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PSEN1 is one of four core proteins in the -secretase endoprotease complex that performs intramembrane cleavage of dozens of integral membrane proteins, including -amyloid precursor protein (APP) that sequentially generates the -carboxy-terminal fragment (CTF) and amyloid-, two polypeptides implicated in AD pathogenesis Ryanodine receptors (RyRs) Ion channels residing in the sarcoplasmic/endoplasmic reticulum membrane and responsible for Ca 2+ release from intracellular stores in excitable tissues, such as muscles and neurons Tau (MAPT) A group of six highly soluble protein isoforms produced by alternative splicing from MAPT that help stabilize the microtubule cytoskeleton of neurons and compose neurofibrillary tangles, a hallmark of Alzheimer disease (AD) TFEB, TFE3 Members of the MiT-TFE family of helixloophelix leucine zipper transcription factors that regulate expression of genes involved in the biogenesis and function of lysosomes and autophagosomes Footnotes Competing interests D.C.R

184 regions of interest were imaged at 1m-resolution

95% LoA: 36.6 to 24.2ms), and high reproducibility across timepoints A and C (CoV: 2.6%