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Introduction: Health disparities arise from biological-environmental interactions. Neuroimaging cohorts are reaching sufficiently large sample sizes such that analyses could evaluate how the environment affects the brain. We present a practical guide for applying geospatial methods to a neuroimaging cohort., Methods: We estimated brain age gap (BAG) from structural magnetic resonance imaging (MRI) from 239 city-dwelling participants in St. Louis, Missouri. We compared these participants to population-level estimates from the American Community Survey (ACS). We used geospatial analysis to identify neighborhoods associated with patterns of altered brain structure. We also evaluated the relationship between Area Deprivation Index (ADI) and BAG., Results: We identify areas in St. Louis, Missouri that were significantly associated with higher BAG from a spatially representative cohort. We provide replication code., Conclusion: We observe a relationship between neighborhoods and brain health, which suggests that neighborhood-based interventions could be appropriate. We encourage other studies to geocode participant information to evaluate biological-environmental interaction., Competing Interests: J.K.W., G.M.B., K.P., P.M., E.S., S.S., A.H.B., S.F., S.K., and B.M.A. report no disclosures. B.A.G. receives research support from Eli Lilly and Avid Radiopharmaceuticals. Neither J.C.M. nor his family own stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. All participants (ages 23–89) completed written informed consent. This study was approved by the WUSTL Institutional Review Board. 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.)

Introduction: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET., Methods: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled., Results: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aβ42/Aβ40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aβ42/Aβ40 predicted amyloid PET burden until a lower level (33.4 Centiloids)., Discussion: CSF Aβ42/Aβ40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aβ42/Aβ40 and may be useful in AD staging., Highlights: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/Aβ40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aβ42/Aβ40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aβ42/Aβ40.CSF Aβ42/Aβ40 may be useful in staging AD., Competing Interests: Julie K. Wisch, Anna H. Boerwinkle, Patrick H. Luckett, Yan Li, Rachel L. Henson, and Beau M. Ances report no disclosures. Brian A. Gordon receives research support from Eli Lilly and Avid Radiopharmaceuticals. James G. Bollinger and Vitaliy Ovod have submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” as co‐inventors and may receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. Tim West, Mathew R. Meyer, and Kristopher M. Kirmess are employees of C2N Diagnostics, which offers the plasma Aβ42/Aβ40 assay used in this article. Tammie L.S. Benzinger has consulted on clinical trials with Biogen, Roche, Janssen, and Eli Lilly. She receives research support from Eli Lilly and Avid Radiopharmaceuticals. Neither John C. 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. Randall J. Bateman co‐founded C2N Diagnostics, which offers the PrecivityAD blood test. Washington University and Randall J. Bateman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. Randall J. Bateman has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb, and Novartis. Randall J. Bateman serves on the Roche Gantenerumab Steering Committee as an unpaid member. Suzanne E. Schindler has analyzed data provided by C2N Diagnostics to Washington University at no cost. She has not received any research funding or personal compensation from C2N Diagnostics or any other for‐profit organization. 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.)

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect., Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes., Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes., Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases., Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations., Competing Interests: Guoqiao Wang, PhD, is the biostatistics core co‐leader for the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and as a statistical consultant for Alector. Eric McDade, DO, is the Associate Director of the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and Alector; as a scientific consultant for Eisai and Eli Lilly and Company; receiving institutional grant support from Eli Lilly and Company, F. Hoffmann‐La Roche, Ltd., and Janssen. Anne M. Fagan, PhD, is the Biomarker Core Leader of the DIAN‐TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and DiademRes and also consults for DiamiR and Siemens Healthcare Diagnostics, Inc. Tammie L.S. Benzinger, MD, PhD, has investigator‐initiated research funding from the NIH, the Alzheimer's Association, the Barnes‐Jewish Hospital Foundation, and Avid Radiopharmaceuticals. Dr. Benzinger participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen, and F. Hoffmann‐La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker's Bureau for Biogen. David B. Clifford, MD, is Medical Director of the DIAN‐TU and serves as scientific consultant to Biogen, Takeda, Millennium, Genzyme, Amgen, F. Hoffmann‐La Roche, Ltd./Genentech, Glaxo Smith Kline, Serono, Inhibikase, Dr Reddy's Lab, Bristol Myers Squibb, Atara, Mitsubishi Tanabe, Excision BioTherapeutics, Up to Date, and Wolters Kluwer; on DSMB/Data Monitoring Committees for Genentech/ F. Hoffmann‐La Roche, Ltd., Wave, EMD Serono, Shire, Pfizer, Sanofi; does legal consulting: Cook County, State Farm, Wilke & Wilke PC, Shevlin Smith, Sal Indomenico PC. He receives research support from NIH NINDS, NIMH, NIAID, NCATS, and NIA. Andrew J. Aschenbrenner, PhD, has served as a consultant for Biogen Inc, and H. Lundbeck HS. Jason Hassenstab, PhD, is a paid consultant for F. Hoffmann‐La Roche, Ltd., Takeda, and Lundbeck, and is on the Data Safety and Monitoring Board for Eisai. Catherine Mummery, MD, is a consultant for Biogen. Mario Masellis, MD, is a consultant to Arkuda Therapeutics, Ionis, and Alector and receives research funding from F. Hoffmann‐La Roche, Ltd., Novartis, and Alector. Serge Gauthier, MD, FRCPC, is a member of the Scientific Advisory Board for Alzheon, Biogen, Eli Lilly and Company, and TauRx and a member of the Data Safety Monitoring Board for ADCS, ATRI, and Banner Health. Scott Andersen, MS; Karen C. Holdridge, MPH; Saptarshi Chatterjee, PhD; John R. Sims, MD; and Roy Yaari, MD are employees and shareholders of Eli Lilly and Company. Randall J. Bateman, MD, is the Director of the DIAN‐TU and Principal Investigator of the DIAN‐TU‐001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN‐TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman‐La Roche, Ltd., and Avid Radiopharmaceuticals), Alzheimer's Association, GHR Foundation, Anonymous Organization, DIAN‐TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann‐La Roche, Ltd./Genentech. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). He has been an invited speaker for Novartis and serves on the Advisory Board for F. Hoffman La Roche, Ltd. Barbara A. Wendelberger, PhD; Susan L. Mills BS; Anna M. Santacruz BS; Kelley A. Coalier, MS; Brian A. Gordon, PhD; Jorge J. Libre‐Guerra, MD; Austin McCullough; Nelly Joseph‐Mathurin, PhD; Charlie Chen; Yan Li, PhD; Chengji Xiong, PhD, have no conflicts of interest to disclose. Paul Delmar, Geoffrey A. Kerchner, Tobias Bittner, and Carsten Hofmann are full‐time employees of F. Hoffmann‐La Roche, Ltd. and own stock in F. Hoffmann‐La Roche, Ltd. David Holtzman, MD, the prior Department Head of Neurology where the research was conducted, is an inventor on patents for solanezumab, which was tested in the DIAN‐TU‐001 clinical trial. If solanezumab is approved as a treatment for AD or dominantly inherited AD, Washington University and Dr. Holtzman will receive part of the net sales of solanezumab from Eli Lilly and Company, which has licensed patents related to solanezumab from Washington University. All the other authors reported no conflicts of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment., Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally., Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset., Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials., Competing Interests: Dr. Clifford Jack serves on an independent data monitoring board for Roche and has consulted for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Saykin receives support from Arkley BioTek (joint NIH SBIR grant); Avid Radiopharmaceuticals (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eli Lilly (collaborative research grant); and Springer‐Nature Publishing (Editorial Office Support as Editor in Chief, Brain Imaging and Behavior). Ophir Keret is an Atlantic Fellow for Equity in Brain Health and thanks the Global Brain Health Institute for supporting his work. Johannes Levin reports speaker fees from Bayer Vital and Roche; consulting fees from Axon Neuroscience; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; non‐financial support from Abbvie; and compensation for duty as part‐time CMO from MODAG, outside the submitted work. John C. Morris reports support from NIH grants P30 AG066444, P01 AG003991, and P01 AG026276 during the conduct of the study. He serves on the Editorial Boards of Brain & Life and Alzheimer's & Dementia. Su Yi was a paid consultant for Green Valley Pharmaceuticals LLC in 2018. Adam M. Staffaroni provides consultation to Takeda and receives research funding from the NIH, the Larry L. Hillblom Foundation, and the Bluefield Project to Cure FTD. Stephan Salloway reports grants, personal fees, and non‐financial support from Biogen; grants and personal fees from Eisai; grants, personal fees, and non‐financial support from Avid; personal fees and non‐financial support from Novartis; grants, personal fees, and non‐financial support from Lilly; personal fees from Genentech; personal fees and non‐financial support from Roche, outside the submitted work. Michael Weiner receives support for his work from the following funding sources: NIH, DOD, PCORI, California Dept. of Public Health, U. Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer's Association, The State of California, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, Fidelity Charitable, and the Veterans Administration. Dr. Weiner has served on advisory boards for Cerecin/Accera, Alzheon, Inc., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Boston University Alzheimer's Disease and CTE Center, MIRIADE at VUmc for Amsterdam UMC, Cytox, Indiana University, Acumen, Brain Health Registry and ADNI. He serves on the Editorial Boards for Alzheimer's & Dementia, TMRI and MRI. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera, Inc., Alzheimer's Drug Discovery Foundation (ADDF), BioClinica, The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, University of Southern California (USC), T3D Therapeutics, Cytox, Guidepoint, and Japanese Organization for Medical Device Development, Inc. (JOMDD). He holds stock options with Alzheon, Inc., Alzeca, and Anven. Bruce L. Miller reported serving on the advisory committee for Cambridge National Institute for Health Research Biomedical Research Centre; serving on the board of directors for J Douglas French Alzheimer's Foundation and Safely You; serving as medical advisor and receiving grant support from The Bluefield Project for Frontotemporal Dementia Research; consulting for Rainwater Charitable Foundation, Stanford Alzheimer's Disease Research Center, Buck Institute, Larry L. Hillblom Foundation, University of Texas Center for Brain Health, University of Washington Alzheimer's Disease Research Center, and Harvard University Alzheimer's Disease Research Center; receiving royalties from Guilford Press, Cambridge University Press, Johns Hopkins Press, and Oxford University Press; serving as editor for Neurocase; serving as section editor for Frontiers in Neurology; and receiving grants P30 AG062422, P01 AG019724, R01 AG057234, and T32 AG023481 from the NIH. Gil D. Rabinovici receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Genentech, Life Molecular Imaging. He has received consulting fees from Axon Neurosciences, Eisai, Genentech, GE Healthcare, Miller Medical Communications, Roche. He is an Associate Editor for JAMA Neurology. Howard J. Rosen reported consulting for Wave Neuroscience outside the submitted work. All other authors have no potential conflicts to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design., Methods: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally., Results: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers., Discussion: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

Introduction: 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11 C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET., Methods: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history., Results: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity., Discussion: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.

Introduction: Structural magnetic resonance imaging is a marker of gray matter health and decline that is sensitive to impaired cognition and Alzheimer's disease pathology. Prior work has shown that both amyloid β (Aβ) and tau biomarkers are related to cortical thinning, but it is unclear what unique influences they have on the brain., Methods: Aβ pathology was measured with [ 18 F] AV-45 (florbetapir) positron emission tomography (PET) and tau was assessed with [ 18 F] AV-1451 (flortaucipir) PET in a population of 178 older adults, of which 123 had longitudinal magnetic resonance imaging assessments (average of 5.7 years) that preceded the PET acquisitions., Results: In cross-sectional analyses, greater tau PET pathology was associated with thinner cortices. When examined independently in longitudinal models, both Aβ and tau were associated with greater antecedent loss of gray matter. However, when examined in a combined model, levels of tau, but not Aβ, were still highly related to change in cortical thickness., Discussion: Measures of tau PET are strongly related to gray matter atrophy and likely mediate relationships between Aβ and gray matter.