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The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system., (© 2024. The Author(s).)

Introduction: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology., Methods: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome)., Results: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO ( n  = 51) versus placebo ( n  = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group ( n  = 34). In the PB and TURSO group ( n  = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups., Discussion: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD., Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases., Competing Interests: S.E.A. was the principal investigator of the PEGASUS trial and contributed to its design, conduct, statistical analyses of the exploratory biomarker assessments, writing and revision of this manuscript. S.E.A. reported receiving institutional grant or sponsored research support from the Alzheimer's Association, Alzheimer Drug Discovery Foundation, Challenger Foundation, John Sperling Foundation, National Institutes of Health, Prion Alliance, AbbVie Inc, AC Immune SA, Amylyx, Athira Pharma Inc, ChromaDex Inc, Cyclerion Therapeutics Inc, EIP Pharma Inc, Janssen Pharmaceutical/Johnson & Johnson, Ionis Pharmaceuticals, Novartis AG, Seer Bioscience Inc, vTv Therapeutics; honoraria for lectures from AbbVie Inc, Biogen Inc, and Eisai Co Ltd; payments for participation on scientific advisory boards of Allyx Therapeutics Inc, Bob's Last Marathon, Quince Therapeutics/Cortexyme Inc, Jocasta Neuroscience, and Sage Therapeutics Inc; consulting fees from Cognito Therapeutics Inc, Cassava Sciences, EIP Pharma Inc, M3 Biotechnology Inc, Orthogonal Neuroscience Inc, Risen Pharmaceutical Technology. S.H. is an employee and owner of Pentara Corporation, which was contracted to perform statistical analyses for the PEGASUS trial, including the clinical efficacy outcomes analyses described in this manuscript; reports consulting fees paid to Pentara from multiple pharmaceutical companies developing therapies for neurodegenerative diseases; and reports data safety monitoring board or advisory board fees from Alzheon, Eisai, and Prothena Biosciences paid to Pentara. J.N.‐J. and N.K. are employees of Pentara Corporation. V.J.W. reports consulting fees from Cognito Therapeutics, unrelated to the present manuscript, and an unpaid scientific advisory committee position in Division 40 of the American Psychological Association. J.M.B. reports clinical trial support from the National Institutes of Health, Eli Lilly, Biogen, AbbVie, AstraZeneca, and Roche, unrelated to the manuscript, and consulting fees from Amylyx Pharmaceuticals, Renew Research, Eisai, Eli Lilly, and Labcorp. M.C. reports grants from the American College of Radiology, the Alzheimer's Association, Novo Nordisk, Avanir Pharmaceuticals, Biogen, and the National Institutes of Health, all paid to the Tennessee Memory Disorders Foundation, and is an Alzheimer's Tennessee Board of Directors and Tennessee Memory Disorders Foundation volunteer. A.J.M. reports advisory board fees from Amylyx Pharmaceuticals and honoraria from the Alzheimer's Association Speaker's Bureau. S.N.V. reports grants to his affiliated institution from Biogen, Eisai, and Eli Lilly and participation on a data safety monitoring board or advisory board for Eli Lilly and Alector Therapeutics. Z.A. receives research support from the National Institutes of Health, Amylyx Pharmaceuticals, and Eli Lilly to her affiliated academic institution; lecture honoraria from Spire Learning and Summus; payment for expert testimony from the city of Naperville (government); support for attending professional society meetings from National Institutes of Health funds and academic institutions of higher learning; advisory board fees and consulting for non‐for‐profit (California Institute for Regenerative Medicine; international governmental funding agencies) and for‐profit organizations (including Eisai, Inc; Summus); and is a Specialty Chief Editor for Frontiers in Neurology. J.N. was the principal investigator for the Icahn School of Medicine at Mount Sinai (MSSM) PEGASUS trial site but was not compensated in this role; is a co‐director of the MSSM Alzheimer's Disease Research Center Outreach, Recruitment, and Engagement and Clinical Cores; and is editor of Focus on Healthy Aging. K.B. reports clinical trial support from Eisai and the Alzheimer's Clinical Trials Consortium, unrelated to this work, and fees for data monitoring committee participation from Eli Lilly. B.C.C. reports grants from the National Institutes of Health, Challenger Foundation, Bright Focus Foundation, Alzheimer's Research UK, and Ono Pharmaceutical to her affiliated institution; reports conference attendance support from Alzheimer's Research UK; and is an Academic Coordinator for the Alzheimer's Research UK Thames Valley Network. H.H.D. contributed to the statistical analyses in Table S4 of the exploratory biomarker assessments described in this manuscript and reports consulting fees from ALZpath and Biogen. R.E.T. is a paid consultant and shareholder in Amylyx Pharmaceuticals and was involved with the PEGASUS trial design and analyzing de‐identified trial results following the completion of the trial but not with the execution of the trial. P.D.Y. is the Chief Medical Officer and has stock and stock option ownership in Amylyx Pharmaceuticals. K.L. was an employee of Amylyx Pharmaceuticals from July 2015 through August 2021 and received stock options while employed with Amylyx Pharmaceuticals. B.A.T. and P.K. have no disclosures to report. Author disclosures are available in the Supporting Information., (© 2024 Amylyx Pharmaceuticals. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion., Methods: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF., Results: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints., Discussion: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity., Clinical Trials Registration: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: While Alzheimer's disease (AD) is defined by amyloid-β plaques and tau tangles in the brain, it is evident that many other pathophysiological processes such as inflammation, neurovascular dysfunction, oxidative stress, and metabolic derangements also contribute to the disease process and that varying contributions of these pathways may reflect the heterogeneity of AD. Here, we used a previously validated panel of cerebrospinal fluid (CSF) biomarkers to explore the degree to which different pathophysiological domains are dysregulated in AD and how they relate to each other., Methods: Twenty-five CSF biomarkers were analyzed in individuals with a clinical diagnosis of AD verified by positive CSF AD biomarkers (AD, n = 54) and cognitively unimpaired controls negative for CSF AD biomarkers (CU-N, n = 26) using commercial single- and multi-plex immunoassays., Results: We noted that while AD was associated with increased levels of only three biomarkers (MMP-10, FABP3, and 8OHdG) on a group level, half of all AD participants had increased levels of biomarkers belonging to at least two pathophysiological domains reflecting the diversity in AD. LASSO modeling showed that a panel of FABP3, 24OHC, MMP-10, MMP-2, and 8OHdG constituted the most relevant and minimally correlated set of variables differentiating AD from CU-N. Interestingly, factor analysis showed that two markers of metabolism and oxidative stress (24OHC and 8OHdG) contributed independent information separate from MMP-10 and FABP3 suggestive of two independent pathophysiological pathways in AD, one reflecting neurodegeneration and vascular pathology, and the other associated with metabolism and oxidative stress., Discussion: Better understanding of the heterogeneity among individuals with AD and the different contributions of pathophysiological processes besides amyloid-β and tau will be crucial for optimizing personalized treatment strategies., Highlights: A panel of 25 highly validated biomarker assays were measured in CSF.MMP10, FABP3, and 8OHdG were increased in AD in univariate analysis.Many individuals with AD had increased levels of more than one biomarker.Markers of metabolism and oxidative stress contributed to an AD multianalyte profile.Assessing multiple biomarker domains is important to understand disease heterogeneity., Competing Interests: Pia Kivisäkk and Steven E. Arnold are named as co‐inventors of a US patent application related to neurological biomarker assays that is jointly held by Massachusetts General Hospital and Meso Scale Diagnostics. BC has received grant funding from Ono Pharmaceutical. SEA has received advisory board or consulting fees from Allyx Therapeutics, Bob's Last Marathon, Boyle Shaughnessy Law, Daewoong Pharmaceutical Co., Eisai, Jocasta Neuroscience, Quince Therapeutics (formerly Cortexyme), Risen Pharmaceutical Technology, and Sage Therapeutics. B.A.T., C.Y.W., E.K., M.B.G., and H.H.D. have no declarations of interest related to to the contents of the work presented herein. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)