Biomarkers.

Background: Fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer's disease (AD). However, as we recently showed, the overall proteome average in CSF exhibits a non-disease related average signal (inter-individual variability), which can reduce the precision of concentration based CSF AD biomarkers. Now, we therefore investigate if several already high performing CSF and plasma AD biomarkers can be improved by normalizing their concentration to a reference protein (e.

Biomarkers.

Background: A key characteristic of Alzheimer's disease (AD) is cerebral aggregation of tau. These aggregates can be quantified and localized with positron emission tomography (PET), which improves the diagnostic and prognostic work-up of AD. However, tau-PET is expensive and not available in clinical settings globally.

Biomarkers.

Background: Cerebrospinal fluid (CSF) proteomics allows for characterization of multiple disease-related biological processes in vivo. These processes likely occur along temporal cascades mirroring disease evolution. This study describes interindividual variation in these cascades, in the context of Alzheimer's disease.

Biomarkers.

Background: Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults.

Method: To uncover atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to structural MRI data from 813 participants (mean ± SD age = 70.

Biomarkers.

Background: A generative model of tau PET was applied to multiple cohorts across the Alzheimer's disease (AD) spectrum, revealing longitudinal changes in tau production and transport. A generalisation of the model accounts for amyloid, tau and neurodegeneration (ATN) interactions and accurately explains longitudinal ATN biomarker data, adding potential for region specific and individualized tracking of ATN biomarkers.

Method: A model of tau spreading and production as measured through PET was developed and applied to longitudinal data from amyloid negative (A-), amyloid positive tau negative (A+T-) and amyloid positive tau positive (A+T+) cohorts from the Alzheimer's disease neuroimaging iniative (ADNI; N = 159) and BioFINDER-2 (BF2; N = 135) datasets.

Biomarkers.

Background: With the development of disease modifying therapies targeting specific pathologies, accurate in vivo biomarkers have become increasingly important for disease classification. Recently, tests for neuronal α-synuclein (Lewy body) pathology have become available, complementing pre-existing tests for Alzheimer's disease (AD) pathology (Aβ and tau fluid and PET biomarkers) and vascular disease (MRI). Here, we aimed to identify and characterize data-driven pathology-based subtypes using these biomarkers.

Biomarkers.

Background: Substantial variability in tau accumulation patterns in Alzheimer's disease (AD) population has now become accepted. Subtype and Stage Inference (SuStaIn) has distinguished four distinct spatiotemporal trajectories of tau pathology: limbic (S1), medial temporal lobe-sparing (S2), posterior (S3), and lateral temporal (S4). A visual method to validate and identify them is a requirement for their clinical translation.

Biomarkers.

Background: Amyloid-negative tau-positive PET (A-T+) participants have been reported in several studies. We assessed the prevalence and characteristics of A-T+ participants in a cohort of cognitively unimpaired individuals with a first-degree family history of Alzheimer's disease (AD) dementia.

Method: We studied 252 participants from the longitudinal PREVENT-AD cohort (mean cognitive follow-up = 3.

Biomarkers.

Background: Several studies have recently emerged describing relationships between cerebrospinal fluid (CSF) proteins and beta-amyloid (Aβ) and tau pathology. While these studies have primarily characterized Alzheimer's disease (AD) proteinopathies using CSF markers, positron emission tomography (PET) more accurately captures these pathologies, especially fibrillar tau pathology. Our objective was to identify the main proteins strongly associated with AD pathology measured by PET, and to further investigate their cellular role using postmortem transcriptomics and immunohistochemistry.

Developing Topics.

Background: Tau pathology, a hallmark of Alzheimer's disease (AD), is thought to spread cell-to-cell via axonal connections, beginning focally before expanding throughout the brain. This study uses computational models to investigate the interplay between network spread and regional vulnerability in influencing tau spread, focusing specifically on MAPT and APOE genes, and Aβ plaques.

Method: 66 regional (Desikan-Killiany atlas) tau-PET standardized uptake value ratio (SUVR) values were extracted from participants in the Swedish BioFINDER-2 study: 429 cognitively normal (CN), 91 subjective cognitive decline (SCD), 168 mild cognitive impairment (MCI), and 182 AD.

Alzheimer's Imaging Consortium.

Background: Substantial variability in tau accumulation patterns in Alzheimer's disease (AD) population has now become accepted. Subtype and Stage Inference (SuStaIn) has distinguished four distinct spatiotemporal trajectories of tau pathology: limbic (S1), medial temporal lobe-sparing (S2), posterior (S3), and lateral temporal (S4). A visual method to validate and identify them is a requirement for their clinical translation.

Alzheimer's Imaging Consortium.

Background: With the development of disease modifying therapies targeting specific pathologies, accurate in vivo biomarkers have become increasingly important for disease classification. Recently, tests for neuronal a-synuclein (Lewy body) pathology have become available, complementing pre-existing tests for Alzheimer's disease (AD) pathology (Aß and tau fluid and PET biomarkers) and vascular disease (MRI). Here, we aimed to identify and characterize data-driven pathology-based subtypes using these biomarkers.

Alzheimer's Imaging Consortium.

Background: Amyloid-negative tau-positive PET (A-T+) participants have been reported in several studies. We assessed the prevalence and characteristics of A-T+ participants in a cohort of cognitively unimpaired individuals with a first-degree family history of Alzheimer's disease (AD) dementia.

Method: We studied 252 participants from the longitudinal PREVENT-AD cohort (mean cognitive follow-up = 3.

Alzheimer's Imaging Consortium.

Background: Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults.

Method: To uncover atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to structural MRI data from 813 participants (mean ± SD age = 70.

Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD.

Cortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness in , or -related bvFTD. Genes associated with cortical thinning in -bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps.

Proteomic changes in Alzheimer's disease associated with progressive Aβ plaque and tau tangle pathologies.

Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer's disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum.

Identification of distinct and shared biomarker panels in different manifestations of cerebral small vessel disease through proteomic profiling.

The pathophysiology underlying various manifestations of cerebral small vessel disease (cSVD) remains obscure. Using cerebrospinal fluid proximity extension assays and co-expression network analysis of 2,943 proteins, we found common and distinct proteomic signatures between white matter lesions (WML), microbleeds and infarcts measured in 856 living patients, and validated WML-associated proteins in three additional datasets. Proteins indicative of extracellular matrix dysregulation and vascular remodeling, including ELN, POSTN, CCN2 and MMP12 were elevated across all cSVD manifestations, with MMP12 emerging as an early cSVD indicator.

Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain.

Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.

Disease staging of Alzheimer's disease using a CSF-based biomarker model.

Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort.

Biomarker-based staging of Alzheimer disease: rationale and clinical applications.

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics.

Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology.

Lewy body (LB) disorders, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. By applying data-driven disease progression modelling to regional neuropathological LB density scores from 814 brain donors, we describe three inferred trajectories of LB pathology that were characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression.

Novel data-driven subtypes and stages of brain atrophy in the ALS-FTD spectrum.

Background: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.

The molecular genetic landscape of human brain size variation.

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW.