Varga, Andrew W.

Abstract The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross‐sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker‐driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.

Background REM sleep behaviour disorder (RBD) is a prodrome of α -synucleinopathy, yet mechanistic pathways are unresolved. Narcolepsy type 1 with RBD (NT1-RBD) provides a human model of orexin deficiency. We tested whether REM motor semiology differs categorically between isolated RBD (iRBD) and NT1-RBD. Methods We retrospectively analyzed blinded video-polysomnographic scorings from 57 patients (iRBD n = 34; NT1-RBD n = 23). Across 857 REM events (iRBD 717; NT1-RBD 140), we classified topography (head/neck, trunk, upper, lower limbs), complexity (elementary vs. complex), content (scenic, violent, self-referential), vocal/orofacial features, spatial distribution and laterality using a pre-specified codebook. The patient was the primary unit of inference. Binary features used Fisher’s exact tests with Cohen’s h ; the per-patient complex-event proportion used Mann–Whitney and Cliff’s δ (bootstrap 95% CI). Robustness checks comprised Beta-Binomial posteriors (Beta [1,1]) and patient-label permutation tests (10,000 permutations). Results REM motor phenotypes diverged categorically. Lower-limb dominance occurred in 18/23 (78.3%) NT1-RBD vs. 7/34 (20.6%) iRBD (Fisher p < 0.0001; Cohen’s h ≈ +1.23), whereas upper-limb dominance occurred in 24/34 (70.6%) iRBD vs. 2/23 (8.7%) NT1-RBD ( p < 0.0001; h ≈ −1.40). Any complex event was present in 27/34 (79.4%) iRBD vs. 3/23 (13.0%) NT1-RBD ( p < 0.0001; h ≈ −1.46); violent enactments in 16/34 (47.1%) vs. 0/23 (0%) ( p < 0.0001; h ≈ −1.51). The per-patient complex-event proportion was higher in iRBD [median 0.21 (0.05–0.33)] than NT1-RBD [0.00 (0.00–0.00)] (Mann–Whitney p < 0.0001; Cliff’s δ = −0.665; 95% CI −0.853 to −0.441). Event-level summaries were concordant; permutation p -values were 0.0001 for upper-limb involvement and 0.0083 for complex behaviour. Conclusion iRBD and NT1-RBD exhibit qualitatively distinct REM motor phenotypes: upper-body-dominant, complex/scenic behaviours in iRBD versus elementary, predominantly bilateral lower-limb behaviours with notable trunk recruitment in NT1-RBD, supported by large effect sizes and convergent robustness checks. These findings motivate mechanistic studies of hypothalamic-brainstem-cortical integration in REM and suggest that semiological profiling may aid stratification in prodromal neurodegeneration.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.