💡 Takeaway:
• NfL is robust but not sufficient alone in low-prevalence settings.
• Diagnostic and prognostic frameworks should move toward standardized multimodal models integrating fluid #biomarkers with established predictors.
#ALS #MND

A huge thanks to all co-authors: Lyduine Collij, Niklas Mattson-Carlgren, Shorena Janelidze, @rikossenkoppele.bsky.social, and Oskar Hansson.

🙏Many thanks to all collaborators in this large study including 12 international cohorts!

🎯The use of plasma p-tau217 will reduce resource demands and burdensome procedures accelerating the development and implementation of early AD therapeutics.

5️⃣ In conclusion, our results support the clinical utility of plasma p-tau217 as stand-alone tool for identifying preclinical AD but adding confirmatory CSF/PET would further improve PPVs as needed in many clinical applications.

4️⃣ Finally, in a subsample we tested whether mass-spectrometry (MS) based methods would improve the results compared to immunoassays (IA). MS showed significantly higher accuracy and sensitivity, but PPV remained comparable to that of IA.

3️⃣ In a hypothetical trial aiming to recruit 100 amyloid-positive individuals, there was >40% reduction in number of PET/CSF tests in blood-based approaches, although the initial number of individuals needed were increased.

2️⃣ Next, we investigated a 2-step approach in which 🩸p-tau217 positive individuals were confirmed with CSF or PET.
With this approach, PPV increased to over 90% while maintaining sensitivity.

1️⃣ In a sample of 2916 cognitively unimpaired individuals we found that plasma p-tau217🩸alone (single-step) was able to determine amyloid-b status with good accuracy and, most importantly, with a positive predictive value (PPV) around 80%.

The study was led by PhD students Pontus Tideman and Linda Karlsson. Thank you also to all co-authors.

Big thanks to all co-authors and collaborators: @rikossenkoppele.bsky.social @aitchbi.bsky.social @jorittmo.bsky.social @jwvogel.bsky.social + those not on bksy

7/🧵 These results suggest that hemispheric difference in Aβ deposition, rather than reduction in connectivity, is associated with asymmetric tau accumulation, highlighting regional vulnerability as a crucial factor in determining the distribution of AD pathology.

6/🧵 More asymmetric tau accumulation was tied to faster cognitive decline, particularly in regions affected at later disease stages.

5/🧵 Longitudinally, Aβ asymmetry at baseline predicted subsequent increase in tau asymmetry over time, especially in participants who hadn’t yet developed neocortical tau deposits. The affected Braak regions depended on disease stage and progression.

4/🧵 We replicated this Aβ-tau asymmetry link across three independent cohorts (OASIS-3, A4, ADNI), showing it is a consistent feature throughout the AD continuum.

3/🧵 There were no significant differences in inter-hemispheric connectivity (functional or structural) between asymmetric and symmetric tau groups. Instead, we observed a strong association between the laterality of Aβ and tau pathology, especially in temporal regions.

2/🧵 We assessed both inter-hemispheric brain connectivity (using RSfMRI and dMRI) and the spatial distribution of Aβ in 452 A+T+ participants from the Swedish BioFINDER-2 cohort to investigate the differences between asymmetric and symmetric tau pathology distribution.

1/🧵 In this study, we tried to disentangle whether tau asymmetry is due to reduction in inter-hemispheric brain connectivity (potentially restricting tau spread), or if it is linked to asymmetric amyloid-beta (Aβ) deposition (indicating greater hemisphere-specific vulnerability to AD pathology).

A huge thanks to all coauthors!
@josephtherr.bsky.social