Kaj Blennow

Alzheimer’s disease genetics converges on microglial and neuronal dysregulation

. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

Transient neurobiological responses to low-level blast during Swedish military special forces breacher training

Introduction Low-level blast (LLB) exposure is a recurring element of military breacher training, yet its biological and cognitive effects remain insufficiently understood. This study investigated the impact of real-world LLB exposure during scheduled breaching training in the Swedish Armed Forces. Methods 14 soldiers participated across two training weeks and underwent repeated assessments of blast exposure, neurocognitive performance and blood-based biomarkers of neurotrauma (tau, neurofilament light, neuron-specific enolase (NSE) and S100B). Blast overpressure was recorded using wearable sensors mounted on the head, chest and shoulder. Cognitive performance was assessed with the tablet-based Defense Automated Neurobehavioural Assessment test battery. Biomarker concentrations were analysed using Simoa and immunoassay platforms. Results Average blast exposure was low (mean peak 13–20 kPa (2–3 pounds per square inch (psi))), although considerable variability occurred depending on operational role and environmental conditions. All biomarkers showed significant fluctuations over time, with an initial increase following exposure. Except for NSE, biomarker levels declined towards baseline within days, suggesting transient physiological responses to LLB exposure. Cognitive results were inconclusive due to limited complete datasets; however, several reaction-time measures improved at follow-up, potentially reflecting training effects rather than blast-related changes. Conclusions The findings demonstrate measurable, but short-lived biomarker responses to realistic LLB exposure, with no clear evidence of cognitive impairment. Limitations include small sample size, uneven exposure levels and high dropout rates. Nevertheless, the study supports the feasibility of combining wearable blast sensors, fluid biomarkers and digital cognitive testing to evaluate blast-related neurobiological effects in operational training environments. The results also support recent guidelines suggesting that peak pressures below 4 psi represent a reasonably safe exposure level. While current exposure levels appear safe, further studies should examine cumulative effects, long-term trajectories and higher-exposure scenarios to refine safety guidelines and monitoring practices.

Correlation of blood biomarkers with microstructural brain injury in survivors of out-of-hospital cardiac arrest

In-hospital mortality among resuscitated out-of-hospital cardiac arrest (OHCA) patients remains high. Identifying patients who will benefit from intensive care while avoiding prolonged, potentially unnecessary treatments is essential. Blood-based biomarkers provide a novel method for evaluating brain injury. The ability of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), neuron-specific enolase (NSE) and total-tau (t-tau) to measure white and grey matter injury is unestablished in comatose OHCA survivors treated with targeted temperature management (TTM) or xenon combined with TTM. We examined correlations between the biomarkers and white and grey matter injury assessed with diffusion tensor imaging (DTI). This was a randomised, single-blind, phase 2 clinical drug trial involving two multi-purpose intensive care units in Finland. It was conducted between August 2009 and March 2015. One hundred and ten comatose OHCA patients aged 24 to 76 years were randomly assigned to either inhaled xenon treatment combined with 24-hour TTM (33°C) (n=55, xenon group) or TTM alone (n=55, control group). MRI data were available from 96 patients, with a median imaging time of 53 hours (interquartile range, 47-64 hours) after OHCA. Biomarker data were obtained from 105 patients. In the control group of 48 patients, after adjusting for age, sex and site, a disruption of white matter microintegrity as measured by decreased fractional anisotropy FA of DTI, the primary endpoint of the trial, showed a significant negative correlation with NfL at 24 h, 48 h and 72 h (ρ -0.28 – -0.37; p<0.05), NSE at 48 h and 72 h (ρ -0.30 – -0.35; p <0.05) and t-tau only at 72 h (ρ -0.30; p <0.05). In the xenon group (n = 48), these correlations were absent at all timepoints. The NfL–FA partial correlations showed progressive divergence between the xenon and control groups, with a statistically significant between-group difference observed at 72 h (ρ = −0.37 vs. ρ = 0.14; p = 0.016). Cortical or basal ganglia grey matter mean diffusivity did not have consistent correlation with biomarker levels at different time points. No statistically significant differences were found between the xenon and control groups in the adjusted geometric mean levels of GFAP, NfL, NSE, or t-tau at various time points following OHCA. In conclusion, NfL correlated with fractional anisotropy in controls but not in the xenon group. This between-group difference reached significance at 72 h, suggesting that xenon may modify the relationship between axonal injury and white matter microstructure after OHCA. Trial registration - clinicaltrials.gov identifier: NCT00879892

The second assessment of the commutability of candidate reference materials for the harmonization of blood neurofilament light chain measurements

Objectives Blood neurofilament light (NfL) is a sensitive biomarker of neuroaxonal injury, but substantial differences in absolute concentrations across analytical platforms underscore the need for assay standardization. This study aimed to evaluate the commutability of candidate reference materials (RMs) generated by spiking serum pools with cerebrospinal fluid (CSF) to support global assay harmonization. Methods The study included 45 individual clinical serum samples and 30 candidate RMs. The RMs comprised three serum pools, each combined with each of three CSF pools at three concentration levels, in addition to the three unspiked serum pools. Commercial NfL measurement procedures (MPs) from six manufacturers (Roche, Fujirebio, Meso Scale Discovery, Bio-Techne, UmanDiagnostics, and Quanterix) were evaluated. Commutability was assessed using a difference in bias approach. Results Spearman correlations between MPs were excellent (ρ=0.96–0.99), although regression slopes differed substantially, with differences up to a 46-fold. Across the 450 RM assessments, 62 % were classified as commutable, 37 % as indeterminate, and 0.66 % as non-commutable. Approximately two-thirds of the uncertainty in the difference in bias was attributable to MP imprecision rather than sample specific effects, suggesting that standardization of NfL measurements is feasible. Conclusions Spiking serum pools with CSF appears to be an effective strategy for consistently producing commutable RMs for NfL measurement. Although the relatively high proportion of indeterminate results indicates a need for improved MP precision or additional replicate measurements, the study supports continued development of SI-traceable reference materials to facilitate standardization of NfL measurements in clinical practice.

Sex differences in locus coeruleus structure and function across the adult lifespan: effects of APOE, Alzheimer’s disease pathology, and estrogen levels

The prevalence of Alzheimer’s disease (AD) is sex-dependent, with females at higher risk than males. While the locus coeruleus (LC) plays a critical role in early AD-related tauopathy, sex differences in LC structure and function remain poorly characterized in vivo in humans despite evidence from animal models. Here, we investigated sex differences in LC structural integrity and activity during an emotional arousal task, as well as the modifying effects of APOE genotype, plasma biomarkers of AD-related pathology, and estrogen levels across the adult lifespan. One hundred and one cognitively unimpaired participants aged 30-85 years were included. LC MRI signal intensity and LC activity were measured at 7T MRI, using dedicated LC MRI sequences, and functional MRI during an emotional arousal task, respectively. Blood samples were collected to measure levels of estradiol, estrone, AD-related plasma biomarkers (p-tau 217 , p-tau 181 , p-tau 231 , GFAP, NfL), and to determine APOE genotype. No overall sex differences were observed in LC MRI signal intensity or activity. Among APOE ε4 non-carriers, females exhibited higher LC MRI signal intensity than males, whereas this sex difference was absent in ε4 carriers. In addition, female ε4 carriers displayed lower LC MRI signal intensity than female ε4 non-carriers. In females, a higher estrone-to-estradiol ratio was associated with lower LC MRI signal intensity among participants older than approximately 56 years in our sample. Finally, females exhibited greater LC activity in response to emotional stimuli in the context of elevated p-tau 217 and GFAP levels compared to males. Our findings provide in vivo evidence that, in females, age-related estradiol decline and APOE carriership are associated with compromised LC structure, whereas greater LC activity is associated with higher AD plasma biomarker levels, supporting the LC as a target for sex-specific AD prevention strategies.

Locus coeruleus activity is related to sleep and 24-h rest-activity rhythms in the context of plasma Alzheimer’s disease markers: a 7T MRI study of older individuals

The brainstem locus coeruleus (LC), an early site of tau pathology and a key regulator of arousal and sleep-wake dynamics, has emerged as a potential neurobiological substrate underlying the relationship between sleep-wake disturbances and AD pathogenesis. Yet, the interplay between LC functional metrics, sleep-wake regulation, and early AD pathology remains poorly understood. Here, we investigated whether plasma AD-related biomarkers moderate the relationship between LC activity and objective sleep-wake measures in asymptomatic older individuals. Fifty-five cognitively unimpaired older adults underwent 10 days of actigraphy, blood drawing, and a daytime 7T MRI protocol including dedicated LC imaging and an affective visual task comprising high-arousing and low-arousing images. Arousal-based LC activity was determined by the high-versus-low-arousal (H > L) contrast. A subset of individuals ( n = 30) also performed three nights of at-home sleep EEG recordings. Plasma AD-related biomarkers included glial fibrillary acidic protein (GFAP) and tau phosphorylated at threonine 181 (ptau 181 ), 217 (ptau 217 ) and 231 (ptau 231 ). Interaction models adjusted for age, sex, BMI and device wear duration showed that, at higher levels of GFAP and several ptau markers, lower LC activation to the emotional stimuli during the task was related to shorter actigraphy-derived sleep duration, lower sleep efficiency (SE), and higher wake after sleep onset (WASO%). We observed similar patterns using 24-h rest–activity rhythm, such that, at higher burden of GFAP and several ptau markers, lower H > L LC was associated with higher intradaily variability (IV) and lower interdaily stability (IS). Examining sleep architecture, we showed that participants with lower LC activation to emotional stimuli during the task and higher burden of different ptau markers exhibited a higher proportion of time spent in N2 sleep stage, along with lower time spent in N3 sleep stage. Lower daytime task-related LC activity was related to shorter, lighter, and more fragmented sleep as well as to disruption of circadian rest-activity patterns in the presence of biomarker evidence of early AD pathology in asymptomatic older individuals. These findings suggest that LC dysfunction may aggravate, while preserved LC function may protect against early AD-related sleep-wake disturbances.

A centiloid-scaled crossover of amyloid and tau influences on plasma p-Tau217 along the Alzheimer’s disease continuum

Plasma p-tau217 reflects both amyloid and tau pathology, but the point at which its dominant association shifts from Aβ to tau remains unclear. We applied a sliding-window approach across three independent cohorts to determine where this transition occurs along the Centiloid continuum. Our analyses consistently identified a distinct inflection point at which plasma p-tau217 begins to track tau more strongly than Aβ. We analyzed data from three cohorts (K-ROAD, ADNI, and TRIAD), combining the ADNI and K-ROAD datasets for analyses because both cohorts used the same ALZpath p-tau217 assay technology and compatible PET quantification pipelines. To characterize how Aβ and tau differentially relate to plasma p-tau217, we performed partial Spearman correlations and a sliding-window analysis to identify the crossover point along the Centiloid continuum. Across all cohorts, plasma p-tau217 showed stronger overall partial correlations with Aβ uptake than with tau uptake. Sliding-window analyses further revealed a consistent crossover at approximately 39 Centiloids, at which the dominant association of plasma p-tau217 shifted from Aβ to tau. Our analyses converged on a transition point near 39 Centiloids, where the predominant pathological correlate of plasma p-tau217 shifted from Aβ to tau. This stage-dependent reversal aligns with the proposed intersection framework and provides empirical support for it.

Targeted proteomics reveal histiocytosis‐associated neurodegeneration signatures

Neurodegeneration (ND) is a severe complication of Langerhans cell histiocytosis (LCH), yet its underlying biology and reliable biomarkers remain poorly defined. The aim of this study was to (1) gain insight into neuroimmunological mechanisms governing ND and (2) assess the clinical value of established and novel biomarkers for ND-LCH. We applied targeted proteomics and neurofilament light chain (NFL) assays to cerebrospinal fluid (CSF) and plasma from LCH patients with and without ND, with control cohorts. ND-LCH exhibited a distinct CSF proteomic profile characterized by increased decoy receptors, including interleukin-1 receptor type 2 (IL-1RT2), macrophage activation markers, and cytotoxic and immunoregulatory proteins. CSF IL-1RT2 showed higher specificity for ND-LCH than CSF NFL (0.99 [0.99-1.0] vs. 0.88 [0.80-0.96]) and tracked longitudinal disease changes. Plasma analyses revealed a complementary immune signature in which NFL correlated with CSF markers, including IL-1RT2, and distinguished ND-LCH from controls. In independent plasma NFL cohorts from France and Japan, elevated levels were confirmed in adults with histiocytosis-associated ND. These findings define a neuroinflammatory signature of ND-LCH and identify IL-1RT2 as a novel candidate biomarker for diagnosis and monitoring.

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

Cohort study demonstrates that CSF p-tau205 tracks pathology and predicts dementia progression across the Alzheimer continuum, highlighting its utility for biological disease staging.

Neurofilament light chain for assessment of brain injury in four porcine cardiac arrest models

Background Anoxic brain injury is the leading cause of death following successful resuscitation after out-of-hospital cardiac arrest. No experimental neuroprotective therapy has translated into clinical benefit. Collaborative efforts to harmonize methods may be essential for translational success. Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury with emerging use in clinical practice, but data on its robustness and association with outcomes in porcine models is limited. Our aim was to use NfL as a quantitative marker to compare brain injury severity in different porcine cardiac arrest models. Methods Forty-four pigs ( Sus scrofa domestica ) were resuscitated after cardiac arrest in different experimental models in four laboratories. Plasma samples were collected prior to the arrest and at 4 and 24 hours after return of spontaneous circulation. NfL concentration was measured using a Single molecule array (Simoa) immunoassay. Results NfL levels changed significantly over time (p <0.001), with similar temporal patterns observed across all laboratories. Inter-laboratory comparisons indicated essentially consistent NfL levels, with modest differences at 24 hours. NfL levels at 24 hours showed an association with no-flow duration (n = 43) in both correlation and univariate regression analyses (p = 0.034, p = 0.041), while no significant associations were found with functional outcomes (n = 26) (p = 0.32, p = 0.20). Conclusion NfL increased consistently across four porcine cardiac arrest models, and higher 24-hour NfL levels were associated with longer no-flow duration, supporting its robustness as a biomarker of neuroaxonal injury. Larger studies are needed to clarify its relationship with functional outcome, as the exploratory analyses were underpowered.

The Association of Umbilical Cord Blood Neurofilament Light With Nonreassuring Fetal Status: A Prospective Observational Study

Prospective observational study evaluates cord blood neurofilament light in newborns with nonreassuring fetal status, suggesting its value as a sensitive biomarker for early neuronal injury.

Cerebrospinal fluid biomarkers reveal transdiagnostic synaptic dysfunction across major psychiatric disorders

Reveals synaptic pathology in psychiatric disorders, suggesting new diagnostic approaches.

Performance of Alzheimer Disease Plasma Biomarkers in Patients With Prion Diseases

Neurofilament light chain and glial fibrillary acidic protein as biomarkers of peripheral nervous system involvement in multiple sclerosis: diagnostic and prognostic evaluation

Retrospective study evaluates biomarkers for disease severity in multiple sclerosis, indicating diagnostic challenges due to polyneuropathy.

Circulating Metabolite Signatures Associated With Amyloid Positivity, Cognitive Performance and Plasma P-tau181 Levels in Cognitively Unimpaired Older Adults

Cross-sectional study uncovers altered lipid metabolites linked to amyloid positivity in cognitively unimpaired older adults, suggesting plasma biomarkers for preclinical Alzheimer disease.

Association of acute blood biomarkers with diffusion tensor imaging and outcome in patients with traumatic brain injury presenting with GCS of 13–15

• 92 mild TBI patients with biomarkers at admission and DTI ≥ 90 days post-injury. • Reduced white matter integrity associates with biomarkers in incomplete recovery. • Fractional anisotropy associates with interleukin 10 (IL-10) and tau. • Mean and radial diffusivity relate to IL-10, tau and glial fibrillary acidic protein. • Similar but non-significant trends were observed in the full and CT-positive cohorts. To assess the association between blood-based biomarkers of different cellular origins and later white matter integrity, measured using post-acute diffusion tensor metrics, and their relation to outcome in patients presenting with Glasgow Coma Scale of 13–15 after traumatic brain injury (TBI). Admission plasma samples for glial fibrillary acidic protein (GFAP), interleukin 10 (IL-10), heart fatty-acid binding protein (H-FABP), S100 calcium-binding protein B (S100B), total tau (T-tau), and amyloid beta 40 and 42 (Aβ40 and Aβ42) were taken for 92 patients. Diffusion-weighted magnetic resonance imaging (DW-MRI) and outcome evaluation was done ≥ 90 days post-injury. Outcome was assessed using Glasgow Outcome Scale-Extended (GOSE) and dichotomized as complete (GOSE 8) and incomplete (GOSE < 8) recovery. Mean fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the skeletonized WM tracts of the whole brain. IL-10 and T-tau showed significant weak-moderate negative correlations with FA, and significant positive correlations with MD and RD in incompletely recovered patients. GFAP showed significant weak positive correlations with MD and RD, while its correlation with FA was slightly below significance threshold after correction for multiple comparison in incompletely recovered patients. Similar trends were observed in the whole cohort and in the CT-positive cohort, although these did not reach statistical significance. Higher acute levels of GFAP, IL-10 and T-tau may be associated with the development of axonal injury. If validated in future studies, these biomarkers may help identify patients who require closer follow-up and DW-MRI.

DEC 2025AarslandNature

Prevalence of Alzheimer’s disease pathology in the community

Cohort study reveals Alzheimer's disease neuropathology increases sharply with age in older adults, suggesting higher dementia burdens in advanced age than previously estimated.

The relationship between CSF/serum immunoglobulin and albumin ratio across laboratories: a retrospective, multi-center study

BACKGROUND: The relationship between cerebrospinal fluid (CSF)/serum immunoglobulin (Ig) ratios (QIg) and CSF/serum albumin ratio (Qalb) is a commonly used biomarker in routine CSF diagnostics. It is used to quantitatively determine the presence of an intrathecal Ig synthesis, which is important for the diagnosis of various inflammatory neurological diseases. Which approach to describe the relationship between Qalb and QIg should be applied has been a matter of debate for decades. OBJECTIVE: To compare different linear and non-linear models to determine which model fits the relationship between QIgG, QIgA, QIgM and Qalb best. METHODS: We included CSF and serum sample pairs collected for routine diagnostic purpose across seven sites of patients without evidence of intrathecal Ig synthesis (defined by negative oligoclonal IgG bands and the condition QIgG > QIgA > QIgM, respectively). Linear, quadratic, cubic, root and power models were fitted for the mean relationship between QIgG, QIgA, QIgM and Qalb, as well as to determine the 97.5th percentile as upper limit of normal (ULN). Model fit was evaluated by various goodness-of-fit measures including mean absolute error (MAE) and the mean percentage error (MPE). RESULTS: A total of 22,207 patients at a median age of 49 (2.5th, 97.5th percentile: 10, 82) years comprising 52% females were included. The median Qalb was 5.8 × 10−3 (2.4 × 10−3, 23 × 10−3), QIgG 3.0 × 10−3 (1.2 × 10−3, 13.4 × 10−3), QIgA 1.7 × 10−3 (0.6 × 10−3, 9.5 × 10−3) and QIgM 0.6 × 10−3 (0.2 × 10−3, 6.0 × 10−3). The goodness-of-fit measures for the mean relationship between QIgG and Qalb were similar across models [maximum difference in MAE (ΔMAE) between models was 0.01 × 10−3, in MPE (ΔMPE) 0.3 percentage points (pp)], but showed higher differences for QIgA [ΔMAE: 0.03 × 10−3, ΔMPE: 3 pp] and even higher for QIgM [ΔMAE: 0.08 × 10−3, ΔMPE: 18 pp] in favor of non-linear models. Similar findings were obtained for ULN (ΔMPE: QIgG 3 pp; QIgA 7 pp; QIgM 13 pp) again in favor of non-linear models. DISCUSSION: Linear and non-linear models can be used to approximate the relationship between QIgG and Qalb. Non-linear models explain the relationship between QIgA, QIgM and Qalb. Appropriate Qalb-dependent ULN for QIgG, QIgA, QIgM based on power model and quantile regression are provided.

Integrative analysis of AT classification, plasma biomarkers, and cognitive trajectories across diverse dementia syndromes

This study reveals cognitive decline trends in dementia, highlighting mixed-effects models and plasma biomarkers across different cognitive impairment types.

Plasma soluble TREM2 is associated with plasma pTau-181 and pTau-231 in cognitively normal older adults at risk of Alzheimer's disease

Investigation reveals positive correlations of plasma sTREM2 with tau biomarkers in cognitively normal adults, indicating implications for early Alzheimer's disease detection.