H. Zetterberg

Plasma p-tau217 and NfL predict incident dementia in the community

Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis.

Importance Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. Objective To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). Design, Setting, and Participants This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Exposures Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Main Outcomes and Measures Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). Results The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. Conclusions and Relevance In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.

CSF complement proteins are associated with early tau pathology and synaptic damage in an asymptomatic population at risk of Alzheimer’s disease

Complement-mediated neuroinflammation has been implicated in Alzheimer’s disease (AD), but its role during the pre-symptomatic phase of the disease remains unclear. In the PREVENT-AD cohort of cognitively unimpaired individuals at increased familial risk of AD, we investigated whether CSF complement proteins relate to early AD pathology and synaptic dysfunction, then assessed our results’ reproducibility across the clinical AD spectrum. Baseline CSF C1q, C3, C3b, and Factor H were measured in relation to CSF AD biomarkers, synaptic proteins, cognition, MRI volumetry, and amyloid and tau PET. Key findings were then examined in 708 participants from ADNI spanning cognitively normal, mild cognitive impairment (MCI), and dementia stages of AD. In PREVENT-AD, C1q was positively associated with CSF P-tau181, T-tau, and multiple synaptic markers including ADAM23, GAP43, SNAP25, and SYT1. Factor H showed similarly strong positive associations with P-tau181, T-tau, ADAM22, ADAM23, GAP43, and SYT1. By contrast, C3 showed minimal associations, while C3b displayed weaker positive relationships with P-tau181, T-tau, ADAM22, and ADAM23. Complement proteins were not robustly associated with amyloid or tau PET, and only C1q related to lower global cognitive performance. In ADNI, C1q emerged as the most consistent analyte, showing positive associations with tau, neurofilament light, and synaptic markers across all diagnostic groups. C3 exhibited predominantly negative associations, whereas C3b and Factor H showed stage-dependent relationships, particularly with evident neurodegeneration and synaptic injury in symptomatic individuals. These findings identify complement dysregulation, especially involving C1q, as an early correlate of tau-linked synaptic pathology, and support a role for complement activation in the AD molecular cascade.

Orexin, Sleep, and Cognition in Alzheimer Disease

Background and Objectives Sleep-wake dysregulation and elevated CSF orexin have been implicated in Alzheimer disease (AD). Sleep spindles (SPs) and slow oscillations (SOs) are linked to cognition and neurodegeneration; however, their relationship with CSF orexin concentrations in symptomatic AD has not been characterized. We investigated whether nonrapid eye movement (NREM) SP-SO activity is associated with CSF orexin and whether these oscillatory features moderate associations between orexin, cognition, neuropsychiatric symptom severity, and AD biomarkers. Methods This prospective observational cohort study was conducted at a tertiary memory clinic in Lleida, Spain. Individuals aged ≥60 years with biomarker-confirmed mild-to-moderate AD (National Institute on Aging-Alzheimer's Association criteria) underwent overnight polysomnography and morning CSF sampling. SP and SO were detected using validated automated algorithms with independent verification and visual quality control. CSF was assayed for orexin-A, amyloid-β42 (Aβ42), phosphorylated tau181 (pTau181), total tau, and YKL-40. Cognitive performance Alzheimer’s Disease Assessment Scale–Cognitive Subscale ([ADAS-Cog], Mini-Mental State Examination (MMSE), California verbal learning test, ROCF) and neuropsychiatric symptoms (NPI) were assessed longitudinally over 36 months. Associations were examined using generalized linear models with robust estimators adjusted for age, sex, Aβ42, and apnea-hypopnea index. Multiple comparisons were controlled using false discovery rate correction. Interaction terms assessed moderation effects. Results Sixty participants (30 women; mean age 74.7 years) were included. Longer SO duration and higher SP density and power were associated with lower CSF orexin concentrations (SP density: β = −187.37 pg/mL, 95% CI −344.93 to −29.80). Orexin was not associated with global sleep continuity metrics. Higher CSF orexin concentrations were associated with worse global cognition (ADAS-Cog: β = 0.014, 95% CI 0.003–0.024; MMSE: β = −0.01, 95% CI −0.011 to −0.004) and greater neuropsychiatric symptom severity (NPI at: β = 0.03, 95% CI 0.011–0.041). Higher orexin was also associated with higher pTau181 (β = 0.11, 95% CI 0.04–0.19), total tau, and YKL-40 (β = 0.37, 95% CI 0.17–0.57). Significant orexin × SP-SO interactions were observed, such that greater oscillatory activity attenuated the adverse associations between orexin and cognitive outcomes, independent of Aβ42 and tau. Discussion In biomarker-confirmed AD, NREM SP and SO activity are associated with CSF orexin concentrations and moderate associations between orexin and longitudinal cognitive and neuropsychiatric outcomes. Limitations include the observational design and absence of a comparator group, precluding causal inference and limiting contextualization relative to normal aging. NREM oscillatory metrics and orexin concentrations may represent complementary physiologic markers for disease monitoring and therapeutic targeting. Trial Registration Information Role of Hypoxia and Sleep Fragmentation in AD; ClinicalTrials.gov Identifier: NCT02814045.

CSF p-tau205: a biomarker of Alzheimer's disease progression and biological staging.

Among soluble tau biomarkers, tau phosphorylation at position T205 (p-tau205) has been suggested to distinctly emergence across Alzheimer's disease (AD) continuum compared to other p-tau and non-phosphorylated tau forms, and a moderate relationship with both amyloid-β and tau aggregated pathologies. To evaluate this and further expand the characterization of this biomarker, we measured cerebrospinal fluid (CSF) p-tau205 using an in-house developed immunoassay in a total of 2069 samples from the BioFINDER-2 (n = 1364) and BioFINDER-1 (n = 705) cohorts. These two cohorts spanned the full AD continuum and were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, baseline p-tau205 levels correlated with Aβ-PET (R² = 0.28), tau-PET (medial temporal: R2 = 0.35, neocortical: R² = 0.29), cortical atrophy (R² = 0.15) and cognition (MMSE, R² = 0.15). Baseline p-tau205 predicted subsequent Aβ accumulation (R² = 0.44) and tau-accumulation measured by PET (R² = 0.33). Longitudinal p-tau205 levels increased more steeply longitudinally in Aβ-positive than Aβ-negative participants (β[95%CI] = 0.16[0.12-0.21], p < 0.001). Longitudinal p-tau205 changes were associated with cortical thinning (R² = 0.32) and cognitive decline (R² ≥ 0.41). When incorporating Aβ42/40, p-tau217 and p-tau205 into a conceptual CSF-based staging model, the final p-tau205-positive stage showed the strongest association with cortical atrophy, cognitive impairment, and risk of progression to dementia (HR = 6.40[4.28-9.59]). These findings support CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging.

The neuropathy-causing GARS1ΔETAQ mutation drives pathology in subsets of motor and sensory neurons in mice

Together, these experiments show that GarsΔETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability.

CSF and plasma tau biomarkers in the Down syndrome–Alzheimer’s disease continuum

These findings highlight the complementary roles of CSF and plasma tau biomarkers in tracking disease progression: CSF biomarkers capture early pathological changes, whereas plasma biomarkers more effectively reflect disease progression within symptomatic stages.

Performance of Alzheimer Disease Plasma Biomarkers in Patients With Prion Diseases

This study provides Class II evidence that plasma NfL/p-tau217 discriminates patients with CJD from those with AD and Diagnosing AD with a single abnormal p-tau plasma biomarker risks misdiagnosing prion diseases as AD.