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A longer isoform, \u201cbig tau,\u201d produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical (\u201csmall\u201d) tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a\u2010long and exon 4a\u2010short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000\u2010fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease\u2010associated changes in brain\u2010derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. 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