{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:09:11Z","timestamp":1788480551344,"version":"build-2803163510"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007306","name":"Arizona Department of Health Services","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007306","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The apolipoprotein E (<jats:italic>APOE<\/jats:italic>) \u03b54 allele is the strongest genetic risk factor for late-onset Alzheimer\u2019s disease (AD) and cardiovascular disease. This study aimed to investigate the interactive effects of <jats:italic>APOE<\/jats:italic> \u03b54 genotype and cardiovascular risk on the microstructure of the nucleus basalis of Meynert (NBM), a key cholinergic region affected early in AD, using advanced diffusion magnetic resonance imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This cross-sectional study included 167 cognitively unimpaired older adults from the Arizona <jats:italic>APOE<\/jats:italic> Cohort. Participants were stratified by genotype: <jats:italic>APOE<\/jats:italic> \u03b54 non-carriers (<jats:italic>N<\/jats:italic> = 83), heterozygous carriers (<jats:italic>N<\/jats:italic> = 51), and homozygous carriers (<jats:italic>N<\/jats:italic> = 33). Cardiovascular risk was quantified using a composite score calculated by assigning points based on the presence of risk factors (myocardial infarction\/peripheral vascular disease, hypertension, diabetes, hypercholesterolemia) and categorized levels of continuous variables (systolic and diastolic blood pressure, body mass index) with higher scores indicating greater risk. Participants underwent comprehensive neuropsychological assessments, structural MRI, diffusion MRI, and Pittsburgh Compound-B (PiB) Positron Emission Tomography imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A significant interaction was found between <jats:italic>APOE<\/jats:italic> genotype and cardiovascular risk on NBM FW levels (<jats:italic>p<\/jats:italic> = 0.02). In <jats:italic>APOE<\/jats:italic> \u03b53\/\u03b53 and \u03b53\/\u03b54 carriers, greater cardiovascular risk was associated with increased NBM FW. Conversely, <jats:italic>APOE<\/jats:italic> \u03b54\/\u03b54 carriers exhibited similar FW values regardless of their cardiovascular risk category. Furthermore, elevated NBM FW accounted for approximately 25% of the variance in systolic blood pressure, homocysteine, and cholesterol-to-HDL ratio (<jats:italic>p<\/jats:italic>\u2019s &amp;lt; 0.01). Cardiovascular risk had a more pronounced effect on corrected fractional anisotropy (FA) than on FW measures (<jats:italic>p<\/jats:italic>\u2019s &amp;lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The findings suggest that the <jats:italic>APOE<\/jats:italic> \u03b54\/\u03b54 accelerates early microstructural alterations within the basal forebrain cholinergic system potentially through mechanisms involving altered lipid homeostasis, compromised neurovascular integrity, and sustained neuroinflammatory responses. These effects appear to indicate a genotype-specific vulnerability. Free-water imaging of the NBM emerges as a sensitive, non-invasive biomarker capable of detecting these <jats:italic>APOE<\/jats:italic>-modulated microstructural changes before overt atrophy or cognitive decline. Understanding the multifactorial pathways through which <jats:italic>APOE<\/jats:italic> \u03b54 and cardiovascular factors confer risk may enable increased understanding in genetically susceptible individuals prior to widespread neurodegeneration.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2025.1597127","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T05:36:34Z","timestamp":1758000994000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Free-water imaging of the nucleus basalis of Meynert in apolipoprotein E4 carriers"],"prefix":"10.3389","volume":"17","author":[{"given":"Edward","family":"Ofori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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Lett."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"105990","DOI":"10.1016\/j.nbd.2023.105990","article-title":"Neuroimaging findings related to glymphatic system alterations in older adults with metabolic syndrome","volume":"177","author":"Andica","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"102794","DOI":"10.1016\/j.nicl.2021.102794","article-title":"The relationship between white matter microstructure and self-perceived cognitive decline","volume":"32","author":"Archer","year":"2021","journal-title":"NeuroImage Clinical."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0306-4522(85)90160-5","article-title":"Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer's disease","volume":"14","author":"Arendt","year":"1985","journal-title":"Neuroscience"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3233\/JAD-150381","article-title":"Treatment of Alzheimer\u2019s disease: the legacy of the cholinergic hypothesis, neuroplasticity, and future directions","volume":"47","author":"Ashford","year":"2015","journal-title":"J Alzheimer's Dis"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1038\/s41598-022-05536-w","article-title":"Contribution of obesity and cardiometabolic risk factors in developing cardiovascular disease: a population-based cohort study","volume":"12","author":"Bakhtiyari","year":"2022","journal-title":"Sci. Rep."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1111\/j.1749-6632.1996.tb34415.x","article-title":"Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer's disease","volume":"777","author":"Beffert","year":"1996","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"fcz018","DOI":"10.1093\/braincomms\/fcz018","article-title":"APOE genotype, hypertension severity and outcomes after intracerebral haemorrhage","volume":"1","author":"Biffi","year":"2019","journal-title":"Brain Commun."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s11906-015-0550-4","article-title":"Hypothalamic signaling mechanisms in hypertension","volume":"17","author":"Carmichael","year":"2015","journal-title":"Curr. Hypertens. Rep."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1056\/NEJMoa0809437","article-title":"Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect","volume":"361","author":"Caselli","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e700","DOI":"10.1212\/wnl.0000000000013206","article-title":"Association of Cognitive Impairment with Free Water in the nucleus basalis of Meynert and locus Coeruleus to Transentorhinal cortex tract","volume":"98","author":"Chu","year":"2022","journal-title":"Neurology"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.neuroimage.2006.01.021","article-title":"An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest","volume":"31","author":"Desikan","year":"2006","journal-title":"NeuroImage"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2830","DOI":"10.1002\/alz.13693","article-title":"Diffusion MRI relates to plasma A\u03b242\/40 in PET negative participants without dementia","volume":"20","author":"DeSimone","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1093\/jnen\/63.2.159","article-title":"ApoE epsilon4 genotype is accompanied by lower metabolic activity in nucleus basalis of Meynert neurons in Alzheimer patients and controls as indicated by the size of the Golgi apparatus","volume":"63","author":"Dubelaar","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e0242696","DOI":"10.1371\/journal.pone.0242696","article-title":"Free water: a marker of age-related modifications of the cingulum white matter and its association with cognitive decline","volume":"15","author":"Edde","year":"2020","journal-title":"PLoS One"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"100206","DOI":"10.1016\/j.cccb.2024.100206","article-title":"Pulse pressure and APOE \u03b54 dose interact to affect cerebral blood flow in older adults without dementia","volume":"6","author":"Edwards","year":"2024","journal-title":"Cereb Circ Cogn Behav."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"3685","DOI":"10.1093\/brain\/awv288","article-title":"Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer\u2019s disease","volume":"138","author":"Fan","year":"2015","journal-title":"Brain"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"eade1474","DOI":"10.1126\/sciadv.ade1474","article-title":"APOE\u03b54 associates with microglial activation independently of a\u03b2 plaques and tau tangles","volume":"9","author":"Ferrari-Souza","year":"2023","journal-title":"Sci. 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Thromb."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/S0022-2275(20)43176-1","article-title":"Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI","volume":"31","author":"Hixson","year":"1990","journal-title":"J. Lipid Res."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3233\/jad-2012-111460","article-title":"Markers of cholesterol metabolism in the brain show stronger associations with cerebrovascular disease than Alzheimer's disease","volume":"30","author":"Hughes","year":"2012","journal-title":"J Alzheimer's Disease"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"3582","DOI":"10.1093\/brain\/awab478","article-title":"APOE4 derived from astrocytes leads to blood\u2013brain barrier impairment","volume":"145","author":"Jackson","year":"2021","journal-title":"Brain"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.neuroimage.2011.09.015","article-title":"FSL","volume":"62","author":"Jenkinson","year":"2012","journal-title":"NeuroImage"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e151","DOI":"10.1212\/WNL.0000000000207401","article-title":"Associations of blood cardiovascular biomarkers with brain free water and its relationship to cognitive decline: a diffusion-MRI study","volume":"101","author":"Ji","year":"2023","journal-title":"Neurology"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1002\/mnfr.200700322","article-title":"Impact of apoE genotype on oxidative stress, inflammation and disease risk","volume":"52","author":"Jofre-Monseny","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1001\/archneurol.2011.2874","article-title":"Preservation of neurons of the nucleus basalis in subcortical ischemic vascular disease","volume":"69","author":"Jung","year":"2012","journal-title":"Arch. Neurol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/s0304-3940(99)00323-7","article-title":"Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease","volume":"267","author":"Kanai","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"100048","DOI":"10.1016\/j.nbas.2022.100048","article-title":"Asymmetric amyloid deposition in preclinical Alzheimer's disease: a PET study","volume":"2","author":"Kjeldsen","year":"2022","journal-title":"Aging Brain"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jalz.2014.07.003","article-title":"The Centiloid project: standardizing quantitative amyloid plaque estimation by PET","volume":"11","author":"Klunk","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/S0021-9150(00)00570-0","article-title":"Apolipoprotein E genotype and cardiovascular disease in the Framingham heart study","volume":"154","author":"Lahoz","year":"2001","journal-title":"Atherosclerosis"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"651388","DOI":"10.3389\/fneur.2021.651388","article-title":"The effect of the APOE-\u03b54 allele on the cholinergic circuitry for subjects with different levels of cognitive impairment","volume":"12","author":"Lai","year":"2021","journal-title":"Front. Neurol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"113183","DOI":"10.1016\/j.celrep.2023.113183","article-title":"ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes","volume":"42","author":"Lee","year":"2023","journal-title":"Cell Rep."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1184609","DOI":"10.3389\/fnagi.2023.1184609","article-title":"Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E \u03b54 allele and age","volume":"15","author":"Lee","year":"2023","journal-title":"Front. 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Psych."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e2221","DOI":"10.1212\/wnl.0000000000007449","article-title":"Cerebral white matter free water: a sensitive biomarker of cognition and function","volume":"92","author":"Maillard","year":"2019","journal-title":"Neurology"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1161\/strokeaha.116.016321","article-title":"Aortic stiffness, increased white matter free water, and altered microstructural integrity: a continuum of injury","volume":"48","author":"Maillard","year":"2017","journal-title":"Stroke"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1177\/0271678x221093579","article-title":"Free-water diffusion MRI detects structural alterations surrounding white matter hyperintensities in the early stage of cerebral small vessel disease","volume":"42","author":"Mayer","year":"2022","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"fcad262","DOI":"10.1093\/braincomms\/fcad262","article-title":"Basal forebrain activity predicts functional degeneration in the entorhinal cortex in Alzheimer's disease","volume":"5","author":"Mieling","year":"2023","journal-title":"Brain Commun."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1002\/cne.902820411","article-title":"Survey of noncortical afferent projections to the basilar pontine nuclei: a retrograde tracing study in the rat","volume":"282","author":"Mihailoff","year":"1989","journal-title":"J. Comp. Neurol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.jalz.2017.09.013","article-title":"Cortical microstructural changes along the Alzheimer's disease continuum","volume":"14","author":"Montal","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"e12356","DOI":"10.1002\/trc2.12356","article-title":"Free water derived by multi-shell diffusion MRI reflects tau\/neuroinflammatory pathology in Alzheimer's disease","volume":"8","author":"Nakaya","year":"2022","journal-title":"Alzheimers Dementia"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"101985","DOI":"10.1016\/j.nicl.2019.101985","article-title":"Free-water imaging of the hippocampus is a sensitive marker of Alzheimer's disease","volume":"24","author":"Ofori","year":"2019","journal-title":"NeuroImage Clinical."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1016\/j.neurobiolaging.2014.10.029","article-title":"Increased free water in the substantia nigra of Parkinson's disease: a single-site and multi-site study","volume":"36","author":"Ofori","year":"2015","journal-title":"Neurobiol. 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Neurosurg."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/978-3-642-33418-4_38","article-title":"Estimation of extracellular volume from regularized multi-shell diffusion MRI","volume":"15","author":"Pasternak","year":"2012","journal-title":"Medical Image Computing Computer Assisted Intervention"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1093\/brain\/awy289","article-title":"Apolipoprotein E4 genotype compromises brain exosome production","volume":"142","author":"Peng","year":"2018","journal-title":"Brain"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"166793","DOI":"10.1016\/j.bbadis.2023.166793","article-title":"Apolipoprotein E \u03b54 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKC\u03b5 mislocalization in cholinergic neuronal cells","volume":"1869","author":"Piccarducci","year":"2023","journal-title":"Biochim. Biophys. Acta (BBA) - Mol. Basis Dis."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1093\/brain\/awv361","article-title":"Free-water imaging in Parkinson's disease and atypical parkinsonism","volume":"139","author":"Planetta","year":"2016","journal-title":"Brain"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.neuroimage.2009.07.025","article-title":"Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging","volume":"49","author":"Reiman","year":"2010","journal-title":"NeuroImage"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"6820","DOI":"10.1073\/pnas.0900345106","article-title":"Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease","volume":"106","author":"Reiman","year":"2009","journal-title":"Proc. Natl. Acad. Sci. 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Neurol."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.neuroimage.2017.04.023","article-title":"Separating blood and water: perfusion and free water elimination from diffusion MRI in the human brain","volume":"156","author":"Rydh\u00f6g","year":"2017","journal-title":"NeuroImage"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"E322","DOI":"10.1152\/ajpendo.00408.2004","article-title":"apoE4 allele and the natural history of cardiovascular risk factors","volume":"289","author":"Scuteri","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"7222","DOI":"10.1007\/s12035-019-1588-0","article-title":"A new neural pathway from the ventral striatum to the nucleus basalis of Meynert with functional implication to learning and memory","volume":"56","author":"Shu","year":"2019","journal-title":"Mol. 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Disord."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"19849","DOI":"10.1038\/s41598-021-98117-2","article-title":"Associations between race, APOE genotype, cognition, and mortality among urban middle-aged white and African American adults","volume":"11","author":"Weiss","year":"2021","journal-title":"Sci. Rep."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"e13","DOI":"10.1161\/HYP.0000000000000065","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA guideline for the prevention, detection, evaluation, and Management of High Blood Pressure in adults: a report of the American College of Cardiology\/American Heart Association task force on clinical practice guidelines","volume":"71","author":"Whelton","year":"2018","journal-title":"Hypertension"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/cercor\/bht210","article-title":"Neurons in the basal forebrain project to the cortex in a complex topographic organization that reflects corticocortical connectivity patterns: an experimental study based on retrograde tracing and 3D reconstruction","volume":"25","author":"Zaborszky","year":"2015","journal-title":"Cereb. Cortex"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.neuroimage.2008.05.055","article-title":"Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain","volume":"42","author":"Zaborszky","year":"2008","journal-title":"NeuroImage"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"5540","DOI":"10.1038\/s41467-020-19264-0","article-title":"APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat. 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