Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer’s disease from amyotrophic lateral sclerosis
Abstract Blood phosphorylated tau 217 (p-tau217) accurately detects Alzheimer’s disease (AD) pathology but is also elevated in amyotrophic lateral sclerosis (ALS), likely reflecting peripheral (big) tau released from muscle. Assays selectively measuring brain-derived (BD-) tau and BD-p-tau217 are therefore needed. We analysed serum BD-tau and p-tau217 in ALS ( n = 139), AD ( n = 101) and controls ( n = 75) using direct immunoassays and after BD-Tau immunoprecipitation (BD-Tau-IP), and tau species in brain ( n = 16), spinal cord ( n = 11) and muscle ( n = 10) by targeted mass spectrometry. With the direct immunoassays, BD-tau and p-tau217 were increased in AD and ALS versus controls. After BD-Tau-IP, BD-tau and BD-p-tau217 were elevated in AD only, improving diagnostic accuracy. Mass spectrometry revealed a central-to-peripheral shift from BD-tau to big tau predominance, with exclusively big p-tau217 detected in muscle. Selective detection of BD-tau species improves the specificity of blood AD biomarkers by reducing peripheral tau confounding.
Authors
- Samir Abu‐Rumeileh (ORCID: https://orcid.org/0000-0003-0631-8506)
- Lucio D’Anna (ORCID: https://orcid.org/0000-0002-4349-3322)
- Julian Conrad (ORCID: https://orcid.org/0000-0001-7912-0571)
- Jens Wiltfang (ORCID: https://orcid.org/0000-0003-1492-5330)
- Antonia Ratti (ORCID: https://orcid.org/0000-0002-4264-6614)
- Dietmar Rudolf Thal (ORCID: https://orcid.org/0000-0002-1036-1075)
- Vincenzo Silani (ORCID: https://orcid.org/0000-0002-7698-3854)
- Alexander Mensch (ORCID: https://orcid.org/0000-0003-0089-4473)
- Julia Krippner
- Henning Großkopf (ORCID: https://orcid.org/0000-0002-5122-2477)
- Lucrezia Hausner (ORCID: https://orcid.org/0000-0001-9009-2356)
- Nicola Ticozzi (ORCID: https://orcid.org/0000-0001-5963-7426)
- Patrick Oeckl (ORCID: https://orcid.org/0000-0002-7652-7023)
- Lutz Froelich (ORCID: https://orcid.org/0000-0003-1494-0813)
- Lorenzo Barba (ORCID: https://orcid.org/0000-0003-1328-3620)
- Hans‐Wolfgang Klafki (ORCID: https://orcid.org/0000-0002-8672-9032)
- Alessio Maranzano (ORCID: https://orcid.org/0000-0002-3642-9584)
- Jochen Hans Weishaupt (ORCID: https://orcid.org/0000-0002-3399-9784)
- Dirk Osterloh (ORCID: https://orcid.org/0009-0002-8832-3164)
- Christopher M. Weise
- Federico Verde (ORCID: https://orcid.org/0000-0002-3977-6995)
- Markus Otto (ORCID: https://orcid.org/0000-0003-4273-4267)
- Ingolf Lachmann (ORCID: https://orcid.org/0000-0002-9225-1493)
- Gisela Stoltenburg (ORCID: https://orcid.org/0000-0002-2534-3064)
- Petra Steinacker (ORCID: https://orcid.org/0000-0001-6697-6522)
- Arthur Guthknecht (ORCID: https://orcid.org/0009-0009-3340-0426)
- Caroline Stapf
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-22
- DOI
- https://doi.org/10.1038/s41467-026-78390-3
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00