{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:01:06Z","timestamp":1788408066547,"version":"build-2803163510"},"reference-count":94,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T00:00:00Z","timestamp":1681084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Estonian Research Council under the framework of EuroNanoMed III JTC 2018 project","award":["CurcumAGE"],"award-info":[{"award-number":["CurcumAGE"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>5xFAD transgenic (TG) mice are used widely in AD preclinical trials; however, data on sample sizes are largely unaddressed. We therefore performed estimates of sample sizes and effect sizes for typical behavioural and neuropathological outcome measures in TG 5xFAD mice, based upon data from single-sex (female) groups. Group-size estimates to detect normalisation of TG body weight to WT littermate levels at 5.5m of age were N = 9\u201315 depending upon algorithm. However, by 1 year of age, group sizes were small (N = 1 \u2013&lt;6), likely reflecting the large difference between genotypes at this age. To detect normalisation of TG open-field hyperactivity to WT levels at 13-14m, group sizes were also small (N = 6\u20138). Cued learning in the Morris water maze (MWM) was normal in Young TG mice (5m of age). Mild deficits were noted during MWM spatial learning and memory. MWM reversal learning and memory revealed greater impairment, and groups of up to 22 TG mice were estimated to detect normalisation to WT performance. In contrast, Aged TG mice (tested between 13 and 14m) failed to complete the visual learning (non-spatial) phase of MWM learning, likely due to a failure to recognise the platform as an escape. Estimates of group size to detect normalisation of this severe impairment were small (N = 6\u20139, depending upon algorithm). Other cognitive tests including spontaneous and forced alternation and novel-object recognition either failed to reveal deficits in TG mice or deficits were negligible. For neuropathological outcomes, plaque load, astrocytosis and microgliosis in frontal cortex and hippocampus were quantified in TG mice aged 2m, 4m and 6m. Sample-size estimates were \u22649 to detect the equivalent of a reduction in plaque load to the level of 2m-old TG mice or the equivalent of normalisation of neuroinflammation outcomes. However, for a smaller effect size of 30%, larger groups of up to 21 mice were estimated. In light of published guidelines on preclinical trial design, these data may be used to provide provisional sample sizes and optimise preclinical trials in 5xFAD TG mice.<\/jats:p>","DOI":"10.1371\/journal.pone.0281003","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T17:29:28Z","timestamp":1681147768000},"page":"e0281003","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Preclinical trials in Alzheimer\u2019s disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice"],"prefix":"10.1371","volume":"18","author":[{"given":"Mahvish","family":"Faisal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Aid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekzod","family":"Nodirov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3363-8583","authenticated-orcid":true,"given":"Miriam A.","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,4,10]]},"reference":[{"issue":"2","key":"pone.0281003.ref001","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019","volume":"7","author":"E Nichols","year":"2022","journal-title":"Lancet Public Health"},{"issue":"S10","key":"pone.0281003.ref002","doi-asserted-by":"crossref","DOI":"10.1002\/alz.051496","article-title":"The estimation of the global prevalence of dementia from 1990\u20102019 and forecasted prevalence through 2050: An analysis for the Global Burden of Disease (GBD) study 2019.","volume":"17","author":"E Nichols","year":"2021","journal-title":"Alzheimer\u2019s & Dementia."},{"key":"pone.0281003.ref003","article-title":"Global action plan on the public health response to dementia 2017\u20132025","author":"WHO","year":"2017","journal-title":"Geneva"},{"issue":"5","key":"pone.0281003.ref004","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1474-4422(18)30499-X","article-title":"Global, regional, and national burden of neurological disorders, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"VL Feigin","year":"2019","journal-title":"Lancet Neurol"},{"issue":"1","key":"pone.0281003.ref005","article-title":"Alzheimer\u2019s disease drug development pipeline: 2021","volume":"7","author":"J Cummings","year":"2021","journal-title":"Alzheimer\u2019s & Dementia: Translational Research & Clinical Interventions."},{"issue":"1","key":"pone.0281003.ref006","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12929-019-0609-7","article-title":"Clinical trials of new drugs for Alzheimer disease","volume":"27","author":"LK Huang","year":"2020","journal-title":"J Biomed Sci"},{"issue":"7","key":"pone.0281003.ref007","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/d41573-019-00074-z","article-title":"Trends in clinical success rates and therapeutic focus.","volume":"18","author":"H Dowden","year":"2019","journal-title":"Nat Rev Drug Discov."},{"key":"pone.0281003.ref008","unstructured":"FDA Grants Accelerated Approval for Alzheimer\u2019s Drug [Internet]. Available from: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-grants-accelerated-approval-alzheimers-drug"},{"key":"pone.0281003.ref009","article-title":"Aducanumab: European agency rejects Alzheimer\u2019s drug over efficacy and safety concerns","volume":"n3127","author":"E. Mahase","year":"2021","journal-title":"BMJ"},{"key":"pone.0281003.ref010","article-title":"Aducanumab for Alzheimer\u2019s disease?","volume":"n1682","author":"S Walsh","year":"2021","journal-title":"BMJ"},{"key":"pone.0281003.ref011","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.62101","article-title":"Improving preclinical studies through replications.","volume":"10","author":"NI Drude","year":"2021","journal-title":"Elife."},{"key":"pone.0281003.ref012","article-title":"We need better animal research, better reported","volume":"k124","author":"F. Godlee","year":"2018","journal-title":"BMJ"},{"key":"pone.0281003.ref013","article-title":"Improving the conduct, reporting, and appraisal of animal research","volume":"j4935","author":"M Ritskes-Hoitinga","year":"2018","journal-title":"BMJ"},{"key":"pone.0281003.ref014","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/164_2019_277","article-title":"General Principles of Preclinical Study Design","volume":"257","author":"W Huang","year":"2020","journal-title":"Handb Exp Pharmacol"},{"issue":"9","key":"pone.0281003.ref015","doi-asserted-by":"crossref","first-page":"e2003779","DOI":"10.1371\/journal.pbio.2003779","article-title":"The Experimental Design Assistant","volume":"15","author":"N Percie du Sert","year":"2017","journal-title":"PLoS Biol"},{"issue":"8","key":"pone.0281003.ref016","doi-asserted-by":"crossref","first-page":"693","DOI":"10.4155\/cli.14.55","article-title":"Two decades testing interventions in transgenic mouse models of Alzheimer\u2019s disease: designing and interpreting studies for clinical trial success.","volume":"4","author":"K Egan","year":"2014","journal-title":"Clin Investig (Lond)"},{"issue":"7","key":"pone.0281003.ref017","doi-asserted-by":"crossref","first-page":"e1001609","DOI":"10.1371\/journal.pbio.1001609","article-title":"Evaluation of Excess Significance Bias in Animal Studies of Neurological Diseases. Bero L, editor","volume":"11","author":"KK Tsilidis","year":"2013","journal-title":"PLoS Biol"},{"issue":"2","key":"pone.0281003.ref018","doi-asserted-by":"crossref","first-page":"e0171790","DOI":"10.1371\/journal.pone.0171790","article-title":"Established patterns of animal study design undermine translation of disease-modifying therapies for Parkinson\u2019s disease.","volume":"12","author":"CJ Zeiss","year":"2017","journal-title":"PLoS One"},{"issue":"4","key":"pone.0281003.ref019","doi-asserted-by":"crossref","first-page":"e0196258","DOI":"10.1371\/journal.pone.0196258","article-title":"Effect size and statistical power in the rodent fear conditioning literature\u2013A systematic review.","volume":"13","author":"CFD Carneiro","year":"2018","journal-title":"PLoS One"},{"issue":"1","key":"pone.0281003.ref020","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1080\/17482960701856300","article-title":"Design, power, and interpretation of studies in the standard murine model of ALS.","volume":"9","author":"S Scott","year":"2008","journal-title":"Amyotrophic Lateral Sclerosis."},{"issue":"7","key":"pone.0281003.ref021","doi-asserted-by":"crossref","first-page":"e3000411","DOI":"10.1371\/journal.pbio.3000411","article-title":"Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0.","volume":"18","author":"N Percie du Sert","year":"2020","journal-title":"PLoS Biol"},{"issue":"7419","key":"pone.0281003.ref022","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature11556","article-title":"A call for transparent reporting to optimize the predictive value of preclinical research","volume":"490","author":"SC Landis","year":"2012","journal-title":"Nature"},{"issue":"4","key":"pone.0281003.ref023","doi-asserted-by":"crossref","first-page":"303","DOI":"10.4103\/0976-500X.119726","article-title":"How to calculate sample size in animal studies","volume":"4","author":"J Charan","year":"2013","journal-title":"J Pharmacol Pharmacother"},{"issue":"4","key":"pone.0281003.ref024","first-page":"341","article-title":"On determining sample size in experiments involving laboratory animals. Lab Anim","volume":"52","author":"M. Festing","year":"2018","journal-title":"Internet]"},{"issue":"2","key":"pone.0281003.ref025","doi-asserted-by":"crossref","first-page":"e0243668","DOI":"10.1371\/journal.pone.0243668","article-title":"Effect size, sample size and power of forced swim test assays in mice: Guidelines for investigators to optimize reproducibility.","volume":"16","author":"NR Smalheiser","year":"2021","journal-title":"PLoS One"},{"issue":"40","key":"pone.0281003.ref026","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer\u2019s Disease Mutations: Potential Factors in Amyloid Plaque Formation","volume":"26","author":"H Oakley","year":"2006","journal-title":"Journal of Neuroscience"},{"issue":"1","key":"pone.0281003.ref027","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2005.01.024","article-title":"Early behavioral deficits in R6\/2 mice suitable for use in preclinical drug testing","volume":"20","author":"M Hickey","year":"2005","journal-title":"Neurobiol Dis"},{"issue":"1","key":"pone.0281003.ref028","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.neuroscience.2008.08.041","article-title":"Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington\u2019s disease mice","volume":"157","author":"MA Hickey","year":"2008","journal-title":"Neuroscience"},{"issue":"3","key":"pone.0281003.ref029","doi-asserted-by":"crossref","DOI":"10.21769\/BioProtoc.3162","article-title":"Assessing Spatial Working Memory Using the Spontaneous Alternation Y-maze Test in Aged Male Mice","volume":"9","author":"E Prieur","year":"2019","journal-title":"Bio Protoc"},{"key":"pone.0281003.ref030","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.mad.2019.03.006","article-title":"Sublethal whole-body irradiation causes progressive premature frailty in mice","volume":"180","author":"E Fielder","year":"2019","journal-title":"Mech Ageing Dev"},{"issue":"3","key":"pone.0281003.ref031","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.molcel.2017.04.005","article-title":"Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival","volume":"66","author":"S Benvegn\u00f9","year":"2017","journal-title":"Mol Cell"},{"key":"pone.0281003.ref032","doi-asserted-by":"crossref","first-page":"106780","DOI":"10.1016\/j.nlm.2018.01.001","article-title":"Rigor and reproducibility in rodent behavioral research","volume":"165","author":"M Gulinello","year":"2019","journal-title":"Neurobiol Learn Mem"},{"issue":"2","key":"pone.0281003.ref033","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nprot.2006.116","article-title":"Morris water maze: procedures for assessing spatial and related forms of learning and memory.","volume":"1","author":"Williams MT Vorhees C v","year":"2006","journal-title":"Nat Protoc"},{"issue":"136","key":"pone.0281003.ref034","doi-asserted-by":"crossref","DOI":"10.3791\/57648","article-title":"Quantifying Microglia Morphology from Photomicrographs of Immunohistochemistry Prepared Tissue Using ImageJ","author":"K Young","year":"2018","journal-title":"Journal of Visualized Experiments"},{"issue":"3","key":"pone.0281003.ref035","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1038\/nprot.2006.277","article-title":"Quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with Congo red histochemical stain","volume":"1","author":"DM Wilcock","year":"2006","journal-title":"Nat Protoc"},{"key":"pone.0281003.ref036","article-title":"Foundations: National Natural Science Foundation of China(31300897);Ph.D.","author":"G Xin","year":"2012","journal-title":"Programs Foundation of Ministry of Education of China"},{"key":"pone.0281003.ref037","article-title":"Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study","author":"AL Oblak","year":"2021","journal-title":"Front Aging Neurosci"},{"issue":"1","key":"pone.0281003.ref038","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41597-021-01054-y","article-title":"Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer\u2019s disease","volume":"8","author":"S Forner","year":"2021","journal-title":"Sci Data"},{"issue":"1","key":"pone.0281003.ref039","doi-asserted-by":"crossref","first-page":"e0147733","DOI":"10.1371\/journal.pone.0147733","article-title":"A Comprehensive Behavioral Test Battery to Assess Learning and Memory in 129S6\/Tg2576 Mice.","volume":"11","author":"A Wolf","year":"2016","journal-title":"PLoS One"},{"key":"pone.0281003.ref040","author":"NP du Sert","year":"2020","journal-title":"The ARRIVE guidelines 2.0 Animal Research: Reporting of In Vivo Experiments"},{"key":"pone.0281003.ref041","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.neuroscience.2015.04.039","article-title":"Butyrylcholinesterase-knockout reduces brain deposition of fibrillar \u03b2-amyloid in an Alzheimer mouse model","volume":"298","author":"GA Reid","year":"2015","journal-title":"Neuroscience"},{"issue":"1","key":"pone.0281003.ref042","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41598-018-19699-y","article-title":"Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer\u2019s disease mouse model 5xFAD","volume":"8","author":"A Boza-Serrano","year":"2018","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0281003.ref043","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1038\/s41467-019-11674-z","article-title":"Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer\u2019s disease model","volume":"10","author":"E Spangenberg","year":"2019","journal-title":"Nat Commun"},{"issue":"9","key":"pone.0281003.ref044","doi-asserted-by":"crossref","first-page":"e12974","DOI":"10.1371\/journal.pone.0012974","article-title":"Phospho-eIF2\u03b1 Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice","volume":"5","author":"L Devi","year":"2010","journal-title":"PLoS One"},{"issue":"1","key":"pone.0281003.ref045","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1096\/fj.12-217497","article-title":"A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer\u2019s disease phenotypes in model mice","volume":"27","author":"V Shukla","year":"2013","journal-title":"The FASEB Journal"},{"issue":"1","key":"pone.0281003.ref046","doi-asserted-by":"crossref","first-page":"19979","DOI":"10.1038\/s41598-019-56408-9","article-title":"ezTrack: An open-source video analysis pipeline for the investigation of animal behavior","volume":"9","author":"ZT Pennington","year":"2019","journal-title":"Sci Rep"},{"issue":"12","key":"pone.0281003.ref047","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1038\/nprot.2013.155","article-title":"Object recognition test in mice","volume":"8","author":"M Leger","journal-title":"Nat Protoc"},{"issue":"1","key":"pone.0281003.ref048","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/jnc.14999","article-title":"Brain region\u2010specific amyloid plaque\u2010associated myelin lipid loss, APOE deposition and disruption of the myelin sheath in familial Alzheimer\u2019s disease mice","volume":"154","author":"I Kaya","year":"2020","journal-title":"J Neurochem"},{"issue":"1","key":"pone.0281003.ref049","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1038\/s41598-021-81304-6","article-title":"Thioflavin-positive tau aggregates complicating quantification of amyloid plaques in the brain of 5XFAD transgenic mouse model.","volume":"11","author":"J Shin","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0281003.ref050","unstructured":"Kane S. Post-hoc Power Calculator [Internet]. ClinCalc. Available from: https:\/\/clincalc.com\/stats\/Power.aspx"},{"key":"pone.0281003.ref051","unstructured":"Stangroom J. Effect Size Calculator for T-Test [Internet]. [cited 2022 Mar 13]. Available from: https:\/\/www.socscistatistics.com\/effectsize\/default3.aspx"},{"key":"pone.0281003.ref052","unstructured":"Compute Sample Size for Selected Power Value [Internet]. [cited 2022 Aug 8]. Available from: https:\/\/www.mathworks.com\/help\/stats\/sampsizepwr.html"},{"key":"pone.0281003.ref053","unstructured":"Kane S. Sample Size Calculator [Internet]. ClinCalc. [cited 2021 Mar 3]. Available from: https:\/\/clincalc.com\/stats\/samplesize.aspx"},{"key":"pone.0281003.ref054","unstructured":"Find sample size [Internet]. Available from: http:\/\/www.biomath.info\/power\/ttest.htm"},{"issue":"2","key":"pone.0281003.ref055","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"F Faul","year":"2007","journal-title":"Behav Res Methods"},{"key":"pone.0281003.ref056","doi-asserted-by":"crossref","first-page":"113214","DOI":"10.1016\/j.bbr.2021.113214","article-title":"Age related weight loss in female 5xFAD mice from 3 to 12 months of age","volume":"406","author":"WH Gendron","year":"2021","journal-title":"Behavioural Brain Research"},{"issue":"3","key":"pone.0281003.ref057","article-title":"Age\u2010related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age","volume":"19","author":"TP O\u2019Leary","year":"2020","journal-title":"Genes Brain Behav"},{"key":"pone.0281003.ref058","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bcp.2017.12.011","article-title":"How often should we expect to be wrong? Statistical power, P values, and the expected prevalence of false discoveries","volume":"151","author":"MJ Marino","year":"2018","journal-title":"Biochem Pharmacol"},{"issue":"5","key":"pone.0281003.ref059","doi-asserted-by":"crossref","first-page":"e562","DOI":"10.1038\/tp.2015.55","article-title":"TrkB reduction exacerbates Alzheimer\u2019s disease-like signaling aberrations and memory deficits without affecting \u03b2-amyloidosis in 5XFAD mice.","volume":"5","author":"L Devi","year":"2015","journal-title":"Transl Psychiatry."},{"key":"pone.0281003.ref060","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.beproc.2017.11.009","article-title":"Variability and temporal dynamics of novel object recognition in aging male C57BL\/6 mice","volume":"157","author":"A Trasch\u00fctz","year":"2018","journal-title":"Behavioural Processes"},{"key":"pone.0281003.ref061","article-title":"Using mice to model Alzheimer\u2019s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models","author":"SJ Webster","year":"2014","journal-title":"Front Genet"},{"key":"pone.0281003.ref062","article-title":"What is the most sensitive measure of water maze probe test performance?","volume":"3","author":"HR Maei","year":"2009","journal-title":"Front Integr Neurosci"},{"issue":"4","key":"pone.0281003.ref063","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1037\/bne0000078","article-title":"Using the spatial learning index to evaluate performance on the water maze","volume":"129","author":"I Tom\u00e1s Pereira","year":"2015","journal-title":"Behavioral Neuroscience"},{"key":"pone.0281003.ref064","article-title":"Visuo\u2010spatial learning and memory impairments in the 5xFAD mouse model of Alzheimer\u2019s disease: Effects of age, sex, albinism, and motor impairments","author":"TP O\u2019Leary","year":"2022","journal-title":"Genes Brain Behav"},{"issue":"1","key":"pone.0281003.ref065","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/msj.20157","article-title":"Neuropathology of Alzheimer\u2019s Disease","volume":"77","author":"DP Perl","year":"2010","journal-title":"Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine"},{"key":"pone.0281003.ref066","first-page":"411","author":"HB Rajamohamedsait","year":"2012","journal-title":"Histological Staining of Amyloid and Pre-amyloid Peptides and Proteins in Mouse Tissue"},{"key":"pone.0281003.ref067","article-title":"Elderly apolipoprotein E-\/- mice with advanced atherosclerotic lesions in the aorta do not develop Alzheimer\u2019s disease-like pathologies.","author":"R Shnerb Ganor","year":"2017","journal-title":"Mol Med Rep"},{"key":"pone.0281003.ref068","doi-asserted-by":"crossref","first-page":"175909141878435","DOI":"10.1177\/1759091418784357","article-title":"Alternative Method to Detect Neuronal Degeneration and Amyloid \u03b2 Accumulation in Free-Floating Brain Sections With Fluoro-Jade","volume":"10","author":"IL Guti\u00e9rrez","year":"2018","journal-title":"ASN Neuro"},{"key":"pone.0281003.ref069","article-title":"Cortical iron regulation and inflammatory response in Alzheimer\u2019s disease and APPSWE\/PS1\u0394E9 mice: a histological perspective","author":"MD Meadowcroft","year":"2015","journal-title":"Front Neurosci"},{"issue":"1","key":"pone.0281003.ref070","doi-asserted-by":"crossref","first-page":"13211","DOI":"10.1038\/s41598-017-13581-z","article-title":"Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury","volume":"7","author":"H Morrison","year":"2017","journal-title":"Sci Rep"},{"issue":"2","key":"pone.0281003.ref071","doi-asserted-by":"crossref","first-page":"82","DOI":"10.4103\/2347-8659.139719","article-title":"A novel method for evaluating microglial activation using ionized calcium-binding adaptor protein-1 staining: cell body to cell size ratio","volume":"1","author":"I Hovens","year":"2014","journal-title":"Neuroimmunol Neuroinflamm"},{"issue":"1","key":"pone.0281003.ref072","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s12974-014-0182-7","article-title":"Quantitative assessment of microglial morphology and density reveals remarkable consistency in the distribution and morphology of cells within the healthy prefrontal cortex of the rat","volume":"11","author":"R Kongsui","year":"2014","journal-title":"J Neuroinflammation"},{"key":"pone.0281003.ref073","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ntt.2014.07.003","article-title":"Value of water mazes for assessing spatial and egocentric learning and memory in rodent basic research and regulatory studies.","volume":"45","author":"C v Vorhees","year":"2014","journal-title":"Neurotoxicol Teratol"},{"issue":"1","key":"pone.0281003.ref074","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.bbr.2011.09.011","article-title":"Both the dorsal hippocampus and the dorsolateral striatum are needed for rat navigation in the Morris water maze","volume":"226","author":"E Miyoshi","year":"2012","journal-title":"Behavioural Brain Research"},{"key":"pone.0281003.ref075","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ntt.2016.08.002","article-title":"Cincinnati water maze: A review of the development, methods, and evidence as a test of egocentric learning and memory.","volume":"57","author":"C v Vorhees","year":"2016","journal-title":"Neurotoxicol Teratol"},{"issue":"15","key":"pone.0281003.ref076","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.3390\/ijms21155553","article-title":"Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice.","volume":"21","author":"Y Son","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0281003.ref077","doi-asserted-by":"crossref","first-page":"15551","DOI":"10.1038\/s41598-020-72755-4","article-title":"Evaluation of the neuroprotective effect of taurine in Alzheimer\u2019s disease using functional molecular imaging","volume":"10","author":"SJ Oh","year":"2020","journal-title":"Sci Rep"},{"issue":"12","key":"pone.0281003.ref078","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.1093\/brain\/awn278","article-title":"Strongly reduced volumes of putamen and thalamus in Alzheimer\u2019s disease: an MRI study","volume":"131","author":"LW de Jong","year":"2008","journal-title":"Brain"},{"issue":"7","key":"pone.0281003.ref079","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.neurobiolaging.2013.01.016","article-title":"Striatal morphology in early-onset and late-onset Alzheimer\u2019s disease: a preliminary study","volume":"34","author":"M Pievani","year":"2013","journal-title":"Neurobiol Aging"},{"issue":"11","key":"pone.0281003.ref080","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1093\/gerona\/glz009","article-title":"Association Between Brain \u03b2-Amyloid and Frailty in Older Adults","volume":"74","author":"M Maltais","year":"2019","journal-title":"The Journals of Gerontology: Series A"},{"key":"pone.0281003.ref081","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.arr.2014.04.004","article-title":"The role of egocentric and allocentric abilities in Alzheimer\u2019s disease: A systematic review","volume":"16","author":"S Serino","year":"2014","journal-title":"Ageing Res Rev"},{"issue":"1","key":"pone.0281003.ref082","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3233\/JAD-201017","article-title":"Egocentric and Allocentric Spatial Memory in Mild Cognitive Impairment with Real-World and Virtual Navigation Tasks: A Systematic Review","volume":"79","author":"C Tuena","year":"2021","journal-title":"Journal of Alzheimer\u2019s Disease"},{"issue":"10","key":"pone.0281003.ref083","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1111\/j.1532-5415.1998.tb04537.x","article-title":"The Association of Weight Change in Alzheimer\u2019s Disease with Severity of Disease and Mortality: A Longitudinal Analysis","volume":"46","author":"H White","year":"1998","journal-title":"J Am Geriatr Soc"},{"issue":"7075","key":"pone.0281003.ref084","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/bmj.314.7075.178","article-title":"Weight loss in people with Alzheimer\u2019s disease: a prospective population based analysis","volume":"314","author":"D Cronin-Stubbs","year":"1997","journal-title":"BMJ"},{"issue":"1","key":"pone.0281003.ref085","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13195-021-00781-z","article-title":"Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer\u2019s disease","volume":"13","author":"O Grau-Rivera","year":"2021","journal-title":"Alzheimers Res Ther"},{"issue":"4","key":"pone.0281003.ref086","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1440-1819.2004.01265.x","article-title":"Improvement in behavioral symptoms and advance of activity acrophase after short-term bright light treatment in severe dementia","volume":"58","author":"A Skjerve","year":"2004","journal-title":"Psychiatry Clin Neurosci"},{"issue":"2","key":"pone.0281003.ref087","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1017\/S1041610205001584","article-title":"Effect of morning bright light treatment for rest\u2013activity disruption in institutionalized patients with severe Alzheimer\u2019s disease","volume":"17","author":"GA Dowling","year":"2005","journal-title":"Int Psychogeriatr"},{"issue":"12","key":"pone.0281003.ref088","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.5664\/jcsm.8078","article-title":"Effects of a Tailored Lighting Intervention on Sleep Quality, Rest\u2013Activity, Mood, and Behavior in Older Adults With Alzheimer Disease and Related Dementias: A Randomized Clinical Trial","volume":"15","author":"MG Figueiro","year":"2019","journal-title":"Journal of Clinical Sleep Medicine"},{"key":"pone.0281003.ref089","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neuroscience.2015.01.035","article-title":"Increased fragmentation of sleep\u2013wake cycles in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"290","author":"M Sethi","year":"2015","journal-title":"Neuroscience"},{"key":"pone.0281003.ref090","first-page":"4","article-title":"Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs","author":"D Lakens","year":"2013","journal-title":"Front Psychol"},{"issue":"6","key":"pone.0281003.ref091","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1080\/13543784.2017.1323868","article-title":"Why do trials for Alzheimer\u2019s disease drugs keep failing? A discontinued drug perspective for 2010\u20132015","volume":"26","author":"D Mehta","year":"2017","journal-title":"Expert Opin Investig Drugs"},{"issue":"2","key":"pone.0281003.ref092","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S1474-4422(16)30395-7","article-title":"The Lancet Neurology. Solanezumab: too late in mild Alzheimer\u2019s disease?","volume":"16","year":"2017","journal-title":"Lancet Neurol."},{"issue":"1","key":"pone.0281003.ref093","doi-asserted-by":"crossref","first-page":"0530","DOI":"10.1523\/ENEURO.0530-21.2021","article-title":"Fallacies in Neuroscience: The Alzheimer\u2019s Edition","volume":"9","author":"K. Herrup","year":"2022","journal-title":"eNeuro"},{"issue":"1","key":"pone.0281003.ref094","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41583-021-00533-w","article-title":"The probabilistic model of Alzheimer disease: the amyloid hypothesis revised.","volume":"23","author":"GB Frisoni","year":"2022","journal-title":"Nat Rev Neurosci"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0281003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T12:37:16Z","timestamp":1702211836000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0281003"}},"subtitle":[],"editor":[{"given":"Thomas H.","family":"Burne","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,10]]},"references-count":94,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0281003","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,10]]}}}