Oskar Hansson’s research while affiliated with Skåne University Hospital and other places

INTRODUCTION Blood‐based biomarkers have demonstrated high accuracy for identifying Alzheimer's disease (AD) pathology. However, the lack of representative cohorts creates a knowledge gap regarding their real‐world applicability. We examined the influence of ethnicity on the diagnostic accuracy of plasma tau phosphorylated at threonine 217 (p‐tau217) in identifying AD. METHODS A total of 1170 mixed memory clinic patients originating from 91 different countries were included. Cerebrospinal fluid or amyloid positron emission tomography supplemented the diagnostic evaluation for 539 patients. Plasma was analyzed for p‐tau217. RESULTS Plasma p‐tau217 concentrations did not differ between ethnic groups, and there was no influence of ethnicity on the diagnostic accuracy of plasma p‐tau217. Plasma p‐tau217 demonstrated strong discriminative ability for AD and AD‐pathology in our ethnically diverse cohort. DISCUSSION Our study suggests that ethnicity does not influence the diagnostic accuracy of plasma p‐tau217. Nonetheless, medical conditions influencing plasma biomarkers may disproportionally affect minoritized groups because of social determinants of health. Highlights Plasma tau phosphorylated at threonine 217 (p‐tau217) was highly accurate in the identification of Alzheimer's disease. Geographic origin did not influence the precision of plasma p‐tau217. Kidney function may influence p‐tau217 concentrations. Representative inclusion in studies and trials should be a priority.

INTRODUCTION Positron emission tomography (PET) imaging with ligands for synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising methodology for measuring synaptic density in Alzheimer's disease (AD). We investigated associations between SV2A concentrations in the brain and cerebrospinal fluid (CSF). METHODS Twenty‐one participants with early AD and 7 cognitively normal (CN) individuals underwent [¹¹C]UCB‐J PET. We used a novel enzyme‐linked immunosorbent assay (ELISA) to measure CSF SV2A. Other synaptic and axonal proteins were also measured in CSF. RESULTS CSF SV2A was lower in AD compared to CN participants. Within the AD group, CSF SV2A was highly correlated with SV2A PET. By contrast, other CSF proteins were generally higher in participants with AD and not associated with SV2A PET. DISCUSSION We report a novel CSF assay for SV2A that is strongly correlated with the PET measurement of SV2A. Our results suggest that CSF SV2A may serve as a biomarker for synaptic density in AD. Highlights Synaptic vesicle glycoprotein 2A (SV2A) measured by a novel cerebrospinal fluid (CSF) enzyme‐linked immunosorbent assay (ELISA) was lower in participants with symptomatic Alzheimer's disease (AD). CSF SV2A was highly correlated with SV2A measured by positron emission tomography (PET) in participants with AD. Other CSF synaptic/axonal proteins were not significantly associated with SV2A PET. CSF SV2A may serve as a biomarker for synaptic density in AD.

Purpose Among visually Tau-PET-positive scans, large variation exists in the size of the visually tau-positive area. Here, we propose a metric quantifying the spatial extent of visual Tau-PET-positivity, termed “TAU-SPEX”, and evaluate associations with visual read status, neurofibrillary tangle (NFT) pathology at autopsy, and cognition. Methods [¹⁸F]flortaucipir data from 1,645 participants (aged 71.9 ± 8.2 years, 50.3% females) from four cohorts were visually read as positive or negative. TAU-SPEX was calculated as the percentage of gray matter voxels with suprathreshold Tau-PET uptake (using a threshold identical to that used for visual reading) in a spatially unconstrained whole-brain mask. We additionally computed Tau-PET SUVr in a whole-brain and temporal meta-region. We tested the performance of TAU-SPEX for distinguishing visually tau-negative from tau-positive participants and for distinguishing participants with and without NFT Braak-V/VI pathology at autopsy (n = 18), and tested associations of TAU-SPEX with concurrent and longitudinal cognition. The performance of TAU-SPEX was compared to SUVr. Results TAU-SPEX demonstrated strong performance in distinguishing tau-negative from tau-positive participants (AUC: 0.97). Moreover, TAU-SPEX showed high accuracy, sensitivity, specificity, positive predictive value and negative predictive value (all > 0.90) for identifying tau-positive participants, and showed high sensitivity (87.5%) and specificity (100.0%) for identifying participants with NFT Braak-V/VI pathology. TAU-SPEX was moderately associated with concurrent (β=-0.36 [-0.29, -0.43], p < 0.001) and longitudinal (β=-0.19 [-0.15, -0.22], p < 0.001) cognition. Across analyses, TAU-SPEX generally outperformed SUVr. Conclusion TAU-SPEX was strongly associated with visual read, NFT Braak-V/VI pathology and cognition, and might be useful in clinical settings as a potential adjunct to [¹⁸F]flortaucipir visual interpretation.

Recent years have seen major advances in tau‐associated brain disorders through interdisciplinary research spanning molecular biology, neuroimaging, clinical trials, and therapeutic development. The Tau2024 Global Conference, hosted by the Alzheimer's Association, CurePSP, and Rainwater Charitable Foundation, showcased these efforts by bringing together researchers and experts worldwide to discuss the latest advancements in tau research. The conference aimed to attract talent and funding to study tauopathies, particularly among early‐career researchers, and to foster interdisciplinary alignment and collaboration around challenges in tau research. In this manuscript, we summarize proceedings of the Tau2024 Global Conference, covering a wide range of topics, including lived experiences of individuals with genetic forms of tauopathies, global perspectives on tauopathies, and molecular mechanisms, brain microenvironments, biomarker developments, clinical trials, and therapeutic approaches to tauopathies. Through international, collaborative efforts, innovative research, and a commitment to inclusivity, researchers worldwide have demonstrated transformative breakthroughs toward diagnosing, treating, and, ultimately, preventing tau‐related diseases. Highlights The Tau2024 Global Conference presented updates and advances in tau research. Blood‐based biomarkers offer specificity and longitudinal monitoring capabilities. There are a range of targetable mechanisms in the cascade of pathogenesis. International collaboration is vital to address disparities in tauopathies.

Aging and Alzheimer's disease (AD) are associated with alterations in functional connectivity (FC), yet their spatial and temporal characteristics remain debated. Whole-cortex functional gradients, which organize regions along axes of functional similarity, are positioned here as a framework for understanding such alterations. Across two independent cohorts (BioFINDER-2, N=973; ADNI, N=129), we demonstrate that hyper- and hypoconnectivity in both healthy aging and biomarker-confirmed AD progression coexist systematically, forming consistent spatial patterns that align with two distinct axes of brain organization. Using a combination of longitudinal and non-linear analyses, we show that the early (but not late) stages of AD pathology accumulation is associated with functional alteration along the sensory-association axis, a pattern that vanishes in later stages of AD. However, functional alteration along the sensory-association axis is associated with worse cognition throughout the AD spectrum, and even in older adults without AD pathology, suggesting that these FC patterns may reflect a general neural response to cognitive strain. Independently of AD, older age was associated with alterations instead along the executive-nonexecutive axis, a finding that was consistent throughout the adult lifespan. These findings highlight the fundamental role of intrinsic functional organization in shaping how the brain responds to aging and to AD, helping to resolve previously reported discrepancies.

Importance While clinical disease stages remained largely unchanged in the 2024 update of the Alzheimer disease (AD) criteria, tau–positron emission tomography (PET) was introduced as a core biomarker and its spatial extent was incorporated into the revised biological stages of the disease. It is important to consider both the clinical and the biological stages and understand their discrepancies. Objective To compare individuals who have discrepant biological and clinical stages with those who have congruent stages in terms of copathologies, comorbidities, and demographics. Design, Setting, and Participants Participants were from the Swedish BioFINDER-2 (inclusion from 2017 through 2023) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (inclusion from 2015 through 2024). BioFINDER-2 included a prospective population-based (cognitively normal [CN] older adults) and memory clinic–based cohort (participants with subjective cognitive impairment [SCD], mild cognitive impairment [MCI], and dementia). ADNI included a volunteer-based sample. All participants who were amyloid-β positive and had undergone tau-PET were included. In BioFINDER-2, 838 participants of a total of 1979 were included, and of 927 with tau-PET in ADNI, 380 were included. Exposures The clinical (CN to dementia) and biological (based on PET; initial [amyloid-β-positive only] to advanced [amyloid-β-positive, elevated, and widespread tau]) stages from the revised AD criteria. Main Outcomes and Measures Cross-sectional measures of neurodegeneration (cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature, neurofilament light [NfL]), α-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics. Results There were 838 BioFINDER-2 participants (mean age, 73.9 [SD, 7.3] years; 431 women [51%]; 407 men [49%]) and 380 ADNI participants (average age, 72.9 [SD, 7.0] years; 194 women [51%]; 186 mean [49%]) included. In BioFINDER-2, 37.7% of the sample had congruent biological and clinical stages (reference group), 51.3% had more advanced clinical impairment compared with their clinical stage (clinical > biological) and 11.0% had the opposite (biological > clinical). The main differences were between the reference group and the clinical > biological group: the latter participants were more often positive for α-synuclein pathology, had higher NfL levels, greater TDP-43–like atrophy, and higher burden of cerebral small vessel disease lesions (all false discovery rate P < .05). The only difference between the biological > clinical and the reference group was that the former had less neurodegeneration (thicker cortex; all false discovery rate P < .001). The main results were replicated in the independent ADNI cohort, where congruent 56.1% of participants had biological and clinical stages; 36.1% were in the category clinical > biological, and 7.9% in biological > clinical. Conclusions and Relevance Copathologies play an important role in symptom severity in individuals who harbor less tau-tangle pathology than expected for their clinical impairment. These results highlight the importance of measuring non–AD biomarkers in patients with AD with worse cognitive impairment than expected based on their biological stage, which could impact the clinical diagnosis and prognosis.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

INTRODUCTION We evaluated differences in p‐tau levels between Alzheimer's disease (AD), a condition with brain‐specific changes in p‐tau, and amyotrophic lateral sclerosis (ALS), a condition associated with increases in peripheral p‐tau levels. METHODS Cerebrospinal fluid and plasma from 668 participants were analyzed using immunoassays specific for the low‐molecular‐weight (LMW) tau isoforms present in the brain (i.e., p‐tau217Lilly, p‐tau181Lilly) and those that detect both LMW‐ and high‐molecular‐weight (HMW) tau expressed in the peripheral nervous system (i.e., p‐tau217AlzPath, p‐tau181UGOT). RESULTS Increases in plasma p‐tau in ALS versus controls were significantly smaller for the LMW‐specific p‐tau assays (15.9%–20.5%) compared with non‐specific assays (92.0%–121.3%). The LMW‐specific p‐tau assays showed significantly larger plasma p‐tau increases in AD versus ALS, discriminating AD from ALS with areas under the curve (AUCs; 0.890.93) higher than the AUCs of the non‐specific assays (0.54–0.74). DISCUSSION LMW‐specific p‐tau assays could be more useful in the diagnostic workup of AD, especially in population‐based communities where conditions causing peripheral neuropathy are frequent. Highlights Increases in plasma phosphorylated tau (p‐tau) in amyotrophic lateral sclerosis (ALS) versus controls were significantly smaller for low‐molecular‐weight (LMW)–specific p‐tau assays (i.e., p‐tau217Lilly, p‐tau181Lilly) compared with p‐tau assays that also detect high‐molecular‐weight (HMW) assays (i.e., p‐tau217AlzPath, p‐tau181UGOT). The LMW‐specific p‐tau assays showed significantly larger increases in plasma p‐tau in AD versus ALS compared with the non‐specific assays. The LMW‐specific p‐tau assays discriminated AD from ALS with higher precision, showing significantly better performance than the non‐specific assays. LMW‐specific p‐tau assays could be more useful in the diagnostic workup of AD, especially in population‐based communities where conditions causing peripheral neuropathy (such as ALS) are frequent.

Background Recent advances now allow detection of brain‐specific proteins in blood, including neurofilament light chain (NfL), a marker of axonal pathology, and glial fibrillary acidic protein (GFAP), indicative of astrocytic activation. Given the evidence of astroglial pathology and neuronal dysfunction in bipolar disorder, and ongoing debates on neuroprogression, we investigated plasma NfL and GFAP levels in affected individuals. Methods This study analysed plasma NfL and GFAP measured in 216 individuals using Simoa. We used bootstrapped general linear models (GLM) to compare plasma NfL and GFAP levels between people with bipolar depression ( n = 120) and healthy controls ( n = 96), adjusting for age, sex, and weight. We examined associations between these biomarkers and clinical variables while adjusting for multiple comparisons. For sensitivity analyses, predictors were evaluated using Bayesian model averaging (BMA). Results Plasma GFAP ( β = 0.21 [0.07, 0.35], p = 0.006) and NfL ( β = 0.06 [0.01, 0.10], p = 0.028) were elevated in people with bipolar depression. Illness duration was positively associated with NfL ( r = 2.97, p = 0.002), and further supported by BMA analysis (posterior inclusion probability, PIP = 0.85). Age of onset was positively associated with GFAP ( r = 0.246 p = 0.041), which was also supported by BMA analysis (PIP = 0.67). Conclusions These findings indicate increased plasma NfL and GFAP levels in bipolar disorder. Our findings support the neuroprogression hypothesis, where prolonged illness duration contributes to neuroaxonal damage. Elevated GFAP in those with later onset suggests a role for neuroinflammation, potentially linked to increased cardiovascular and metabolic comorbidities.