{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:27:51Z","timestamp":1785421671173,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,30]]},"group-title":"Neuroscience","reference-count":107,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100021528","name":"Advancing a Healthier Wisconsin Endowment","doi-asserted-by":"crossref","award":["5520482"],"award-info":[{"award-number":["5520482"]}],"id":[{"id":"10.13039\/100021528","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100021528","name":"Advancing a Healthier Wisconsin Endowment","doi-asserted-by":"crossref","award":["5520760"],"award-info":[{"award-number":["5520760"]}],"id":[{"id":"10.13039\/100021528","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R03AG087390"],"award-info":[{"award-number":["R03AG087390"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Genome-wide studies in late-onset Alzheimer\u2019s disease (LOAD) have uncovered many risk loci, yet identifying the causal genes and clarifying how these genetic signals connect to molecular and cellular mechanisms relevant to AD pathogenesis\n                    <jats:italic>in vivo<\/jats:italic>\n                    remains challenging.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Using\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    as a model to identify LOAD-associated genes that drive neurodegenerative processes, we focused on 14 understudied genes and their homologs:\n                    <jats:italic>ABI3\/abi-1<\/jats:italic>\n                    ,\n                    <jats:italic>B4GALT3\/bre-4<\/jats:italic>\n                    ,\n                    <jats:italic>CCDC6\/T09B9.4<\/jats:italic>\n                    ,\n                    <jats:italic>CLPTM1<\/jats:italic>\n                    (two homologs\n                    <jats:italic>C36B7.6<\/jats:italic>\n                    and\n                    <jats:italic>R166.2<\/jats:italic>\n                    ),\n                    <jats:italic>CNN2\/cpn-2<\/jats:italic>\n                    ,\n                    <jats:italic>DMWD\/wdr-20<\/jats:italic>\n                    ,\n                    <jats:italic>ECHDC3\/ech-2<\/jats:italic>\n                    ,\n                    <jats:italic>MADD\/aex-3<\/jats:italic>\n                    ,\n                    <jats:italic>NCK2\/nck-1<\/jats:italic>\n                    ,\n                    <jats:italic>RABEP1\/rabn-5<\/jats:italic>\n                    ,\n                    <jats:italic>RIN3\/rin-1<\/jats:italic>\n                    ,\n                    <jats:italic>SLC39A13\/zipt-13<\/jats:italic>\n                    ,\n                    <jats:italic>TRAM1\/tram-1<\/jats:italic>\n                    , and\n                    <jats:italic>USP6NL\/tbc-17<\/jats:italic>\n                    . We knocked down these genes by RNAi and quantified lifespan, aging-associated degeneration of two neuron classes, PVD and PLM, and associative learning and short-term memory.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Lifespan was unaffected by most knockdowns, and only\n                    <jats:italic>nck-1<\/jats:italic>\n                    and\n                    <jats:italic>tbc-17<\/jats:italic>\n                    shortened lifespan. Across neuronal assays, multiple homologs modulated aging with clear neuron-class selectivity. Knockdown of\n                    <jats:italic>aex-3<\/jats:italic>\n                    ,\n                    <jats:italic>C36B7.6<\/jats:italic>\n                    ,\n                    <jats:italic>cpn-2<\/jats:italic>\n                    ,\n                    <jats:italic>ech-2<\/jats:italic>\n                    ,\n                    <jats:italic>rabn-5<\/jats:italic>\n                    ,\n                    <jats:italic>rin-1<\/jats:italic>\n                    ,\n                    <jats:italic>T09B9.4<\/jats:italic>\n                    , and\n                    <jats:italic>zipt-13<\/jats:italic>\n                    attenuated late-life PVD degeneration, whereas\n                    <jats:italic>R166.2<\/jats:italic>\n                    and\n                    <jats:italic>tram-1<\/jats:italic>\n                    accelerated early PVD aging. Only two genes affected PLM aging:\n                    <jats:italic>R166.2<\/jats:italic>\n                    knockdown exacerbated degeneration, while\n                    <jats:italic>tbc-17<\/jats:italic>\n                    knockdown attenuated it despite its lifespan-shortening effect. In PLM neurons,\n                    <jats:italic>tbc-17<\/jats:italic>\n                    knockdown, targeting a Rab GTPase-activating protein, also preserved mitochondrial architecture during early aging and shifted heat stress-induced mitochondrial remodeling toward a pattern consistent with improved quality control. In behavioral assays,\n                    <jats:italic>ech-2<\/jats:italic>\n                    knockdown, targeting an enoyl-CoA-hydratase, enhanced short-term memory during early stages of aging. To further assess how LOAD-linked genes interact with A\u03b2-driven neurodegeneration, we developed a model that combines the PVD aging assay with a background expressing human A\u03b2\n                    <jats:sub>1-42<\/jats:sub>\n                    panneuronally. In this model, A\u03b2 expression accelerated age-dependent PVD degeneration, whereas\n                    <jats:italic>ech-2<\/jats:italic>\n                    knockdown abolished this A\u03b2-induced effect.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Our findings show that conserved homologs of several understudied LOAD risk genes causally modulate neuronal aging\n                    <jats:italic>in vivo<\/jats:italic>\n                    in a neuron-class-selective manner, often dissociable from organismal longevity. This\n                    <jats:italic>C. elegans<\/jats:italic>\n                    framework translates human genetic associations into quantitative, aging-linked neuronal phenotypes, and our results further emphasize early endosomal and lipid-related processes as key pathways that warrant functional testing in neuronal aging. This study also provides a tractable platform to prioritize targets for cross-species validation and to test synergy with established LOAD risk genes.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.26.714531","type":"posted-content","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:05:28Z","timestamp":1774897528000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional Analysis of Late-Onset Alzheimer\u2019s Disease Risk Genes in\n                  <i>Caenorhabditis elegans<\/i>\n                  Identifies Regulators of Neuronal Aging"],"prefix":"10.64898","author":[{"given":"Swapnil G","family":"Waghmare","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI 53226, United States of America"},{"name":"Neuroscience Research Center, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI 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