Kaj Blennow’s research while affiliated with Paris Brain Institute, French National Centre for Scientific Research and other places

INTRODUCTION Cognitively unimpaired (CU) amyloid beta (Aβ)+ individuals with elevated plasma glial fibrillary acidic protein (GFAP) have an increased risk of Alzheimer's disease (AD)‐related progression. We tested the utility of plasma GFAP for population enrichment CU populations in clinical trials. METHODS We estimated longitudinal progression, effect size, and costs of hypothetical clinical trials designed to test an estimated 25% drug effect on reducing tau positron emission tomography (PET) accumulation in the medial temporal lobe (MTL) and temporal neocortical region (NEO‐T). RESULTS CU GFAP+/Aβ+ individuals present an increased annual rate of change and effect size in tau PETMTL and tau PETNEO‐T compared to the other groups. An enrichment strategy selecting CU GFAP+/Aβ+ individuals would require a smaller sample size (≈ 57% reduction) and fewer Aβ PET scans (≈ 74% reduction) than trials enriched with Aβ PET alone, reducing total clinical trial costs by up to 64%. DISCUSSION Our results suggest that clinical trials focusing on preclinical AD recruiting Aβ+ individuals with elevated GFAP levels would improve cost effectiveness. Highlights Cognitively unimpaired (CU) glial fibrillary acidic protein (GFAP)+/amyloid beta (Aβ)+ shows increased changes in tau positron emission tomography (PET) . CU GFAP+/Aβ+ enriched clinical trials require a reduced sample size compared to Aβ+ only. CU GFAP+/Aβ+ enrichment reduces Aβ PET scans required and costs. CU GFAP+/Aβ+ enrichment allows the selection of individuals at early stages of the Alzheimer's disease continuum.

Background Cerebral complications of pre-eclampsia are a leading cause of maternal mortality. Better understanding of the pathophysiology may enable the development of novel strategies to protect the maternal brain. We aimed to investigate blood-brain barrier injury and neuroinflammatory pathways in women with eclampsia and pre-eclampsia compared to normotensive pregnancies. Methods This observational cross-sectional study conducted between March 2021 and June 2023, included women with eclampsia, pre-eclampsia, and normotensive pregnancies admitted to Tygerberg Hospital, Cape Town, South Africa who underwent caesarean delivery. Cerebrospinal fluid and plasma samples were collected during caesarean delivery. Blood-brain barrier injury was assessed using immunonephelometry for albumin and ELISA assays for claudin-5 and matrix metalloproteinase-9 (MMP-9). Neuroinflammatory markers were analysed on the multiplex Bio-Plex Pro Human Cytokine-Screening assay. Data were analysed using parametric methods after log transformation and are presented as fold changes (geometric mean ratios) between groups. Findings The study included 129 women: Eleven had eclampsia, 17 had pre-eclampsia with end-organ complications, 88 had pre-eclampsia without end-organ complications, and 13 with normotensive pregnancies. Women with eclampsia had increased cerebrospinal fluid concentrations of claudin-5 (2.7-fold, 95% CI 1.4–5.1, p = 0.002 vs normotensive control) and MMP-9 (2.5-fold, 95% CI 1.1–5.3, p = 0.024 vs pre-eclampsia with end-organ complications). They also demonstrated increased cerebrospinal fluid cytokine levels compared to normotensive controls, reflecting inflammatory recruitment (Interleukin-8: 7.2-fold, 95% CI 2.7–18.5, p < 0.001), cytotoxicity (Interleukin-6: 20.7-fold, 95% CI 6.4–63.6, p < 0.001), and immune modulation (Interleukin-10: 2.0-fold, 95% CI 1.2–3.1, p = 0.004). Neuroprotective markers were reduced in eclampsia (stem cell factor: 0.5-fold, 95% CI 0.3–0.8, p = 0.005) compared to normotensive controls. There was no correlation between cytokine concentrations in the cerebrospinal fluid and plasma. Women with pre-eclampsia showed less pronounced changes indicative of blood-brain barrier injury and immune modulation. Interpretation Eclampsia is associated with blood-brain barrier injury and acute neuroinflammation originating from cerebral tissue, inducing cytotoxicity. This may be an underlying mechanism for seizures and cerebral injury in eclampsia and pre-eclampsia.

Background Patients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The objective was to analyse whether plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau231 (p-Tau231) are elevated in patients with CKD and to identify independent predictors of these biomarkers, with an emphasis on the role of measured glomerular filtration rate (mGFR). Methods In this cross-sectional cohort study, we included 110 patients with CKD stages 3 and 4 (estimated GFR 15–59 ml/min/1.73 m²) without manifest cerebrovascular disease or dementia, and 55 healthy controls. Biomarkers of neurological disorders were measured with ultrasensitive single molecule array methods. Results Plasma concentrations (median [IQR]) of NfL (37.5 [22.1–47.5] vs. 13.4 [10.5–16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1–38.7] vs. 13.9 [10.5–16.3] ng/L, p < 0.001) and GFAP (190 [140–281] vs. 153 [116–211] ng/L, p < 0.001) were elevated in patients with CKD vs. controls. Measured GFR was negatively correlated with NfL (r = − 0.706, p < 0.001), p-Tau231 (r = − 0.561, p < 0.001), and GFAP (r = − 0.385, p < 0.001). In multivariable linear regression models, mGFR was an independent predictor of log-transformed plasma concentrations of NfL (standardized beta coefficient [β] = − 0.439, p < 0.001) and GFAP (β = − 0.321, p < 0.001). Conclusion Patients with CKD had elevated plasma concentrations of NfL, p-Tau231 and GFAP compared with controls, and these biomarkers were inversely correlated with mGFR. Measured GFR was a significant, independent predictor of plasma concentrations of NfL and GFAP in patients with CKD. The mechanisms underlying this association need further investigation. Plasma levels of NfL and GFAP should be interpreted cautiously in patients with marked reductions in GFR.

INTRODUCTION Neuroinflammation may have sex‐specific effects on white matter injury and impact the development of dementia. METHODS Human chitinase‐3‐like protein‐1 (YKL‐40) concentrations at baseline were related to white matter hyperintensity (WMH) volume, free water (FW), and FW‐corrected fractional anisotropy using linear effects models (for cross‐sectional outcomes) and linear mixed‐effects models (for longitudinal outcomes), adjusting for demographic and medical risk factors. Models were repeated with a sex‐interaction term and then stratified by sex. RESULTS In stratified analyses, greater baseline YKL‐40 concentrations were associated with increased WMHs in females but not males in the parietal (females p = 0.04; males p = .34) and temporal lobes (females p = 0.005; males = p = 0.71) longitudinally. YKL‐40 associations with FW and FW‐corrected fractional anisotropy were null. DISCUSSION Results suggest that neuroinflammation is a sex‐specific driver of WMHs (but not FW) in females. Differential sequelae of neuroinflammation may be one reason that females have a greater burden of WMHs. Highlights ·Cerebrospinal fluid YKL‐40 is associated with white matter hyperintensities in females but not males cross‐sectionally and longitudinally. ·Longitudinally, cerebrospinal fluid YKL‐40 is associated with white matter hyperintensities in the parietal and temporal lobes, regions that exhibit early pathological changes in Alzheimer's disease . ·Cerebrospinal fluid YKL‐40 is not associated with white matter microstructural measures.

Background While the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer’s disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted ‘X’ in the ATX(N) framework, remain poorly understood. Methods Using an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF proteins across the AD continuum in three independent cohorts, finely staged by Aβ/tau positron emission tomography (PET), fluid biomarkers, or brain biopsy. Weighted protein co-expression network analysis identified clusters of proteins robustly correlating in all three cohorts which sequentially changed with AD progression. Obtained protein clusters were correlated with fluid biomarker measurements (phosphorylated tau (p-tau) species including p-tau 181 , p-tau 217 , and p-tau 205 , as well as Aβ), Aβ/tau PET imaging, and clinical parameters to discern disease-relevant clusters which were modelled across the AD continuum. Results Neurodegeneration-related proteins (e.g . , 14–3-3 proteins, PPIA), derived from different brain cell types, strongly correlated with fluid as well as imaging biomarkers and increased early in the AD continuum. Among them, the proteins SMOC1 and CNN3 were highly associated with Aβ pathology, while the 14–3-3 proteins YWHAZ and YWHAE as well as PPIA demonstrated a strong association with both Aβ and tau pathology as indexed by PET. Endo-lysosomal proteins (e.g., HEXB, TPP1, SIAE) increased early in abundance alongside neurodegeneration-related proteins, and were followed by increases in metabolic proteins such as ALDOA, MDH1, and GOT1 at the mild cognitive impairment (MCI) stage. Finally, later AD stages were characterized by decreases in synaptic/membrane proteins (e.g., NPTX2). Conclusions Our study identified proxies of Aβ and tau pathology, indexed by PET, (SMOC1, YWHAE, CNN3) and highlighted the dynamic fluctuations of the CSF proteome over the disease course, identifying candidate biomarkers for disease staging beyond Aβ and tau.

The adaptive immune system and neurodegenerative Alzheimer’s disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, ex vivo T-cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards β-amyloid peptide and display an early enrichment of CD8+ T effector memory cells re-expressing CD45RA (TEMRA cells) in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T-cells. Conversely, in MCI we observed increased frequencies of CD8+ TEMRA/effector cells in the periphery characterized by a pro-inflammatory gene expression profile, and generally decreased antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial to promote specific CD4+ T-cell responses in the preclinical stage, while in MCI it may be important to therapeutically target CD8+ T-cell responses if these prove to be harmful.

Importance As amyloid-targeted therapies have become commercially available, the monitoring of cerebral amyloid angiopathy (CAA), which is an important risk factor for amyloid-related imaging abnormalities, has received increasing attention. However, comprehensive evidence on the association between Alzheimer disease (AD) plasma biomarkers and various CAA imaging markers is still lacking. Objective To examine the association of CAA imaging markers with downstream AD plasma biomarkers in relation to amyloid-β (Aβ) uptake on positron emission tomography (PET) and whether their interplay is associated with cognitive changes. Design, Setting, and Participants This registry-based cohort study in 25 hospitals across South Korea recruited participants aged 45 years or older who were registered between January 1, 2016, and December 31, 2023. Participants were categorized as having no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type. Exposures Cerebral amyloid angiopathy imaging markers assessed by magnetic resonance imaging, including cerebral microbleeds (CMBs), cortical superficial siderosis, white matter hyperintensities, lacunes, and enlarged perivascular spaces. Main Outcomes and Measures Plasma phosphorylated tau-217 (p-tau217) was measured using a commercial assay. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were measured using a single-molecule assay on a single platform. All participants underwent amyloid PET imaging. Associations of CAA and vascular imaging markers with downstream AD plasma biomarkers were investigated using linear regression. Results A total of 1708 participants were included (mean [SD] age, 71.2 [8.4] years; 1044 female [61.1%]). The mean (SD) follow-up period was 4.3 (3.1) years. Lobar CMB counts and the presence of CAA were associated with downstream AD plasma biomarkers, including p-tau217 (β = 0.12 [95% CI, 0.05-0.18] and 0.29 [95% CI, 0.12-0.47], respectively), GFAP (β = 0.07 [95% CI, 0.03-0.12] and 0.20 [95% CI, 0.09-0.31], respectively), and NfL (β = 0.07 [95% CI, 0.03-0.11] and 0.16 [95% CI, 0.06-0.25], respectively) with and without the mediation of Aβ uptake on PET (indirect effect: lobar CMBs–p-tau217, 59.8% [β = 0.07 (95% CI, 0.03-0.11)]; lobar CMBs-GFAP, 49.3% [β = 0.04 (95% CI, 0.01-0.06)]; lobar CMBs-NfL, 20.9% [β = 0.01 (95% CI, 0.01-0.03)]; CAA–p-tau217, 50.9% [β = 0.15 (95% CI, 0.06-0.24)]; CAA-GFAP, 39.2% [β = 0.08 (95% CI, 0.03-0.13)]; CAA-NfL, 19.2% [β = 0.03 (95% CI, 0.01-0.05)]). Amyloid-β uptake fully mediated the associations between cortical superficial siderosis and downstream AD plasma markers. In contrast, hypertensive arteriosclerotic vascular imaging markers, including lacunes, deep CMBs, and enlarged perivascular spaces in basal ganglia, were associated with only NfL levels (β = 0.07 [95% CI, 0.01-0.13], 0.20 [95% CI, 0.08-0.32], and 0.14 [95% CI, 0.06-0.23], respectively), regardless of Aβ uptake on PET. Finally, there were interactive associations of lobar CMBs in conjunction with p-tau217 levels (β = −0.56 [95% CI, −0.79 to −0.34]) and GFAP levels (β = −0.44 [95% CI, −0.70 to −0.17]) with annual Mini-Mental State Examination changes. Conclusions and Relevance In this cohort study of participants with no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type, a novel association was found among CAA imaging markers, downstream AD plasma biomarkers, and cognitive declines in relation to brain Aβ burdens. The findings emphasize the importance of understanding the clinical effects of amyloid-related imaging abnormality–like CAA imaging markers in light of upcoming amyloid-targeted therapies.

Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day. In this crossover design, 16 normal-weight, healthy men underwent three highly standardized in-lab nights of SR (4.25 h/night) and normal sleep (NS, 8.5 h/night) in randomized order, with 88 CVD blood protein biomarkers quantified using the Olink technology (and selected validation using ELISA) in the morning, evening, and immediately before and repeatedly after 30 min of high-intensity exercise. We found significant time-of-day-dependent changes in several CVD biomarkers. Whereas several proteins were exercise-induced across sleep conditions (such as the canonical exerkines IL- 6 and BDNF), exercise-induced proteomic dynamics differed in response to recurrent SR, compared with following NS. Moreover, SR compared with NS resulted in a biomarker profile previously associated with increased prospective risk of several CVDs across large-scale cohorts (such as higher circulating levels of IL-27 and LGALS9). Our findings highlight how dynamic physiology can modulate CVD biomarker levels. These results also underscore the need to consider sleep duration as a key determinant of cardiovascular health—an emphasis reflected in recent American Heart Association guidelines. Further studies in women, older individuals, and patients with prior CVD, and across different chronotypes and dietary schedules are warranted.

INTRODUCTION To understand the role of neuroinflammation in Alzheimer's disease (AD), we characterized immune‐related proteins in central and peripheral biofluids. METHODS Selection of participants from the Translational Biomarker of Aging and Dementia (TRIAD) cohort with available translocator protein (TSPO) positron emission tomography (PET), cerebrospinal fluid (CSF) (n = 97), and plasma (n = 165). Biofluid samples analyzed with Olink technology (368 inflammation proteins). RESULTS Elevated proteins levels in CSF of TSPO‐positive individuals were identified. Functional enrichment analysis of CSF proteins revealed processes implicated in AD (MAPK, ERK cascades, cytokine, and leukocyte signaling). Selected candidates (CXCL1 and TNFRSF11B) showed high correlation with each other in CSF and with TSPO PET signal, but weaker associations with amyloid and tau PET. No significantly changed proteins in plasma between TSPO groups were found. DISCUSSION This explorative study identified two potential targets in CSF showing correlations with TSPO, amyloid and tau PET, suggesting a direct link between neuroinflammation, expression of these proteins and their potential implication in AD. Highlights Several proteins are elevated in CSF of TSPO PET‐positive individuals, linking them to neuroinflammation. Elevated CSF proteins were enriched in pathways such as MAPK, ERK, and cytokine signaling, linking them to the AD pathophysiology. Candidate proteins (CXCL1 and TNFRSF11B) correlated strongly with TSPO PET, particularly in brain regions known to be affected in AD. Although none of the plasma proteins remained significant after multiple comparisons correction when comparing their expression between TSPO groups, as done for CSF, candidate CSF proteins were found to correlate with plasmatic proteins, highlighting the complexity of the immune system.

Importance The defining pathological features of Alzheimer disease (AD) may also be contributing factors in other dementias. Objective To examine the prevalence of β-amyloid (Aβ) and tau pathophysiological changes as indicated by cerebrospinal fluid biomarkers, as well as their association with clinical disease progression, across a broad range of dementias. Design, Setting, and Participants In this cross-sectional study with a duration of 12 years (October 5, 2010, to August 31, 2022), clinical data from the Swedish registry for cognitive disorders and dementia (SveDem) were merged with clinical routine biomarker measurements of the core cerebrospinal fluid biomarkers of AD: Aβ1-42, total tau (t-tau), and phosphorylated tau 181 (p-tau181). Participants were individuals with a dementia diagnosis who had a complete set of cerebrospinal fluid Aβ1-42, t-tau, and p-tau measurements registered less than 3 years after the date of diagnosis. Data were analyzed from April to November 2023. Exposures Age, sex, and dementia diagnosis. Main Outcomes and Measures Biomarker profiles in relation to diagnosis and cognitive status as indicated by Mini-Mental State Examination (MMSE) scores. Results Among 15 004 individuals with a dementia diagnosis in the SveDem database, 13 882 were included in this study (7328 females [53%], 6554 males [47%]; median [IQR] age, 74 [68-79] years). Apart from the AD groups (early-onset AD, 1150 [68%]; late-onset AD, 3392 [65%]; mixed AD and vascular dementia, 1038 [52%]), the dementia not otherwise specified group had the most patients (443 [25%]) with a clear AD-like biomarker profile, while Parkinson disease dementia and the frontotemporal dementia groups had the smallest shares (15 [9%] and 51 [8%], respectively). MMSE score was associated with cerebrospinal fluid Aβ1-42 in late-onset AD, vascular dementia, frontotemporal dementia, and dementia not otherwise specified; with t-tau in late-onset AD, early-onset AD, and dementia not otherwise specified; and with p-tau181 in early-onset AD. Conclusions and Relevance Aβ-related pathology is a defining feature of AD, and most patients clinically diagnosed with AD have biomarker evidence of this process, but the same is found in other dementias, although less commonly. Cerebrospinal fluid biomarker concentrations of AD-like pathology were associated with cognitive function but mainly in patients with an AD-related diagnosis (early- and late-onset AD).