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Introduction: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population., Methods: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population ( N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years)., Results: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex ( p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET ( p = 0.0007) and volume ( p = 0.0006). Lateral temporal FDG PET ( p = 0.006) and volume ( p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group., Discussion: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age., Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate., Competing Interests: Dawn Matthews is CEO of ADM Diagnostics, Inc., Scientific Advisor to the Alzheimer's Drug Development Foundation, and Co‐Chair of the Radiological Society of North America PET Tau Profile Working Group and PET Amyloid Profile Working Group, and reports that ADM Diagnostics received grant funding (2R44AG060861‐02) from the National Institutes of Aging, University of Arizona subaward (R01 AG063826), and University of Arizona subaward (R01 AG075122‐01 during the conduct of this work. She reports support for attending meetings and/or travel hotel and registration fees from Alzheimer's Drug Discovery Foundation, and stock or stock options in ADM Diagnostics and Abiant. Jefferson Kinney reports a grant from the National Institutes of General Medical Sciences (NIGMS) COBRE grant #P20GM109025, along with grants NIH NIA R01 AG074392‐01, NIH NIA P20 AG068053‐01, and R01AG062762‐01A1. Aaron Ritter reports payment from Corium Pharmaceuticals and Lundbeck/Otsuka for speaker board and advertisement board. He also has a leadership role in Alzheimer's Association Orange County Board and Alzheimer's Family Center. Ana Lukic, Randolph Andrews, and Lauren Koenig are employees of ADM Diagnostics, Inc. Carolyn Revta has nothing to disclose. Babak Tousi received a grant from the Alzheimer's Drug Discovery Foundation during the study, and has received consulting fees from Eisai, Biogen, Lilly, GE Healthcare, Kisbee, and Otsuka. He received honoraria from Eisai and Lily, support for attending meetings or travel from Novo Nordisk, and participated in a Data Safety Monitoring Board or Advisory Board at Eisai and Lilly. James Leverenz reports the grant P30AG072959, a Scientific Advisory leadership role for the Lewy Body Dementia Association, and receipt of ligands and software for imaging from GE Healthcare. Howard Fillit founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, which funded the rasagiline clinical trial, and has provided consulting support to the following pharmaceutical companies: Otsuka, LifeWorx, and Alector. He reports royalties from Icahn School of Medicine at Mount Sinai, and participation in a DSMB at Alector. He reports stock or stock options at CarePredict, and other non‐financial interests with the Lilly GERAS study and Roche Genentech Claims study. Howard Feldman reports a service agreement through UCSD with the Cleveland Clinic for data management and biostatistics during the conduct of the original study; grants from Annovis (QR Pharma), Vivoryon (Probiodrug), AC Immune, Biohaven Pharmaceuticals, and LuMind Foundation, and service agreements through UCSD for consulting with LuMind Foundation, Novo Nordisk, Arrowhead Pharmaceuticals, and Axon Neurosciences Roche/Genentech Pharmaceuticals. He reports support for attending meetings and/or travel for Novo Nordisk, and Royal Society of Canada; participation in DMC and DSMB for Tau Consortium, Rooche/Genentech Pharmaceuticals, and Janssen Research and Development; and philanthropic support for Alzheimer therapeutic research. Jeffrey Cummings reports grants from the National Institutes of General Medical Sciences (NIGMS) COBRE grant #P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P30AG072959; NIA grant R35AG71476; NIA R25 AG083721‐01; Alzheimer's Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; Joy Chambers‐Grundy Endowment during the conduct of the study. He reports consulting fees from Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol‐Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He reports participation in Data Safety Monitoring Board or Advisory Board for Acadia, Biogen, Genentech, Grifols, Janssen, Karuna, Otsuka, reMYND, Roche, Signant Health and stock or stock options for Artery, Vaxxinity, Behrens, Alzheon, MedAvante‐Prophase, and Acumen. Finally, outside the submitted work he is Chief Scientific Advisor to CNS Innovations, LLC and owns the copyright for the Neuropsychiatric Inventory (NPI). Kate Zhong and Erin Toledano Strom have nothing to disclose. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The apolipoprotein E ( APOE ) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau 181 ). Three hundred fifty participants underwent imaging, and 270 had ptau 181 . We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau 181 . Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau 181 . This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.

Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship., Methods: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in Saint Louis, MO, with stroke participants recruited from acutely hospitalized patients and non-stroke participants from community living older adults who were research volunteers. Our assessment included radiologic reads of infarcts, microbleeds, and white matter hyperintensitites (WMH); a Pittsburgh Compound B PET measure of cortical β-amyloid binding; quantitative measures of hippocampal and WMH volume; longitudinal Mini Mental State Examination (MMSE) scores; and Clinical Dementia Rating (CDR) 1 year post-stroke., Results: A total of 243 participants were enrolled, 81 of which had a recent ischemic stroke. Participants had a mean age of 75, 57% were women, and 52% were African American. Cortical amyloid did not differ significantly by race, stroke status, or CDR post-stroke. There were racial differences in MMSE scores at baseline (mean 26.8 for African Americans, 27.9 for non-Hispanic whites, p = 0.03), but not longitudinally. African Americans were more likely to have microbleeds (32.8% vs 22.6%, p = 0.04), and within the acute stroke group, African Americans were more likely to have small infarcts (75.6% vs 56.8%, p = 0.049)., Conclusion: Preclinical Alzheimer disease did not show evidence of being a risk factor for stroke nor predictive of post-stroke dementia. We did not observe racial differences in β-amyloid levels. However, even after controlling for several vascular risk factors, African Americans with clinical stroke presentations had greater levels of vascular pathology on MRI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Volumetric biomarkers for Alzheimer disease (AD) are attractive due to their wide availability and ease of administration, but have traditionally shown lower diagnostic accuracy than measures of neuropathological contributors to AD. Our purpose was to optimize the diagnostic specificity of structural MRIs for AD using quantitative, data-driven techniques., Methods: This retrospective study assembled several non-overlapping cohorts (total n = 1287) with publicly available data and clinical patients from Barnes-Jewish Hospital (data gathered 1990-2018). The Normal Aging Cohort (n = 383) contained amyloid biomarker negative, cognitively normal (CN) participants, and provided a basis for determining age-related atrophy in other cohorts. The Training (n = 216) and Test (n = 109) Cohorts contained participants with symptomatic AD and CN controls. Classification models were developed in the Training Cohort and compared in the Test Cohort using the receiver operating characteristics areas under curve (AUCs). Additional model comparisons were done in the Clinical Cohort (n = 579), which contained patients who were diagnosed with dementia due to various etiologies in a tertiary care outpatient memory clinic., Results: While the Normal Aging Cohort showed regional age-related atrophy, classification models were not improved by including age as a predictor or by using volumetrics adjusted for age-related atrophy. The optimal model used multiple regions (hippocampal volume, inferior lateral ventricle volume, amygdala volume, entorhinal thickness, and inferior parietal thickness) and was able to separate AD and CN controls in the Test Cohort with an AUC of 0.961. In the Clinical Cohort, this model separated AD from non-AD diagnoses with an AUC 0.820, an incrementally greater separation of the cohort than by hippocampal volume alone (AUC of 0.801, p = 0.06). Greatest separation was seen for AD vs. frontotemporal dementia and for AD vs. non-neurodegenerative diagnoses., Conclusions: Volumetric biomarkers distinguished individuals with symptomatic AD from CN controls and other dementia types but were not improved by controlling for normal aging., Competing Interests: Declaration of Competing Interest GS Day is supported by a mentored career development award (K23AG064029), through additional research/grant support from the National Institutes of Health (P01AG03991, R56AG057195, U01AG057195) and from philanthropic support of the BJHF Willman Scholar Fund. Prior research has benefited from an in-kind gift of radiopharmaceuticals from Avid Radiopharmaceuticals. GS Day holds stock in ANI Pharmaceuticals, Inc., serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc.), and has provided record review and expert medical testimony on legal cases pertaining to management of Wernicke. Amber Salter receives consulting fees for statistical reviews for the journal Circulation: Cardiovascular Imaging. Joy Snider does consulting with Eisai. Cyrus Raji does consulting for Brainreader ApS and Neurevolution LLC. Nupur Ghoshal has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. Ghoshal receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH. Michelle Miller-Thomas received payment as a site investigator for a multiple sclerosis imaging study sponsored by Biogen MA Inc. (completed May 2019), which is unrelated to this work. Miller-Thomas receives ongoing salary support from the Barnes Jewish Hospital Foundation to support her work on Neuroradiology Advanced Imaging, which is directly related to this manuscript. JC Morris is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276 and UF1AG032438. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Tammie Benzinger participated in clinical trials sponsored by Eli Lilly, Roche, and Biogen. Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) provided doses of (18)F-florbetapir, partial funding for (18)F-florbetapir scanning, precursor for (18)F-flortaucipir, and technology transfer for manufacturing of (18)F-flortaucipir. *DIAN Consortium: Ricardo Allegri, Fatima Amtashar, Randy Bateman, Tammie Benzinger, Sarah Berman, Courtney Bodge, Susan Brandon, William (Bill) Brooks, Jill Buck, Virginia Buckles, Sochenda Chea, Jasmeer Chhatwal, Patricio Chrem, Helena Chui, Jake Cinco, Jack Clifford, Carlos Cruchaga, Mirelle D'Mello, Tamara Donahue, Jane Douglas, Noelia Edigo, Nilufer Erekin-Taner, Anne Fagan, Marty Farlow, Angela Farrar, Howard Feldman, Gigi Flynn, Nick Fox, Erin Franklin, Hisako Fujii, Cortaiga Gant, Samantha Gardener, Bernardino Ghetti, Alison Goate, Jill Goldman, Brian Gordon, Neill Graff-Radford, Julia Gray, Jenny Gurney, Jason Hassenstab, Mie Hirohara, David Holtzman, Russ Hornbeck, Siri Houeland DiBari, Takeshi Ikeuchi, Snezana Ikonomovic, Gina Jerome, Mathias Jucker, Celeste Karch, Kensaku Kasuga, Takeshi Kawarabayashi, William (Bill) Klunk, Robert Koeppe, Elke Kuder-Buletta, Christoph Laske, Jae-Hong Lee, Johannes Levin, Daniel Marcus, Ralph Martins, Neal Scott Mason, Colin Masters, Denise Maue-Dreyfus, Eric McDade, Lucy Montoya, Hiroshi Mori, John Morris, Akem Nagamatsu, Katie Neimeyer, James Noble, Joanne Norton, Richard Perrin, Marc Raichle, John Ringman, Jee Hoon Roh, Jee Hoon Roh, Stephen Salloway, Peter Schofield, Hiroyuki Shimada, Tomoyo Shiroto, Mikio Shoji, Wendy Sigurdson, Hamid Sohrabi, Paige Sparks, Kazushi Suzuki, Laura Swisher, Kevin Taddei, Jen Wang, Peter Wang, Mike Weiner, Mary Wolfsberger, Chengjie Xiong, Xiong Xu, (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)