{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:25:30Z","timestamp":1785421530070,"version":"3.56.0"},"posted":{"date-parts":[[2025,6,25]]},"group-title":"Neuroscience","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["K99AG075184"],"award-info":[{"award-number":["K99AG075184"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG048076"],"award-info":[{"award-number":["R01AG048076"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG074339"],"award-info":[{"award-number":["R01AG074339"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG060747"],"award-info":[{"award-number":["R01AG060747"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30AG066515"],"award-info":[{"award-number":["P30AG066515"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Amyloid-\u03b2 (A\u03b2) and tau pathology begin accumulating decades before clinical symptoms and are influenced by\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54, a key genetic risk factor for Alzheimer\u2019s disease (AD). Although the presence of A\u03b2, tau, and\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9\u00b15.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. A\u03b2 was measured using CSF A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  \/A\u03b2\n                  <jats:sub>40<\/jats:sub>\n                  or Florbetaben-PET imaging and tau was measured using CSF pTau\n                  <jats:sub>181<\/jats:sub>\n                  . Hippocampal univariate activity and cortical reinstatement \u2013 that is, reinstatement of patterns of neocortical activity that were present during memory encoding \u2013 were measured during successful memory retrieval. Analyses revealed that\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 was independently associated with greater A\u03b2 and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54. Among\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 non-carriers, A\u03b2 burden was linked to a pattern of hippocampal hyperactivity. Among\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 carriers, CSF pTau\n                  <jats:sub>181<\/jats:sub>\n                  was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Hippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimer\u2019s disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 in cognitively unimpaired older adults. Amyloid-\u03b2-related hyperactivity was observed in the hippocampus among\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 non-carriers, while CSF pTau\n                    <jats:sub>181<\/jats:sub>\n                    was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 carriers. Our findings highlight synergistic effects of\n                    <jats:italic>APOE<\/jats:italic>\n                    and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.20.660774","type":"posted-content","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T17:25:23Z","timestamp":1750872323000},"source":"Crossref","is-referenced-by-count":0,"title":["Synergistic effects of\n                  <i>APOE<\/i>\n                  \u03b54 and Alzheimer\u2019s pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults"],"prefix":"10.64898","author":[{"given":"Alexandra N.","family":"Trelle","sequence":"first","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Psychology, Stanford University, Stanford, CA 94305"},{"name":"Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0640-5247","authenticated-orcid":false,"given":"Edward N.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305"},{"name":"Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"America","family":"Romero","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayle K.","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon J.","family":"Sha","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Greicius","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305"},{"name":"Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin I.","family":"Andreasson","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305"},{"name":"Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA 94305"},{"name":"Chan Zuckerberg Biohub, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey A.","family":"Kerchner","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Mormino","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305"},{"name":"Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0624-4543","authenticated-orcid":false,"given":"Anthony D.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Psychology, Stanford University, Stanford, CA 94305"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041210111440000_2025.06.20.660774v1.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2504-20.2021"},{"key":"2026041210111440000_2025.06.20.660774v1.2","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00710-6"},{"key":"2026041210111440000_2025.06.20.660774v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz378"},{"key":"2026041210111440000_2025.06.20.660774v1.4","doi-asserted-by":"crossref","unstructured":"Bondi MW , Houston WS , Eyler LT , Brown GG (2007) fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease.","DOI":"10.1016\/S0513-5117(08)70077-2"},{"key":"2026041210111440000_2025.06.20.660774v1.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200008173430701"},{"key":"2026041210111440000_2025.06.20.660774v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2026041210111440000_2025.06.20.660774v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206171109"},{"key":"2026041210111440000_2025.06.20.660774v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1162844"},{"key":"2026041210111440000_2025.06.20.660774v1.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"2026041210111440000_2025.06.20.660774v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12295"},{"key":"2026041210111440000_2025.06.20.660774v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jagp.2016.12.021"},{"key":"2026041210111440000_2025.06.20.660774v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3806"},{"key":"2026041210111440000_2025.06.20.660774v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0235-4"},{"key":"2026041210111440000_2025.06.20.660774v1.14","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03550160069041"},{"key":"2026041210111440000_2025.06.20.660774v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0564-18.2018"},{"key":"2026041210111440000_2025.06.20.660774v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.08.009"},{"key":"2026041210111440000_2025.06.20.660774v1.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811879106"},{"key":"2026041210111440000_2025.06.20.660774v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116336"},{"key":"2026041210111440000_2025.06.20.660774v1.19","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bht194"},{"key":"2026041210111440000_2025.06.20.660774v1.20","doi-asserted-by":"crossref","unstructured":"Gorgolewski K , Burns CD , Madison C , Clark D , Halchenko YO , Waskom ML , Ghosh SS (2011) Nipype: A Flexible, Lightweight and Extensible Neuroimaging Data Processing Framework in Python. Front Neuroinformatics 5 Available at: http:\/\/journal.frontiersin.org\/article\/10.3389\/fninf.2011.00013\/abstract [Accessed September 2, 2021].","DOI":"10.3389\/fninf.2011.00013"},{"key":"2026041210111440000_2025.06.20.660774v1.21","unstructured":"Gorgolewski KJ , Esteban O , Markiewicz CJ , Ziegler E , Ellis DG , Notter MP , Jarecka D , Johnson H , Burns C , Manh\u00e3es-Savio A (2018) Nipype. Sopware."},{"key":"2026041210111440000_2025.06.20.660774v1.22","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.1424"},{"key":"2026041210111440000_2025.06.20.660774v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2010.04.004"},{"key":"2026041210111440000_2025.06.20.660774v1.24","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1397-18.2018"},{"key":"2026041210111440000_2025.06.20.660774v1.25","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R075481"},{"key":"2026041210111440000_2025.06.20.660774v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2025.103765"},{"key":"2026041210111440000_2025.06.20.660774v1.27","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac299"},{"key":"2026041210111440000_2025.06.20.660774v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"2026041210111440000_2025.06.20.660774v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp062"},{"key":"2026041210111440000_2025.06.20.660774v1.30","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.5216"},{"key":"2026041210111440000_2025.06.20.660774v1.31","doi-asserted-by":"crossref","unstructured":"Knopman DS , Lundt ES , Therneau TM , Albertson SM , Gunter JL , Senjem ML , Schwarz CG , Mielke MM , Machulda MM , Boeve BF , Jones DT , Graff-Radford J , Vemuri P , Kantarci K , Lowe VJ , Petersen RC , Jack CR , Alzheimer\u2019s Disease Neuroimaging Initiative (2021) Association of Initial \u03b2-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment. JAMA Neurol 78:217.","DOI":"10.1001\/jamaneurol.2020.3921"},{"key":"2026041210111440000_2025.06.20.660774v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00368-3"},{"key":"2026041210111440000_2025.06.20.660774v1.33","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4328-13.2014"},{"key":"2026041210111440000_2025.06.20.660774v1.34","doi-asserted-by":"crossref","unstructured":"La Joie R , Visani AV , Lesman-Segev OH , Baker SL , Edwards L , Iaccarino L , Soleimani-Meigooni DN , Mellinger T , Janabi M , Miller ZA , Perry DC , Pham J , Strom A , Gorno-Tempini ML , Rosen HJ , Miller BL , Jagust WJ , Rabinovici GD (2021) Association of APOE4 and Clinical Variability in Alzheimer Disease With the Pattern of Tau-and Amyloid-PET. Neurology 96 Available at: https:\/\/www.neurology.org\/doi\/10.1212\/WNL.0000000000011270 [Accessed April 5, 2024].","DOI":"10.1212\/WNL.0000000000011270"},{"key":"2026041210111440000_2025.06.20.660774v1.35","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx320"},{"key":"2026041210111440000_2025.06.20.660774v1.36","doi-asserted-by":"crossref","unstructured":"Lowe VJ et al. (2019) Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults. Neurology 93 Available at: https:\/\/www.neurology.org\/doi\/10.1212\/WNL.0000000000007728 [Accessed April 26, 2024].","DOI":"10.1212\/WNL.0000000000007728"},{"key":"2026041210111440000_2025.06.20.660774v1.37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2028-17.2017"},{"key":"2026041210111440000_2025.06.20.660774v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy103"},{"key":"2026041210111440000_2025.06.20.660774v1.39","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhr255"},{"key":"2026041210111440000_2025.06.20.660774v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.08.076"},{"key":"2026041210111440000_2025.06.20.660774v1.41","doi-asserted-by":"publisher","DOI":"10.1001\/archgenpsychiatry.2011.1893"},{"key":"2026041210111440000_2025.06.20.660774v1.42","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181e3966e"},{"key":"2026041210111440000_2025.06.20.660774v1.43","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.1858"},{"key":"2026041210111440000_2025.06.20.660774v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01150-x"},{"key":"2026041210111440000_2025.06.20.660774v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2022.101594"},{"key":"2026041210111440000_2025.06.20.660774v1.46","doi-asserted-by":"publisher","DOI":"10.1126\/science.1117645"},{"key":"2026041210111440000_2025.06.20.660774v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199903)45:3<358::AID-ANA12>3.0.CO;2-X"},{"key":"2026041210111440000_2025.06.20.660774v1.48","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00836-1"},{"key":"2026041210111440000_2025.06.20.660774v1.49","unstructured":"Sheng J , Trelle AN , Romero A , Park J , Tran TT , Sha SJ , Andreasson KI , Wilson EN , Mormino EC , Wagner AD (in press) Top-down attention and Alzheimer\u2019s pathology impact cortical selectivity during learning, influencing episodic memory in older adults. Sci Advances."},{"key":"2026041210111440000_2025.06.20.660774v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/nature24016"},{"key":"2026041210111440000_2025.06.20.660774v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.003"},{"key":"2026041210111440000_2025.06.20.660774v1.52","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25395"},{"key":"2026041210111440000_2025.06.20.660774v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.07.003"},{"key":"2026041210111440000_2025.06.20.660774v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09558-3"},{"key":"2026041210111440000_2025.06.20.660774v1.55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3054-13.2014"},{"key":"2026041210111440000_2025.06.20.660774v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.09.037"},{"key":"2026041210111440000_2025.06.20.660774v1.57","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.4421"},{"key":"2026041210111440000_2025.06.20.660774v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0688-6"},{"key":"2026041210111440000_2025.06.20.660774v1.59","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00338.2011"},{"key":"2026041210111440000_2025.06.20.660774v1.60","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55335"},{"key":"2026041210111440000_2025.06.20.660774v1.61","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011477"},{"key":"2026041210111440000_2025.06.20.660774v1.62","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14442"},{"key":"2026041210111440000_2025.06.20.660774v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.12.012"},{"key":"2026041210111440000_2025.06.20.660774v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.117199"},{"key":"2026041210111440000_2025.06.20.660774v1.65","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12173"},{"key":"2026041210111440000_2025.06.20.660774v1.66","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0228-7"},{"key":"2026041210111440000_2025.06.20.660774v1.67","doi-asserted-by":"crossref","unstructured":"Young CB , Johns E , Kennedy G , Belloy ME , Insel PS , Greicius MD , Sperling RA , Johnson KA , Poston KL , Mormino EC , for the Alzheimer\u2019s Disease Neuroimaging Initiative, the A4 Study Team (2023) APOE effects on regional tau in preclinical Alzheimer\u2019s disease. Mol Neurodegener 18:1.","DOI":"10.1186\/s13024-022-00590-4"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.06.20.660774","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T17:11:25Z","timestamp":1776013885000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.06.20.660774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":67,"URL":"https:\/\/doi.org\/10.1101\/2025.06.20.660774","relation":{},"subject":[],"published":{"date-parts":[[2025,6,25]]},"subtype":"preprint"}}