Longitudinal tau‐PET accumulation and downstream effects in amyloid‐beta negative cognitively unimpaired individuals

Topic: Brain proteins, microglia and lab models

16% of individuals were identified as tau-accumulators. They were older, had lower levels of Aβ as indicated by a higher CSF Aβ42/40 ratio (no difference on Aβ-PET) and numerically higher CSF MTBR-tau243/Aβ40 (not significant, note missingness; Figure 1B+C). Tau-accumulators showed significantly greater tau-PET at baseline and accumulation in regions not included in Braak I-IV (all p <0.001). Additionally, we observed more atrophy in BA35 (Figure 2A, not after age-adjustment) and numerically worse baseline cognitive performance, but no difference in decline over time (Figure 2B). In the whole sample, Braak I-IV tau-PET accumulation was significantly associated with increased age, more BA35 atrophy and at trend-level with higher levels of CSF Aβ42/40 and CSF MTBR-tau243/Aβ40 (Figure 3). A subgroup of Aβ- CU individuals show longitudinal tau accumulation across the neocortex. Preliminary results suggest an association with a tau-specific CSF biomarker and focal atrophy, which did not translate to changes in cognition. We will complement our analyses with a data-driven approach of classifying tau-accumulators.

Key findings

• 16% of individuals were identified as tau-accumulators.
• They were older, had lower levels of Aβ as indicated by a higher CSF Aβ42/40 ratio (no difference on Aβ-PET) and numerically higher CSF MTBR-tau243/Aβ40 (not significant, note missingness; Figure 1B+C).
• Tau-accumulators showed significantly greater tau-PET at baseline and accumulation in regions not included in Braak I-IV (all p <0.001).
• Additionally, we observed more atrophy in BA35 (Figure 2A, not after age-adjustment) and numerically worse baseline cognitive performance, but no difference in decline over time (Figure 2B).
• In the whole sample, Braak I-IV tau-PET accumulation was significantly associated with increased age, more BA35 atrophy and at trend-level with higher levels of CSF Aβ42/40 and CSF MTBR-tau243/Aβ40 (Figure 3).

Why it matters

Among amyloid-negative cognitively unimpaired individuals, 16% showed longitudinal tau accumulation across the neocortex, with preliminary links to a tau-specific CSF biomarker and focal atrophy but no difference in cognitive decline over time. The authors describe these as preliminary results, and no treatment, cure, or prevention is tested.

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Study details

• Study designlongitudinal study
• Participants29
• Evidence strengthModerate

Read the original

• DOI: 10.1002/alz70856_104826
• PubMed: 41498671
• Original source →
• Free full text: Alzheimer s & Dementia →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{wuestefeld2025-41498671,
  author  = {Wuestefeld, Anika and Spotorno, Nicola and Binette, Alexa Pichet and Mattsson, Niklas and Ossenkoppele, Rik and Palmqvist, Sebastian and Smith, Ruben and Stomrud, Erik and others},
  title   = {{Longitudinal tau‐PET accumulation and downstream effects in amyloid‐beta negative cognitively unimpaired individuals}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70856_104826},
  pmid    = {41498671},
  url     = {https://doi.org/10.1002/alz70856_104826}
}

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