Biology subjects

Mattsson-Carlgren, N.

Publications and source records attributed to Mattsson-Carlgren, N..

12 recordsLinked to original sources

bioRxiv2026

A coordinated and reproducible multicellular response to AD pathology

While single-cell measurements of the Alzheimer's disease (AD) brain allow investigation of vulnerable cells in unprecedented depth, reported findings are heterogeneous, mostly descriptive and often ignore interdependence of cellular responses. Operationalization of these findings requires a multi-cellular model of AD that is robust and reproducible. Here, we utilize a coordinated multicellular community approach across 2.3 million nuclei from 427 ROSMAP donors to identify robust multicellular axes associated with AD pathology and sex. The AD signature comprised profound alteration to RORB-GABRG excitatory neurons and disrupted oligodendrocyte precursor cell signaling. A separate set of AD-related cell-type specific molecular processes with strong sexual dimorphism also emerged. Importantly, these signatures developed and ROSMAP predicted neuropathology and sex, respectively, in a completely independent dataset (SEA-AD). These findings altogether summarize a highly consistent multi-cellular response to AD pathology in the human brain, creating a baseline cellular model to which perturbation and treatment experiments can be compared.

neuroscience↗

bioRxiv2026

Stable episodic memory and high education do not influence the rate of Alzheimer's disease pathology as measured by plasma p-tau217

Alzheimers disease (AD) neuropathological changes can be detected with blood-based biomarkers during the long preclinical phase that precedes clinical diagnosis. Tau phosphorylated at threonine 217 (p-tau217) has been found to closely correlate with brain A{beta} burden. A recent large-scale cross-sectional study showed elevated p-tau217 concentrations in older individuals (Aarsland et al., 2025). This increase was higher in those with AD dementia and mild cognitive impairment (MCI), and lower in those with intact cognition and higher educational attainment. Thus, intact cognition and higher education may be associated with lower levels of AD neuropathological changes. Here we tested this hypothesis using longitudinal data from the population-based Betula study (n=1005; 1531 samples). The results revealed increases with increasing age over 10 years in p-tau217, where individuals with accelerated episodic-memory decline had the strongest increase. There were no differences in p-tau217 trajectories between individuals with lower or higher education or with well-maintained or age-typical decline in episodic memory. The lack of association with education was further replicated in the independent BioFINDER-2 cohort. These findings underscore the value of plasma p-tau217 for detecting early pathological changes in population-based settings but provide no support that individuals with well-maintained episodic memory or high educational attainment are spared from neuropathological changes.

neuroscience↗

bioRxiv2026

Dynamical Aβ-Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression

Alzheimers disease is characterised by the pathological interaction of two proteins, amyloid-beta (A{beta}) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of A{beta}, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of A{beta}, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of A{beta} and tau, network-based tau propagation, A{beta}-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional A{beta}, tau, and neurodegeneration data. Using the dATN model, we show that A{beta}-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of A{beta} and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting A{beta}, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD. One Sentence SummaryColocalisation of A{beta} and tau predicts regional tau progression and optimal A{beta}-targeted intervention windows, while tau predicts neurodegeneration.

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bioRxiv2025

Patient-specific functional brain architecture explains cortical patterns of tau PET in Alzheimer's disease

The spatial distribution of tau pathology, a key correlate of neurodegeneration and cognitive decline in Alzheimer's disease (AD), varies markedly across individuals. While tau is thought to spread along brain networks, the role of inter-individual variability in accounting for these patterns remains underexplored. Using resting-state fMRI and tau-PET from 805 BioFINDER participants across the AD continuum, with replication in ADNI (n=361) and A4 (n=336), we studied whether subject-specific functional connectivity (FC) profiles enhance the characterization of tau deposition patterns. A hybrid approach integrating individual and group-average FC explained individual tau-PET topographies better than either FC representation alone, particularly in symptomatic individuals and at finer spatial resolutions. Hybrid FC also better captured individual tau topographies than canonical tau-PET maps derived from cohort-level data. These effects were specific to tau and not similarly observed for {beta}-amyloid, and the explanatory advantage of FC-based models increased with spatial granularity. Furthermore, baseline hybrid FC explained follow-up tau-PET topography better than template FC, suggesting that individualized baseline connectivity contains information about future tau-PET progression. The main FC model-comparison findings replicated in ADNI and A4. Collectively, these findings show that individual functional brain architecture is associated with heterogeneity in tau-PET topography. While not establishing a causal propagation mechanism, our findings are consistent with network-spread models. This work advances the methodological characterization of tau-PET heterogeneity in AD and highlights functional connectivity as a potentially informative marker of individual tau-PET trajectories.

neuroscience↗

bioRxiv2025

Age and Alzheimer's disease affect functional connectivity along separate axes of functional brain organization

Aging and Alzheimers disease (AD) are accompanied by alterations to large-scale communication patterns in the brain, which can be tracked in vivo using functional connectivity (FC). The location, direction and relevance of these changes remain widely debated, though they are rarely studied in the context of whole-cortex communication dynamics. In two independent cohorts (BioFINDER-2, N=973; ADNI, N=129), we show that FC changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory-association axis. Meanwhile, age-related functional changes occur along the representation-executive axis consistently throughout the adult lifespan. These findings together suggest AD and aging both alter major but orthogonal functional pathways in the brain. More broadly, our findings position whole-brain connectivity dynamics as a unifying framework for interpreting functional changes across the adult lifespan.

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bioRxiv2025

Brain network dynamics determine tau presence while regional vulnerability governs tau load in Alzheimer's disease

In Alzheimers disease (AD), tau pathology accumulates gradually throughout the brain, with clinical decline reflecting tau progression. A comprehensive understanding of, first, whether tau propagation is predominantly governed by connectome-based diffusion, regional vulnerability, or an interplay of both, and second, which types of brain connectivity or regional factors best explain tau propagation, remains crucial for advancing our understanding of AD progression. Here, we apply multi-scale, biologically informed disease progression simulations to human data, to disentangle the influence of local mechanisms on global tau progression patterns in AD. We find that whether tau reaches a brain region (presence) and how much tau accumulates there (load) are governed by different mechanisms. Tau presence patterns are highly consistent across the population, and can be largely explained through synaptic spread through white-matter networks and excitatory-inhibitory dynamics. Meanwhile tau load differs across people, and is driven by a combination of synaptic spread and intrinsic or extrinsic regional properties, including regional {beta}-amyloid load, MAPT gene expression and regional blood flow. Finally, while distinct tau patterns in the population could each be explained by established AD mechanisms, our models highlight a role of distinct brain networks (parietal networks in MTL-sparing AD tau subtype) and neurotransmitter systems (cholinergic system in posterior subtype). Together, this work suggests that network dynamics likely determine the sequence of regional tau progression, while individual-specific tissue-vulnerability factors influence regional tau load.

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bioRxiv2025

Hemispheric Asymmetry of Tau Pathology is Related to Asymmetric Amyloid Deposition in Alzheimer's Disease

The distribution of tau pathology in Alzheimers disease (AD) shows remarkable inter-individual heterogeneity, including hemispheric asymmetry. However, the factors driving this asymmetry remain poorly understood. We explored whether tau asymmetry is linked to i) reduced inter-hemispheric brain connectivity (potentially restricting tau spread), or ii) asymmetry in amyloid-beta (A{beta}) distribution (indicating greater hemisphere-specific vulnerability to AD pathology). 452 participants from the Swedish BioFINDER-2 cohort with evidence of both A{beta} pathology (CSF A{beta}42/40 or neocortical A{beta}-PET) and tau pathology (temporal tau-PET), were categorised as left asymmetric (n=102), symmetric (n=306), or right asymmetric (n=44) based on temporal lobe tau-PET uptake distribution. Edge-wise inter-hemispheric functional (RSfMRI; n=318) and structural connectivity (dMRI; n=352) patterns were examined but no differences in inter-hemispheric functional or structural connectivity were found between groups. However, a strong association was observed between tau and A{beta} laterality patterns based on PET uptake (n=233; {beta}=0.632, p<0.001), which was replicated in three independent cohorts (n=234; {beta}=0.535, p<0.001). In a longitudinal A{beta}-positive sample, baseline A{beta} asymmetry predicted the progression of tau laterality over time (n=289; {beta}=0.025, p=0.028). These findings suggest that tau asymmetry is not associated with a weaker inter-hemispheric connectivity but might reflect hemispheric differences in vulnerability to A{beta} pathology, underscoring the role of regional vulnerability in determining the distribution of AD pathology.

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bioRxiv2024

Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer's disease

BackgroundThe medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimers disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking. MethodsBioFINDER-2 participants with memory impairment, abnormal amyloid-{beta} status and tau-PET were included. Forty-one EOAD individuals aged [≥]65 years and, as comparison, late-onset AD (LOAD, [≤]70 years, n=154) and A{beta}-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. ResultsAD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found. ConclusionsWe found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies.

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bioRxiv2023

Personalised Regional Modelling Predicts Tau Progression in the Human Brain

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimers disease, and its accumulation exhibits a rich spatio-temporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatio-temporal process is orchestrated - namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimers disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics on two independent cohorts, with subjects in early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathologic tau seeds, and subjects in late stage disease (Braak stage 3/4 onwards) characterised primarily by local production of tau. Furthermore, we demonstrate that the model can accurately predict subject-specific longitudinal tau accumulation at a regional level, potentially providing a new clinical tool to monitor and classify patient disease progression. TeaserA mechanistic model reveals tau protein dynamics in Alzheimers, showing stage-specific shifts in transport and local production.

neuroscience↗

bioRxiv2023

Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimers disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related mechanisms which vary between individuals, such as CSF production and clearance rates. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our novel reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.

neuroscience↗

bioRxiv2021

Independent information from PET, CSF and plasma biomarkers of tau pathology in Alzheimer's disease

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimers disease (AD) related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n=400) and ADNI (n=371). All had tau-PET ([18F]RO948 in BioFINDER-2, [18F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66% and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOE{varepsilon}4-carriership and A{beta}-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially A{beta} pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.

neuroscience↗

bioRxiv2020

Time between milestone events in the Alzheimer's disease amyloid cascade

ObjectiveEstimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimers disease. MethodsIn a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of A{beta}, tau, and decreases in cognition with respect to the time of A{beta}-positivity. ResultsSmall effect sizes of change in CSF A{beta}42 and regional A{beta} PET were estimated to occur several decades before A{beta}-positivity. Increases in CSF tau occurred 11-12 years before A{beta}-positivity. Temporoparietal tau PET showed increases 4-5 years before A{beta}-positivity. Subtle cognitive dysfunction was observed 7-9 years before A{beta}-positivity. ConclusionsIncreases in tau and cognitive dysfunction occur years before the presence of significant A{beta}. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments.

neuroscience↗