer's Association Global Biomarker Standardisation Consortium plasma phospho-tau Round Robin study engaged assay developers in a blinded case-control study on plasma p-tau, aiming to learn which assays provide the largest fold-changes in AD compared to non-AD, have the strongest relationship between plasma and cerebrospinal fluid (CSF), and show the most consistent relationships between methods (commutability) in measuring both patient samples and candidate reference materials (CRM)., Methods: Thirty-three different p-tau biomarker assays, built on eight different analytical platforms, were used to quantify paired plasma and CSF samples from 40 participants. AD biomarker status was categorised as "AD pathology" (n=25) and "non-AD pathology" (n=15) by CSF Aβ42/Aβ40 (US-FDA; CE-IVDR) and p-tau181 (CE-IVDR) methods. The commutability of four CRM, at three concentrations, was assessed across assays., Findings: Plasma p-tau217 consistently demonstrated higher fold-changes between AD and non-AD pathology groups, compared to other p-tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p-tau217 assays provided the highest median fold-changes. In CSF, p-tau217 assays also performed best, and exhibited substantially larger fold-changes than their plasma counterparts, despite similar diagnostic performance. P-tau217 showed the strongest correlations between plasma assays (rho=0.81 to 0.97). Plasma p-tau levels were weakly-to-moderately correlated with CSF p-tau, and correlations were non-significant within the AD group alone. The evaluated CRM were not commutable across assays., Interpretation: Plasma p-tau217 measures had larger fold-changes and discriminative accuracies for detecting AD pathology, and better agreement across platforms than other plasma p-tau variants. Plasma and CSF markers of p-tau, measured by immunoassays, are not substantially correlated, questioning the interchangeability of their continuous relationship. Further work is warranted to understand the pathophysiology underlying this dissociation, and to develop suitable reference materials facilitating cross-assay standardisation., Funding: Alzheimer's Association (#ADSF-24-1284328-C)., Competing Interests: CONFLICTS OF INTEREST All biomarker measurements were performed by the assay developers in-house without cost. ALZpath p-tau217 was performed at the University of Gothenburg (UGOT) and Lilly immunoassays were performed at the University of Lund. C2N Diagnostics declined to participate in the study. N.J.A. has given lectures in symposia sponsored by Eli-Lilly, Roche Diagnostics, and Quanterix. NJA has declined paid opportunities from ALZpath. A.K. has no conflicts of interest. W.S.B. has no conflicts of interest. L.G. has no conflicts of interest. U.A. has no conflicts of interest. B.A. has no conflicts of interest. M.D. is an employee of AbbVie and holds stock or stock options. S.B. is an employee of AbbVie and holds stock or stock options. J.V. is employee of ADx NeuroSciences. C.L. is an employee of ADx NeuroSciences. M.V.L. is an employee of ADx NeuroSciences. E.S. is an employee of ADx NeuroSciences. S.I. is an employee of Alamar Biosciences H.Y.J. is an employee of Alamar Biosciences X.Y. is an employee of Alamar Biosciences A.F-H. is an employee of Alamar Biosciences B.Z. is an employee of Alamar Biosciences Y.L. is an employee of Alamar Biosciences A.Jeromin is an employee of ALZpath, Inc., and has stock options. M.V. is an employee of Fujirebio Europe N.V. N.L.B. is an employee of Fujirebio Europe N.V H.K. is a former employee of Janssen R&D D.B. has no conflicts of interest. G.T-B. is an employee of Janssen R&D and has stock options. D.B. has no conflicts of interest. S.J. has no conflicts of interest. S-Y.Y is an employee of MagQu Co., Ltd.C.D. C.D. is employee of Meso Scale Diagnostics, LLC D.R. is an employee of Meso Scale Diagnostics, LLC G.S. is an employee of Meso Scale Diagnostics, LLC J.W. is an employee of Meso Scale Diagnostics, LLC K.M. is an employee of Quanterix M.K. is an employee of Quanterix A.Jethwa is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. L.S. is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. O.H. 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. R.R has no conflicts of interest. J.G. has no conflicts of interest. P.K. has no conflicts of interest. F.G-O. has no conflicts of interest. L.M-G. has no conflicts of interest. L.M.S. has served as a consultant or on advisory boards for Biogen, Roche Diagnostics, Fujirebio; receives grant support from NIA/ADNI with QC oversight responsibilities and in-kind support from Fujirebio and Roche Diagnostics automated immunoassay platforms and reagents. K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. J.M.S. has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly; given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen; and is Chief Medical Officer for ARUK. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).

Introduction: Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed., Methods: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories., Results: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive., Discussion: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression., Highlights: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Biomarkers have been essential to understanding Alzheimer's disease (AD) pathogenesis, pathophysiology, progression, and treatment effects. However, each biomarker measure is a representation of the biological target, the assay used to measure it, and the variance of the assay. Thus, biomarker measures are difficult to compare without standardization, and the units and magnitude of effect relative to the disease are difficult to appreciate, even for experts. To facilitate quantitative comparisons of AD biomarkers in the context of biologic and treatment effects, we propose a biomarker standardization approach between normal ranges and maximum abnormal AD ranges, which we refer to as CentiMarker, similar to the Centiloid approach used in PET., Methods: We developed a standardization scale that creates percentile values ranging from 0 for a normal population to 100 for the most abnormal measures across disease stages. We applied this scale to CSF and plasma biomarkers in autosomal dominant AD, assessing the distribution by estimated years from symptom onset, between biomarkers, and across cohorts. We then validated this approach in a large national sporadic AD cohort., Results: We found the CentiMarker scale provided an easily interpretable metric of disease abnormality. The biologic changes, range, and distribution of several AD fluid biomarkers including amyloid-β, phospho-tau and other biomarkers, were comparable across disease stages in both early onset autosomal dominant and sporadic late onset AD., Discussion: The CentiMarker scale offers a robust and versatile framework for the standardized biological comparison of AD biomarkers. Its broader adoption could facilitate biomarker reporting, allowing for more informed cross-study comparisons and contributing to accelerated therapeutic development., Competing Interests: All the other authors reported no conflicts of interest.

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C 2 N Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups., (© 2024. The Author(s).)

Introduction: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau 181 ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog)., Methods: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression., Results: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aβ- individuals (HR = 3.11; p = 2.6e-09)., Discussion: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease., Highlights: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau 181 , GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults., Methods: The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid β (Aβ) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls., Results: The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aβ, tau, or p-tau levels, or tau/Aβ or p-tau/Aβ ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (β, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up., Conclusions: During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aβ) changes or greater cognitive decline., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Evaluating correlations between disease biomarkers and clinical outcomes is crucial in biomedical research. During the early stages of many chronic diseases, changes in biomarkers and clinical outcomes are often subtle. A major challenge to detecting subtle correlations is that studies with large sample sizes are usually needed to achieve sufficient statistical power. This challenge is even greater when biofluid and imaging biomarker data are used because the required procedures are burdensome, perceived as invasive, and/or expensive, limiting sample sizes in individual studies. Combining data across multiple studies may increase statistical power, but biomarker data may be generated using different assay platforms, scanner types, or processing protocols, which may affect measured biomarker values. Therefore, harmonizing biomarker data is essential to combining data across studies. Bridging studies involve re-processing of a subset of samples or imaging scans to evaluate how biomarker values vary by studies. This presents an analytic challenge on how to best harmonize biomarker data across studies to allow unbiased and optimal estimates of their correlations with standardized clinical outcomes. We conceptualize that a latent biomarker underlies the observed biomarkers across studies, and propose a novel approach that integrates the data in the bridging study with the study-specific biomarker data for estimating the biological correlations between biomarkers and clinical outcomes. Through extensive simulations, we compare our method to several alternative methods/algorithms often used to estimate the correlations. Finally, we demonstrate the application of this methodology to a real-world multi-center Alzheimer's disease biomarker study to correlate cerebrospinal fluid biomarker concentrations with cognitive outcomes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ 42 ), phosphorylated tau 181 (p-tau 181 ), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau 181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ 42 . First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN PD ) using CSF Aβ 42 (A), p-tau 181 (T), and serum NfL (N) and tested ATN PD prediction of longitudinal cognitive decline in PD., Methods: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATN PD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected)., Results: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ 2 : p = 1). Patients with PD had overall lower CSF p-tau 181 (β = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aβ 42 ( p = 0.061) or NfL ( p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ 42 ( p = 0.18), p-tau 181 ( p = 1), or t-tau ( p = 0.96). Using ATN PD , PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37, p = 0.00077) than all other ATN PD statuses including A+ alone (A+T-N-; n = 75; 21%)., Discussion: In patients with early PD, CSF p-tau 181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATN PD (incorporating CSF Aβ 42 , CSF p-tau 181 , and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

The challenges facing tree orchard production in the coming years will be largely driven by changes in the climate affecting the sustainability of farming practices in specific geographical regions. Identifying key traits that enable tree crops to modify their growth to varying environmental conditions and taking advantage of new crop improvement opportunities and technologies will ensure the tree crop industry remains viable and profitable into the future. In this review article we 1) outline climate and sustainability challenges relevant to horticultural tree crop industries, 2) describe key tree crop traits targeted for improvement in agroecosystem productivity and resilience to environmental change, and 3) discuss existing and emerging genomic technologies that provide opportunities for industries to future proof the next generation of orchards., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kerr, Shehnaz, Paudel, Manivannan, Shaw, Johnson, Velasquez, Tanurdžić, Cazzonelli, Varkonyi-Gasic and Prentis.)

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway., Content: Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers., Summary: CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Majority of dementia research is conducted in non-Hispanic White participants despite a greater prevalence of dementia in other racial groups. To obtain a better understanding of biomarker presentation of Alzheimer's disease (AD) in the non-Hispanic White population, this study exclusively examined AD biomarker abnormalities in 85 Black and/or African American participants within the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were classified by the ADNI into 3 clinical groups: cognitively normal, mild cognitive impairment, or dementia. Data examined included demographics, apolipoprotein E (APOE) ε4, cerebrospinal fluid (CSF) Aβ 1-42 , CSF total tau (t-tau), CSF phosphorylated tau (p-tau), 3T magnetic resonance imaging (MRI), and measures of cognition and function. Analyses of variance and covariance showed lower cortical thickness in 5 of 7 selected MRI regions, lower hippocampal volume, greater volume of white matter hyperintensities, lower measures of cognition and function, lower measures of CSF Aβ 1 -42 , and greater measures of CSF t-tau and p-tau between clinical groups. Our findings confirmed greater AD biomarker abnormalities between clinical groups in this sample., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Timely detection of the pathophysiological changes and cognitive impairment caused by Alzheimer's disease (AD) is increasingly pressing because of the advent of biomarker-guided targeted therapies that may be most effective when provided early in the disease. Currently, diagnosis and management of early AD are largely guided by clinical symptoms. FDA-approved neuroimaging and cerebrospinal fluid biomarkers can aid detection and diagnosis, but the clinical implementation of these testing modalities is limited because of availability, cost, and perceived invasiveness. Blood-based biomarkers (BBBMs) may enable earlier and faster diagnoses as well as aid in risk assessment, early detection, prognosis, and management. Herein, we review data on BBBMs that are closest to clinical implementation, particularly those based on measures of amyloid-β peptides and phosphorylated tau species. We discuss key parameters and considerations for the development and potential deployment of these BBBMs under different contexts of use and highlight challenges at the methodological, clinical, and regulatory levels., Competing Interests: Declaration of interests H.H. is an employee of Eisai and serves as reviewing editor for the journal Alzheimer’s & Dementia. H.H. is the inventor of 11 patents and has received no royalties for: In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders patent no. 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases patent no. 8298784; Neurodegenerative Markers for Psychiatric Conditions publication no. 20120196300; In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders publication no. 20100062463; In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders publication no. 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases publication no. 20090263822; In Vitro Method for The Diagnosis of Neurodegenerative Diseases patent no. 7547553; CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases publication no. 20080206797; In Vitro Method for The Diagnosis of Neurodegenerative Diseases publication no. 20080199966; Neurodegenerative Markers for Psychiatric Conditions publication no. 20080131921; and Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: US patent no. 10921330. J.C. has provided consultation to Acadia, Actinogen, Alkahest, Alpha Cognition, AriBio, Biogen, BioVie, Cassava, Cerecin, Corium, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, GAP Innovations, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, PRODEO, Prothena, reMYND, Resverlogix, Roche, Sage Therapeutics, Signant Health, Simcere, Sunbird Bio, Suven, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. A.N. ha no personal conflicts to declare, but his employer NCGG shares some patents with Shimadzu and receives royalty. S.M. serves on the board of directors of Senscio Systems and the scientific advisory board of AiCure Technologies, ALZpath, and Boston Millennia Partners and has received consulting fees from Biogen, C(2)N, Eisai, Novartis, and Roche/Genentech. S.O. has multiple patents on precision medicine for neurodegenerative diseases and is the founding scientist of Cx Precision Medicine, Inc. L.M.S. has received compensation for teaching activities from Biogen. Y.H., M.C., and R.B. are employees of Eisai. A.V. declares no competing interests related to the present paper. A.V.’s contribution to this paper reflects entirely and exclusively his own academic expertise on the matter. A.V. was an employee of Eisai (November 2019–June 2021). A.V. has not received any fees or honoraria since November 2019. Before November 2019, A.V. received lecture honoraria from Roche, MagQu, and Servier. K.B. has served as a consultant and on advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the Gothenburg University Ventures Incubator Program. S.E.S. has analyzed data provided by C(2)N Diagnostics to Washington University and served on an advisory board for Eisai., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aβ 42 , tTau, and pTau 181 ) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

Background: Animal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans., Methods: This was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively., Results: There were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aβ), tau, or phospho-tau 181p levels, or on the tau/Aβ or p-tau 181p /Aβ ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [-0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses., Conclusions: Intraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults., Clinical Trial Registration: NCT01993836., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes., Methods: We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI)., Results: The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants., Discussion: The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile., Objective: To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications., Design, Setting, and Participants: This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023., Exposures: Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240)., Main Outcomes and Measures: Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET., Results: A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile., Conclusion and Relevance: Results suggest that the CSF A-T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.

Introduction: Synaptic degeneration is a key part of the pathophysiology of neurodegenerative diseases, and biomarkers reflecting the pathological alterations are greatly needed., Method: Seventeen synaptic proteins were quantified in a pathology-confirmed cerebrospinal fluid cohort of patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar degeneration (FTLD; n = 53), and Lewy body spectrum of disorders (LBD; n = 21), as well as healthy controls (HC; n = 48)., Results: Comparisons revealed four distinct patterns: markers decreased across all neurodegenerative conditions compared to HC (the neuronal pentraxins), markers increased across all neurodegenerative conditions (14-3-3 zeta/delta), markers selectively increased in AD compared to other neurodegenerative conditions (neurogranin and beta-synuclein), and markers selectively decreased in LBD and FTLD compared to HC and AD (AP2B1 and syntaxin-1B)., Discussion: Several of the synaptic proteins may serve as biomarkers for synaptic dysfunction in AD, LBD, and FTLD. Additionally, differential patterns of synaptic protein alterations seem to be present across neurodegenerative diseases., Highlights: A panel of synaptic proteins were quantified in the cerebrospinal fluid using mass spectrometry. We compared Alzheimer's disease, frontotemporal degeneration, and Lewy body spectrum of disorders. Pathology was confirmed by autopsy or familial mutations. We discovered synaptic biomarkers for synaptic degeneration and cognitive decline. We found differential patterns of synaptic proteins across neurodegenerative diseases., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Within Lewy body spectrum disorders (LBSD) with α-synuclein pathology (αSyn), concomitant Alzheimer's disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p-tau 181 ) is sensitive to AD neuropathologic change (ADNC) in clinical AD, and plasma glial fibrillary acidic protein (GFAP) is associated with the presence of β-amyloid plaques. While these plasma biomarkers are well tested in clinical and pathological AD, their diagnostic and prognostic performance for concomitant AD in LBSD is unknown., Methods: In autopsy-confirmed αSyn-positive LBSD, we tested how plasma p-tau 181 and GFAP differed across αSyn with concomitant ADNC (αSyn+AD; n = 19) and αSyn without AD (αSyn; n = 30). Severity of burden was scored on a semiquantitative scale for several pathologies (e.g., β-amyloid and tau), and scores were averaged across sampled brainstem, limbic, and neocortical regions., Results: Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β = 0.31, 95% CI = 0.065-0.56, and P = 0.015), after covarying for age at plasma, plasma-to-death interval, and sex; plasma p-tau 181 was not (P = 0.37). Next, linear models tested associations of AD pathological features with both plasma analytes, covarying for plasma-to-death, age at plasma, and sex. GFAP was significantly associated with brain β-amyloid (β = 15, 95% CI = 6.1-25, and P = 0.0018) and tau burden (β = 12, 95% CI = 2.5-22, and P = 0.015); plasma p-tau 181 was not associated with either (both P > 0.34)., Interpretation: Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β-amyloid plaques., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

While Alzheimer's disease (AD) is associated with inner retina thinning (retinal nerve fiber layer and ganglion cell layer), we have observed photoreceptor outer nuclear layer (ONL) thinning in patients with frontotemporal lobar degeneration tauopathy (FTLD-Tau) compared to normal controls. We hypothesized that ONL thinning may distinguish FTLD-Tau from patients with biomarker evidence of AD neuropathologic change (ADNC) and will correlate with FTLD-Tau disease severity. Predicted FTLD-Tau (pFTLD-Tau; n = 21; 33 eyes) and predicted ADNC (pADNC; n = 24; 46 eyes) patients were consecutively enrolled, underwent optical coherence tomography macula imaging, and disease was categorized (pFTLD-Tau vs. pADNC) with cerebrospinal fluid biomarkers, genetic testing, and autopsy data when available. Adjusting for age, sex, and race, pFTLD-Tau patients had a thinner ONL compared to pADNC, while retinal nerve fiber layer and ganglion cell layer were not significantly different. Reduced ONL thickness correlated with worse performance on Folstein Mini-Mental State Examination and clinical dementia rating plus frontotemporal dementia sum of boxes for pFTLD-Tau but not pADNC. Photoreceptor ONL thickness may serve as an important noninvasive diagnostic marker that distinguishes FTLD-Tau from AD neuropathologic change., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Lumbar puncture (LP) to collect and examine cerebrospinal fluid (CSF) is an important option for the evaluation of Alzheimer's disease (AD) biomarkers but it is not routinely performed due to its invasiveness and link to adverse effects (AE)., Methods: We include all participants who received at least one LP in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study. For comparison between groups, two-sample t -tests for continuous, and Pearson's chi-square test for categorical variables were performed., Results: Two hundred twenty-seven LP-related AEs were reported by 172 participants after 1702 LPs (13.3%). The mean age of participants who reported at least one AE was 69.79 (standard deviation (SD) 6.3) versus none 72.44 (7.17) years ( p  < 0.001) with female predominance (115/172 = 67.4% vs 435/913 = 48%), and had greater entorhinal cortical thickness and hippocampal volume (3.903 (0.782) vs 3.684 (0.775) mm, p  = 0.002; 7.38 (1.06) vs 7.05 (1.15) mm 3 , p  < 0.001), respectively., Discussion: We found that younger age, female sex, and greater thickness of the entorhinal cortex were associated with a higher rate of LP-related AE reports., Competing Interests: All authors have no conflicts to disclose. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Crucial to the success of clinical trials targeting early Alzheimer's disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers., Methods: Longitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ-)] subgroups. Baseline plasma (p-tau 181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ- subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement., Results: A total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ- subgroups, including Aβ- CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78-0.93] and more modestly in CN (0.65-0.73)., Conclusions: The present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ- CN indicates the potential use of these biomarkers in predicting a normal age-related decline., (© 2023. The Author(s).)

Introduction: Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed., Methods: We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinson's disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimer's Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants., Results: Likely CNS-derived EVs in plasma were significantly reduced in AD compared to HCs in both cohorts. Integrative models including CNS-derived EV markers and AD markers present on EVs reached area under the curve of 0.915 in discovery cohort and 0.810 in validation cohort., Discussion: This study demonstrated that robust and rapid analysis of individual neuron-derived synaptic function-related EVs in peripheral blood may serve as a helpful marker of synaptic dysfunction in AD and dementia., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Epidemiological studies report an association between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and clinically diagnosed Alzheimer's disease (AD). We examined the association between TBI/PTSD and biomarker-defined AD., Methods: We identified 289 non-demented veterans with TBI and/or PTSD and controls who underwent clinical evaluation, cerebrospinal fluid (CSF) collection, magnetic resonance imaging (MRI), amyloid beta (Aβ) and tau positron emission tomography, and apolipoprotein E testing. Participants were followed for up to 5.2 years., Results: Exposure groups (TBI, PTSD, and TBI + PTSD) had higher prevalence of mild cognitive impairment (MCI: P < .0001) and worse Mini-Mental State Examination scores (PTSD: P = .008; TBI & PTSD: P = .009) than controls. There were no significant differences in other cognitive scores, MRI volumes, Aβ or tau accumulation, or in most longitudinal measures., Discussion: TBI and/or PTSD were not associated with elevated AD biomarkers. The poorer cognitive status of exposed veterans may be due to other comorbid pathologies., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity., Methods: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype., Results: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons)., Discussion: Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study., Highlights: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aβ) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aβ42/40 predicted amyloid positron emission tomography status better than Aβ42 or Aβ40 alone., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally., Methods: In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time., Results: This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (n CU- = 197); CU Aβ-positive (n CU+ = 55), mild cognitively impaired (MCI) Aβ-negative (n MCI- = 228), MCI Aβ-positive (n MCI+ = 193), and AD dementia Aβ-positive (n AD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline ( p = 0.01), worse brain atrophy ( p = 8.8 × 10 -27 ), and worse MMSE scores ( p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10 -14 ]). Despite the significant association with Aβ pathology (η 2 Aβ PET = 0.09, P Aβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η 2 pTau-181 = 0.53, P pTau-181 < 0.001; η 2 tTau = 0.59, P tTau < 0.001)., Discussion: High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia., (© 2022 American Academy of Neurology.)

Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022., Methods: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials., Results and Discussion: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort., Methods: Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N = 70), MCI (N = 75), and AD dementia (N = 50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p-tau181 was measured using the Quanterix SiMoA HD-X platform., Results: Plasma p-tau181 differentiated pathology-confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p-Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p-tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia., Interpretation: Plasma p-tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p-tau181 are associated with faster cognitive and functional decline., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aβ pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics. These measures of Aβ aggregation, e.g. plaques, protofibrils, and oligomers, are medically invasive and often only available at specialized medical centers or not covered by medical insurance, and PET scans are costly. Therefore, a major goal in recent years has been to identify blood-based biomarkers that can accurately detect AD pathology with cost-effective, minimally invasive procedures.To assess the performance of plasma Aβ assays in predicting amyloid burden in the central nervous system (CNS), this review compares twenty-one different manuscripts that used measurements of 42 and 40 amino acid-long Aβ (Aβ42 and Aβ40) in plasma to predict CNS amyloid status. Methodologies that quantitate Aβ42 and 40 peptides in blood via immunoassay or immunoprecipitation-mass spectrometry (IP-MS) were considered, and their ability to distinguish participants with amyloidosis compared to amyloid PET and CSF Aβ measures as reference standards was evaluated. Recent studies indicate that some IP-MS assays perform well in accurately and precisely measuring Aβ and detecting brain amyloid aggregates., (© 2022. The Author(s).)

Background: Alzheimer's disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC., Methods: We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [ 3 H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 μl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [ 3 H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF., Results: We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aβ. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC., (© 2022. The Author(s).)

Despite the strong association of the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway with tumor initiation, recurrence, and metastasis, the mechanism by which this pathway regulates cancer progression is not well understood. Here, we report that IIS supports breast cancer stem cell (CSC) self-renewal in an IRS2-phosphatidylinositol 3-kinase (PI3K)-dependent manner that involves the activation and stabilization of MYC. IRS2-PI3K signaling enhances MYC expression through the inhibition of GSK3β activity and suppression of MYC phosphorylation on threonine 58, thus reducing proteasome-mediated degradation of MYC and sustaining active pS62-MYC function. A stable T58A-Myc mutant rescues CSC function in Irs2 -/- cells, supporting the role of this MYC stabilization in IRS2-dependent CSC regulation. These findings establish a mechanistic connection between the IIS pathway and MYC and highlight a role for IRS2-dependent signaling in breast cancer progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important for normal mammary gland biology, and dysregulation of their expression and function drives breast cancer risk and progression through activation of downstream signaling effectors, often in a subtype-dependent manner. The IGF signaling pathway has also been implicated in resistance to current therapeutic strategies, including ER and HER2 targeting drugs. Unfortunately, efforts to target IGF signaling for the treatment of breast cancer have been unsuccessful, due to a number of factors, most significantly the adverse effects of disrupting IGF signaling on normal glucose metabolism. We highlight here the recent discoveries that provide enthusiasm for continuing efforts to target IGF signaling for the treatment of breast cancer patients.

Background and Objectives: CSF biomarkers β-amyloid 1-42 (Aβ 42 ), phosphorylated tau 181 (p-tau 181 ), total tau (t-tau), and neurogranin (Ng) can diagnose Alzheimer disease (AD) in life. However, it is unknown whether CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test whether biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aβ 42 , p-tau 181 , t-tau, and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD + αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD + αSyn affected the diagnostic accuracy of 2 CSF-based strategies: the amyloid/tau/neurodegeneration (ATN) framework and the t-tau/Aβ 42 ratio., Methods: Inclusion criteria were neuropathologic diagnoses of AD, mixed AD + αSyn, and αSyn. A convenience sample of nonimpaired controls was selected with available CSF and a Mini-Mental State Examination (MMSE) ≥ 27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aβ 42 , p-tau 181 , t-tau, and Ng differences across AD and AD + αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic β-amyloid and tau. Receiver operating characteristic and area under the curve (AUC), including 95% CI, evaluated diagnostic accuracy., Results: Participants were 61 patients with AD, 39 patients with mixed AD + αSyn, 20 patients with αSyn, and 61 controls. AD had similar median age (73 [interquartile range {IQR} = 12] years), MMSE (23 [IQR = 9]), and sex distribution (male = 49%) compared with AD + αSyn age (70 [IQR = 13] years; p = 0.3), MMSE (25 [IQR = 9.5]; p = 0.19), and sex distribution (male = 69%; p = 0.077). ANCOVAs showed that AD + αSyn had lower p-tau 181 (F(1,94) = 17, p < 2.6e-16), t-tau (F(1,93) = 11, p = 0.0004), and Ng levels (F(1,50) = 12, p = 0.0004) than AD; there was no difference in Aβ 42 ( p = 0.44). Models showed increasing αSyn related to lower p-tau 181 (β = -0.26, SE = 0.092, p = 0.0065), t-tau (β = -0.19, SE = 0.092, p = 0.041), and Ng levels (β = -0.2, SE = 0.066, p = 0.0046); αSyn was not a significant factor for Aβ 42 ( p = 1). T-tau/Aβ 42 had the highest accuracy when detecting AD, including mixed AD + αSyn cases (AUC = 0.95; CI 0.92-0.98)., Discussion: Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau 181 , t-tau, and Ng levels and can affect diagnostic accuracy in patients with AD., (© 2022 American Academy of Neurology.)

Background: Recently, tau PET tracers have shown strong associations with clinical outcomes in individuals with cognitive impairment and cognitively unremarkable elderly individuals. flortaucipir PET scans to measure tau deposition in multiple brain areas as the disease progresses. This information needs to be summarized to evaluate disease severity and predict disease progression. We, therefore, sought to develop a machine learning-derived index, SPARE-Tau, which successfully detects pathology in the earliest disease stages and accurately predicts progression compared to a priori-based region of interest approaches (ROI)., Methods: 587 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort had flortaucipir scans, structural MRI scans, and an Aβ biomarker test (CSF or florbetapir PET) performed on the same visit. We derived the SPARE-Tau index in a subset of 367 participants. We evaluated associations with clinical measures for CSF p-tau, SPARE-MRI, and flortaucipir PET indices (SPARE-Tau, meta-temporal, and average Braak ROIs). Bootstrapped multivariate adaptive regression splines linear regression analyzed the association between the biomarkers and baseline ADAS-Cog13 scores. Bootstrapped multivariate linear regression models evaluated associations with clinical diagnosis. Cox-hazards and mixed-effects models investigated clinical progression and longitudinal ADAS-Cog13 changes. The Aβ positive cognitively unremarkable participants, not included in the SPARE-Tau training, served as an independent validation group., Results: Compared to CSF p-tau, meta-temporal, and averaged Braak tau PET ROIs, SPARE-Tau showed the strongest association with baseline ADAS-cog13 scores and diagnosis. SPARE-Tau also presented the strongest association with clinical progression in cognitively unremarkable participants and longitudinal ADAS-Cog13 changes. Results were confirmed in the Aβ+ cognitively unremarkable hold-out sample participants. CSF p-tau showed the weakest cross-sectional associations and longitudinal prediction., Discussion: Flortaucipir indices showed the strongest clinical association among the studied biomarkers (flortaucipir, florbetapir, structural MRI, and CSF p-tau) and were predictive in the preclinical disease stages. Among the flortaucipir indices, the machine-learning derived SPARE-Tau index was the most sensitive clinical progression biomarker. The combination of different biomarker modalities better predicted cognitive performance., Competing Interests: Dr. Shaw provides quality control oversight for the Roche Electrosys immunoassay platform as part of the ADNI-3 study. Dr. Weiner has served on the Scientific Advisory Boards for Alzheon, Inc., Accera, Merck, Nestle (Nolan), PCORI (PPRN), Eli Lilly, Delfino Logic Ltd. (for Merck), Dolby Ventures, Brain Health Registry, and ADNI. He served on the editorial boards for Alzheimer’s & Dementia and MRI. He has provided consulting and/or acted as a speaker/lecturer to Synarc, Pfizer, Accera, Inc., Alzheimer’s Drug Discovery Foundation (ADDF), Merck, BioClinica, Eli Lilly, Howard University, Guidepoint, Denali Therapeutics, Nestle/Nestec, GLG Research, Atheneum Partners, BIONEST Partners, American Academy of Neurology (AAN), and Society for Nuclear Medicine and Molecular Imaging (SNMMI). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors report no competing interests.

Importance: Biomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) associated with tau (FTLD-tau) or TDP-43 (FTLD-TDP)., Objective: To test whether plasma biomarkers glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), or their ratio (GFAP/NfL) differ between FTLD-tau and FTLD-TDP., Design, Setting, and Participants: This retrospective cross-sectional study included data from 2009 to 2020 from the University of Pennsylvania Integrated Neurodegenerative Disease Database, with a median (IQR) follow-up duration of 2 (0.3-4.2) years. The training sample was composed of patients with autopsy-confirmed and familial FTLD; nonimpaired controls were included as a reference group. The independent validation sample included patients with FTD with a clinical diagnosis of progressive supranuclear palsy syndrome (PSPS) associated with tau (PSPS-tau) or amytrophic lateral sclerosis (ALS) associated with TDP-43 (ALS-TDP). In patients with FTLD with autopsy-confirmed or variant-confirmed pathology, receiver operating characteristic (ROC) curves tested the GFAP/NfL ratio and established a pathology-confirmed cut point. The cut point was validated in an independent sample of patients with clinical frontotemporal dementia (FTD). Data were analyzed from February to July 2022., Exposures: Clinical, postmortem histopathological assessments, and plasma collection., Main Outcomes and Measures: ROC and area under the ROC curve (AUC) with 90% CIs evaluated discrimination of pure FTLD-tau from pure FTLD-TDP using plasma GFAP/NfL ratio; the Youden index established optimal cut points. Sensitivity and specificity of cut points were assessed in an independent validation sample., Results: Of 349 participants with available plasma data, 234 met inclusion criteria (31 controls, 141 in the training sample, and 62 in the validation sample). In the training sample, patients with FTLD-tau were older than patients with FTLD-TDP (FTLD-tau: n = 46; mean [SD] age, 65.8 [8.29] years; FTLD-TDP: n = 95; mean [SD] age, 62.3 [7.82] years; t84.6 = 2.45; mean difference, 3.57; 95% CI, 0.67-6.48; P = .02) but with similar sex distribution (FTLD-tau: 27 of 46 [59%] were male; FTLD-TDP: 51 of 95 [54%] were male; χ21 = 0.14; P = .70). In the validation sample, patients with PSPS-tau were older than those with ALS-TDP (PSPS-tau: n = 31; mean [SD] age, 69.3 [7.35] years; ALS-TDP: n = 31; mean [SD] age, 54.6 [10.17] years; t54.6 = 6.53; mean difference, 14.71; 95% CI, 10.19-19.23; P < .001) and had fewer patients who were male (PSPS-tau: 9 of 31 [29%] were male; ALS-TDP: 22 of 31 [71%] were male; χ21 = 9.3; P = .002). ROC revealed excellent discrimination of FTLD-tau from FTLD-TDP by plasma GFAP/NfL ratio (AUC = 0.89; 90% CI, 0.82-0.95; sensitivity = 0.73; 90% CI, 0.65-0.89; specificity = 0.89; 90% CI, 0.78-0.98), which was higher than either GFAP level alone (AUC = 0.65; 90% CI, 0.54-0.76) or NfL levels alone (AUC = 0.75; 90% CI, 0.64-0.85). In the validation sample, there was sensitivity of 0.84 (90% CI, 0.66-0.94) and specificity of 0.81 (90% CI, 0.62-0.91) when applying the autopsy-derived plasma GFAP/NfL threshold., Conclusions and Relevance: The plasma ratio of GFAP/NfL may discriminate FTLD-tau from FTLD-TDP.

Objective: Plasma phosphorylated tau (p-tau 181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p-tau 181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p-tau 181 in ALS., Methods: Patients were clinically or pathologically diagnosed with ALS (n = 130) or AD (n = 79), or were healthy non-impaired controls (n = 26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau 181 and postmortem neuron loss., Results: A Wilcoxon test showed plasma p-tau 181 was higher in ALS than controls (W = 2,600, p = 0.000015), and ROC analyses showed plasma p-tau 181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p-tau 181 was associated with LMN signs in cervical (W = 827, p = 0.0072), thoracic (W = 469, p = 0.00025), and lumbosacral regions (W = 851, p = 0.0000029). In support of LMN findings, plasma p-tau 181 was associated with neuron loss in the spinal cord (rho = 0.46, p = 0.017), but not in the motor cortex (p = 0.41). Cerebrospinal spinal fluid p-tau 181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings., Interpretation: We found strong evidence that plasma p-tau 181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818., (© 2022 American Neurological Association.)

Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer's disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer's disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer's disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer's disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer's disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-β42, amyloid-β40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B ( 11 C-PiB) and 18 F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aβ40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aβ42 (49.51 pg/ml, 95% confidence interval: -98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11 C-PiB in the parahippocampal region (-0.1104, 95% confidence interval: -0.19, -0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (-11.41 s, 95% confidence interval: -11.94, -10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: -0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer's disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer's disease, and warrant further investigation given the lack of clear treatment options for this devastating illness., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored., Objectives: To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences., Design, Setting, and Participants: This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020., Main Outcomes and Measures: Main outcomes were plasma and CSF amyloid-β (Aβ) 42, Aβ40, phosphorylated tau181 (p-tau181), and neurofilament light. General linear models were used for key comparisons., Exposures: Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state)., Results: This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aβ42 (adjusted mean difference, -1.20 pg/mL; 95% CI, -2.33 to -0.07 pg/mL), Aβ40 (adjusted mean difference, -37.78 pg/mL; 95% CI, -60.16 to -15.39 pg/mL), p-tau181 (adjusted mean difference, -4.66 pg/mL; 95% CI, -7.05 to -1.90 pg/mL), and neurofilament light (adjusted mean difference, -1.58; 95% CI, -2.83 to -0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aβ42 and Aβ40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index., Conclusions and Relevance: In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aβ40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.

What Is This Summary About?: This is a plain language summary of an article published in Alzheimer's & Dementia . It looks at a type of test called a lumbar puncture (also known as spinal tap) used in people suspected of having Alzheimer's disease or some other form of dementia. This summary focuses on how to do a lumbar puncture safely., Why Is This Important?: Alzheimer's disease is a progressive condition, which means it gets worse over time. This leads to difficulties with thinking and memory. People with Alzheimer's disease show a build up of proteins called amyloid-β and tau in the brain. This is followed by a gradual loss of brain cells and brain function. The changes in the brain are thought to occur years before symptoms appear. Lumbar puncture is a medical procedure during which samples of cerebrospinal fluid are collected. In Alzheimer's disease, it is used to examine cerebrospinal fluid biomarkers that can help diagnose disease. Lumbar puncture is traditionally considered as a painful and invasive procedure with frequent side effects. However, multiple studies indicate that a lumbar puncture can be performed safely. Side effects are typically mild and do not require specialist intervention., What Are the Key Takeaways?: Despite the low risk of serious complications associated with a lumbar puncture, physicians and their patients may be reluctant to recommend or undergo this procedure. Patient education, specialist training, as well as new methods concerning patient safety are important factors to support the widespread use of lumbar puncture in Alzheimer's disease.

Introduction: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests., Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients., Results: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis., Discussion: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)