{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T03:46:44Z","timestamp":1784605604748,"version":"3.55.0"},"posted":{"date-parts":[[2025,6,25]]},"group-title":"Neuroscience","reference-count":141,"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\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Alzheimer\u2019s disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer\u2019s disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1\n                  <jats:sup>\u0394E9\/WT<\/jats:sup>\n                  , PSEN1\n                  <jats:sup>M146V\/WT<\/jats:sup>\n                  , or APP\n                  <jats:sup>swe\/WT<\/jats:sup>\n                  . Our CO model reveals time-progressive accumulation of amyloid beta (A\u03b2) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau species. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of A\u03b2 and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"661453v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:p>","DOI":"10.1101\/2025.06.25.661453","type":"posted-content","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T14:30:28Z","timestamp":1750861828000},"source":"Crossref","is-referenced-by-count":5,"title":["Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer\u2019s disease iPSC-derived cortical 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