Melikyan ZA, Al-Darsani Z, Jiang L
… +6 more, Colcord KA, Paganini-Hill A, Bukhari SA, Montine TJ, Kawas CH, Corrada MM
Acta Neuropathol
· 2026 Apr · PMID 41942821
·
Full text
Although intermediate/high Alzheimer's Disease Neuropathologic Change (ADNC) is associated with dementia in many older adults, some remain cognitively normal and are often referred to as resilient to ADNC. We aim to exam...Although intermediate/high Alzheimer's Disease Neuropathologic Change (ADNC) is associated with dementia in many older adults, some remain cognitively normal and are often referred to as resilient to ADNC. We aim to examine health, lifestyle, and neuropathologic factors that distinguish older adults with dementia vs. normal cognition in the presence of intermediate/high ADNC. Participants were from The 90 + Study, a longitudinal study of aging in southern California. This cross-sectional analysis included participants with an intermediate/high ADNC on neuropathologic exam and normal cognition or dementia diagnosis on case conference. We analyzed 11 neuropathologic changes, both vascular and neurodegenerative, dichotomized as present/absent, and the total number of neuropathologies. To examine the association of health and lifestyle factors and neuropathologic changes (predictors) with cognitive diagnosis at consensus case conference, dementia vs. normal cognition, (outcome), we used logistic regression adjusted for demographics. Among 235 participants (mean age at death = 98 years, 70% women), 33% maintained normal cognition. Participants with heart disease (OR = 0.45; 95% CI = 0.25, 0.81) and hypertension (OR = 0.53; 95% CI = 0.29, 0.95) had lower likelihood of dementia. In contrast, participants with a history of transient ischemic attacks (OR = 3.00; 95% CI = 1.46, 6.18), Lewy Body Disease (OR = 2.73; 95% CI = 1.14, 6.58), hippocampal sclerosis (OR = 2.70; 95% CI = 1.06, 6.86), Limbic-predominant Age-related TDP-43 Encephalopathy neuropathologic change (OR = 2.80; 95% CI = 1.53, 5.12), and a high number of non-ADNCs (OR = 4.46; 95% CI = 2.01, 9.92) had higher likelihood of dementia. Arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, and microvascular lesions were not associated with dementia. In this study, the presence of neurodegenerative neuropathologic changes other than ADNC and the absence of hypertension distinguish oldest old individuals with dementia from those with normal cognition. Understanding mechanisms underlying normal cognition in those with ADNC may provide important clues to prevention and resilience to the effects of AD neuropathology.
Haq I, Ngo JC, Roy N
… +11 more, Lee E, Choudhury MA, Soni RK, Teich AF, Mayeux RP, De Jager PL, He Y, Wu X, Bennett DA, Olah M, Sher F
Acta Neuropathol
· 2026 Apr · PMID 41942750
·
Full text
Microglial dysfunction is a hallmark of Alzheimer's disease (AD), yet the molecular mechanisms driving these impairments remain poorly defined. Genetic studies implicate several AD-associated genes in regulating microgli...Microglial dysfunction is a hallmark of Alzheimer's disease (AD), yet the molecular mechanisms driving these impairments remain poorly defined. Genetic studies implicate several AD-associated genes in regulating microglial activity, including SORL1, which encodes the sorting receptor SorLA. Although SorLA is highly expressed in microglia, its functional role in cellular homeostasis has remained unclear. Here, we investigated SorLA function using human brain tissue, primary microglia from rapid autopsies, and CRISPR-engineered human iPSC-derived microglia and neurons. Integrated multi-omics analyses, including single-cell RNA sequencing, lipidomics, and proteomics, together with biochemical and functional assays, revealed that SorLA deficiency induces endoplasmic reticulum (ER) stress and interferon signaling, promotes lipid droplet accumulation, and impairs phagocytic and immune functions. Protein co-complex mapping and structural modeling identified ER-associated proteins co-enriched with SorLA, including SUN2, calnexin (CANX), and multiple COPI complex components (COPA, COPB1, COPG1, ARCN1), implicating SorLA in ER proteostasis and intracellular trafficking. Notably, SORL1 deletion in iPSC-derived neurons recapitulated key phenotypes observed in microglia, including lipid droplet accumulation and SorLA-SUN2 co-immunoprecipitation, indicating that this ER-associated pathway operates across distinct brain cell types. Together, these findings identify an ER-related role for SorLA that extends beyond its established function in endocytic trafficking. Loss of SorLA triggers maladaptive stress responses, perturbs lipid handling, and compromises cellular resilience, thereby contributing to AD-relevant cellular dysfunction.
Kleefeld F, Teran Gamboa J, Pinal-Fernandez I
… +25 more, Preusse C, Nelke C, Goebel HH, Mensch A, Mossakowski A, Miah MU, Diaz-Manera J, Torchia E, Bortolani S, Hentschel A, Funke A, Souvannanorath S, Authier FJ, Malfatti E, Gehrig J, Mammen AL, Casal-Dominguez M, De Winter J, De Ridder W, Ruck T, Schneider U, Roos A, Gallardo E, Tasca G, Stenzel W
Acta Neuropathol
· 2026 Apr · PMID 41934478
·
Full text
Brachio-cervical inflammatory myopathy (BCIM) is a rare and under-characterized subtype of idiopathic inflammatory myopathies (IIM), marked by prominent upper limb and neck muscle involvement. Since its initial descripti...Brachio-cervical inflammatory myopathy (BCIM) is a rare and under-characterized subtype of idiopathic inflammatory myopathies (IIM), marked by prominent upper limb and neck muscle involvement. Since its initial description in 2006, few studies have addressed its clinical spectrum or pathogenesis, and its potential overlap with systemic sclerosis (SSc) remains a matter of debate. Here, we aimed to characterize the clinical, histopathological, and molecular features of BCIM in a large multicenter cohort and determine whether BCIM represents a characteristic clinico-pathological syndrome within the IIM spectrum or reflects an atypical presentation of SSc-associated myositis. We studied 26 patients with clinically and histologically confirmed BCIM from seven European centers. Clinical data, treatment responses, and autoantibody profiles were collected retrospectively from participating centers. Histopathological and immunohistochemical analyses were performed on muscle biopsies, and 12 muscle biopsy specimens underwent bulk RNA sequencing, including a comparison with 669 non-BCIM myositis datasets. Proteomic profiling was performed in an independent subset. Clinical overlap with SSc was defined using the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. The cohort was predominantly female (88%) with a mean age of 51 years [standard deviation (SD) ± 15.0]. Core features included asymmetrical proximal upper limb weakness (100%), dropped head (62%), dysphagia (46%), and facial weakness (54%). Although 35% showed clinical overlap with SSc, 65% of patients did not meet SSc criteria. All patients received corticosteroids; 65% required additional immunosuppression, yet complete clinical remission was uncommon in this retrospective cohort, although outcome assessment was limited by heterogeneous follow-up. Histopathology revealed dense endomysial inflammation with T cell predominance and prominent endo- and perimysial B-cell/plasma-cell-rich clusters with variable fibrosis. CD45⁺ and CD8⁺ cells were more abundant in patients without SSc overlap. RNA sequencing revealed a strong B-cell/plasma-cell signature, M2-like macrophage polarization, and downregulation of mitochondrial gene expression. Proteomics highlighted broad alterations in oxidative phosphorylation, aerobic respiration, and ATP synthesis pathways. BCIM shows a characteristic constellation of clinical, histological, and molecular features within the IIM spectrum. While a subset of patients meets criteria for SSc overlap, many do not, and the consistent presence of B-cell-rich inflammation together with downregulation of mitochondrial transcripts and proteins highlights shared pathogenic mechanisms within the cohort. These findings support the concept of BCIM as a myositis syndrome with heterogeneous SSc association and highlight a prominent B-cell/plasma-cell signature in BCIM, which warrants further evaluation of B-cell-directed approaches in future, prospective studies.
Hill E, Patel MM, Ribes JM
… +20 more, Linehan J, Zhang F, Jakubcova T, Hamdan S, Tomlinson A, Ercolani T, Schmidt C, Ahmed P, Thirlway G, Argentina F, Marinho AT, Jones E, Kaye N, Fitzhugh C, Jackson GS, Brandner S, Klöhn PC, Collinge J, Cunningham TJ, Mead S
Acta Neuropathol
· 2026 Mar · PMID 41913024
·
Full text
Acta Neuropathol
· 2026 Mar · PMID 41888437
·
Full text
Selective vulnerability of motor neurons is a defining feature of amyotrophic lateral sclerosis (ALS) and provides a valuable framework for uncovering mechanisms that distinguish resilient from vulnerable neuronal popula...Selective vulnerability of motor neurons is a defining feature of amyotrophic lateral sclerosis (ALS) and provides a valuable framework for uncovering mechanisms that distinguish resilient from vulnerable neuronal populations. We investigated whether dysregulation of neuroprotective microRNAs (miRNAs), miR-9-5p and miR-124-3p, contributes to the differential susceptibility of motor neuron subtypes. We focused on cervical spinal motor neurons (SMNs), which undergo drastic degeneration in ALS, and oculomotor neurons (OMNs), which remain functionally intact and rarely degenerate, allowing preservation of eye movement in ALS patients. Using a modified multiplexed fluorescent in situ hybridization protocol combined with immunofluorescence, we quantified the expression of miR-9-5p and miR-124-3p in cervical SMNs and OMNs from ALS and control cases. We observed significant downregulation of both miRNAs in ALS SMNs, while their expression was maintained in ALS OMNs. Stratification of ALS SMNs by TDP-43 pathological status revealed similarly reduced miRNA expression in neurons with and without cytoplasmic inclusions, suggesting that miRNA downregulation occurs independently of visible TDP-43 pathology. We assessed the localization of the Dicer cofactor TRBP and found that it colocalized with TDP-43 inclusions in ALS SMNs, suggesting that TRBP sequestration could prevent proper miRNA processing. However, TRBP remained normally localized in neurons without cytoplasmic inclusions, indicating that sequestration cannot fully account for miRNA reduction across all ALS motor neurons. These findings support a model in which early or subtle disruptions, preceding visible pathology, may also contribute to miRNA downregulation in ALS. By identifying preserved miRNA networks as correlates of oculomotor neuron resilience in ALS, this work also exposes new therapeutic targets potentially capable of reinstating miRNA expression and reprogramming vulnerable SMNs.
Kaddatz H, Wenzel L, Pril E
… +9 more, Meien S, Harz V, Burkert L, Behrangi N, Zimmermann A, Frintrop L, Amor S, Kipp M, Heinig L
Acta Neuropathol
· 2026 Mar · PMID 41876812
·
Full text
Oligodendrocytes are essential for myelin production, maintenance, and repair, and their dysfunction contributes to the pathogenesis of demyelinating diseases such as multiple sclerosis (MS). Here, we identify an early s...Oligodendrocytes are essential for myelin production, maintenance, and repair, and their dysfunction contributes to the pathogenesis of demyelinating diseases such as multiple sclerosis (MS). Here, we identify an early stress-associated oligodendrocyte state characterized by a rapid, post-transcriptional loss of the lineage-defining transcription factor Oligodendrocyte Transcription Factor 2 (OLIG2). Using the cuprizone model of toxic demyelination, we observed an early appearance of OLIG2 expressing oligodendrocytes, followed by the emergence of OLIG2-negative oligodendrocytes at later stages. This observation was particularly pronounced among cells expressing the integrated stress response marker Activating Transcription Factor 3 (ATF3). Transcriptomic analysis, quantitative PCR, and combined in situ hybridization-immunohistochemistry confirmed that these changes occurred without a corresponding reduction in Olig2 mRNA levels, indicating that OLIG2 protein loss is a stress-induced, post-transcriptional event not captured by RNA-level profiling. A similar phenotype was observed in a reversible metabolic stress paradigm (i.e., chronic starvation model) and in post-mortem MS lesions, where stressed oligodendrocytes showed reduced or absent OLIG2 protein expression. Pharmacological intervention with the sphingosine-1-phosphate receptor modulator siponimod during cuprizone intoxication attenuated OLIG2 protein loss, indicating that this stress-induced state is pharmacologically modifiable. These findings reveal a transient and potentially reversible phenotype in stressed oligodendrocytes that may precede overt cell loss or demyelination. Thus, OLIG2 protein loss may serve as an early indicator of oligodendrocyte stress and a possible therapeutic target for preserving myelin integrity in demyelinating disorders. These findings have additional methodological implications as stressed oligodendrocytes may evade detection using OLIG2-based lineage markers.
Pascual JR, Rivera I, Nguyen H
… +24 more, Ngo PT, Hoang A, Andrews EJ, Rouanet J, Wright ST, Sordo L, Kofler J, Ikonomovic MD, Lai F, Mapstone M, Christian BT, Handen BL, Lott IT, Doran E, Hom CL, Harp J, Schmitt F, Tudorascu DL, Ances BM, Phelan M, Liu L, Flores-Aguilar L, Head E, Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) Investigators
Acta Neuropathol
· 2026 Mar · PMID 41865347
·
Full text
Individuals with Down syndrome (DS) have an increased risk of developing Alzheimer disease (AD), with nearly all individuals exhibiting AD neuropathology, including amyloid beta (Aβ) plaques and neurofibrillary tangles (...Individuals with Down syndrome (DS) have an increased risk of developing Alzheimer disease (AD), with nearly all individuals exhibiting AD neuropathology, including amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT), by age 40 years. Fluid AD biomarker studies highlight an increase in several phosphorylated tau (p-tau) epitopes in DS. However, neuropathological measures of p-tau epitopes in DS have not been examined. Therefore, our main objective was to characterize p-tau epitope burdens across the DS lifespan at autopsy. We analyzed postmortem brain samples of 98 individuals with late-onset AD (LOAD), DS with AD neuropathology (DSAD), young DS (below 40 years of age), and age-matched neurotypical controls, ranging from 1 to 96 years of age. Immunohistochemical and digital pathology measures of p-tau epitopes at threonine 181 (pThr181), threonine 217 (pThr217), and threonine 231 (pThr231) burdens in the frontal cortex were compared across groups. We observed similar pThr181, pThr217, and pThr231 burdens between DSAD and LOAD, despite DSAD cases being younger on average. Observed pThr181, pThr217, and pThr231 burdens were higher in DSAD compared to young DS and neurotypical controls. Generalized additive models (GAMs) were used to model the cross-sectional trajectory of p-tau epitope burdens across the DS lifespan. Estimated age breakpoints revealed a significant rise in frontal cortex pThr231 at age 40, followed by pThr181 and pThr217 at age 42. In summary, our findings revealed an age-associated increase in p-tau epitopes across the DS lifespan. Our results have the potential to inform future associations between neuropathological and biofluid and neuroimaging biomarker measures of p-tau epitopes.
Saleem T, Möbius W, Schmitz M
… +14 more, da Silva Correia A, Thomas C, Canaslan S, Hermann P, Göbel S, Zafar S, Root E, Stadelmann C, Andreoletti O, Hoppert M, Fleming Outeiro T, Ferrer I, Younas N, Zerr I
Acta Neuropathol
· 2026 Mar · PMID 41851356
·
Full text
Rapidly progressive Alzheimer's disease (rpAD) is a rare subtype with rapid decline, but its molecular underpinnings remain poorly defined. Here, brain-derived tau oligomers (TauO) were systematically compared across non...Rapidly progressive Alzheimer's disease (rpAD) is a rare subtype with rapid decline, but its molecular underpinnings remain poorly defined. Here, brain-derived tau oligomers (TauO) were systematically compared across nondemented controls, slowly progressive AD (spAD), and rpAD to test whether subtype-specific TauO signatures align with clinical aggressiveness. TauO were immunoprecipitated from frontal cortex using T22 antibody and characterized by Western blotting, transmission electron microscopy, label-free quantitative proteomics, and SH-SY5Y toxicity assays, complemented by longitudinal analysis of tau phosphorylation in inoculated 3xTg AD mice. T22-positive high-molecular-weight TauO were successfully enriched from all groups, where rpAD TauO exhibited compact, densely packed oligomers under TEM and the highest phosphorylation at pS396 and pS422, exceeding both spAD and controls (p ≤ 0.0327). In 3xTg mice, pS396 showed an early increase followed by a late decline, consistent with dynamic shifts in tau solubility during disease evolution. Brain-derived TauO from spAD and rpAD, but not recombinant tau monomers or control-derived TauO, significantly reduced SH-SY5Y cell viability. Proteomic profiling identified 2388 TauO-associated proteins, including a shared 556-protein core and a striking expansion of rpAD-unique interactors (n = 1101). In controls and spAD, the core TauO interactome was enriched for translation, proteostasis, mitochondrial respiration, and vesicle-trafficking pathways, whereas these modules were absent in rpAD. Instead, rpAD TauO showed selective enrichment of aldehyde detoxification, amino-acid and carbon metabolism, and actin-regulatory modules, alongside increased association of SERPINA1, ALDH9A1, MAPRE3, DPYSL2, DPYSL3, and NFASC and reduced coupling to mitochondrial (MRPL17) and complement (C9) components. These convergent structural, post-translational, toxic, and interactome changes indicate that rpAD is defined by a biochemically distinct TauO species embedded in a metabolic and cytoskeleton-focused network, providing a mechanistic framework for its aggressive clinical course and a basis for subtype-specific biomarker and therapeutic strategies.
Barone C, Wang R, Cooke S
… +4 more, Ng HP, Ferreira RS, Miranda HC, Qi X
Acta Neuropathol
· 2026 Mar · PMID 41838122
·
Full text
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and cytoplasmic mislocalization of TDP-43. While metabolic dysfunction is increasingly reco...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and cytoplasmic mislocalization of TDP-43. While metabolic dysfunction is increasingly recognized in ALS, the mechanistic link between impaired energy metabolism and TDP-43 pathology remains unknown. Here, we show that cytoplasmic TDP-43 directly disrupts glycolysis by targeting hexokinase 1 (HK1), the first rate-limiting enzyme of the pathway. In cells expressing a TDP-43 variant lacking its nuclear localization signal and in patient-derived iPSC motor neurons, TDP-43 accumulation in the cytoplasm reduces glycolytic capacity, indicating a neuron-intrinsic metabolic defect. Across cellular models including patient-derived neurons, TDP-43 mutant mice, and postmortem spinal cord tissue from ALS patients, we observe consistent decreases in HK1 protein level, mitochondrial association, and enzymatic activity, despite unchanged transcript levels. Mechanistically, cytoplasmic TDP-43 directly binds to HK1, disassociating it from mitochondria and promoting its sequestration into insoluble aggregates. This mislocalization impairs glycolysis and increases neuronal vulnerability. Notably, compensation for HK1 loss reduces cytoplasmic TDP-43 and ubiquitin accumulation, improves motor performance, and prolongs survival in TDP-43-associated ALS models. Together, these findings identify a previously unrecognized mechanism by which TDP-43 impairs glycolysis through HK1 misregulation and highlight glycolytic restoration as a potential therapeutic strategy in ALS.
Tran NLK, Hou X, Heckman MG
… +11 more, Fiesel FC, Koga S, Watkins MM, Sledge HJ, Gibbs JR, Traynor BJ, Dalgard CL, Scholz SW, Dickson DW, Springer W, Ross OA
Acta Neuropathol
· 2026 Mar · PMID 41776125
·
Full text
Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy i...Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration.
Tlais D, Zhang Q, Roach JT
… +16 more, Tinkle CL, Lin T, Li X, Mostafa A, Moreira DC, McNall-Knapp RY, Rush SZ, Le BH, Sinno S, Ramnarayan A, Ginn KF, Partap S, Onar-Thomas A, Furtado LV, Bag AK, Chiang J
Acta Neuropathol
· 2026 Mar · PMID 41770225
·
Full text
Previous studies have demonstrated poor outcomes in pediatric patients with H3 G34-mutant diffuse hemispheric glioma (DHG). However, the biological basis for this therapeutic resistance remains poorly understood. Further...Previous studies have demonstrated poor outcomes in pediatric patients with H3 G34-mutant diffuse hemispheric glioma (DHG). However, the biological basis for this therapeutic resistance remains poorly understood. Furthermore, the effectiveness of temozolomide (TMZ) and the role of surgery in pediatric patients remain uncertain. Therefore, we performed a multi-institutional retrospective analysis of the clinical, imaging, and molecular characteristics of 36 pediatric (≤ 18 years) patients with newly diagnosed H3 G34-mutant DHG. The median age of the cohort was 14 years (8-18 years). The median progression-free survival (PFS) was 0.7 years (95% CI 0.4-1.2 years), and the median overall survival (OS) was 1.8 years (95% CI 1.1-3.2 years). Gross total resection (GTR) was associated with improved PFS (p = 0.0046). Infiltration of three or more brain lobes (gliomatosis cerebri) was noted in 22.6% (7/31) of patients at presentation. Twenty-one patients (58.3%) received frontline TMZ and had improved PFS (p = 0.0049) compared to those who did not. Low MGMT expression was associated with better PFS (p = 0.0039) and better OS (p < 0.0001). In pediatric DHG, gene body/intronic CpG methylation, rather than promoter methylation, correlated with MGMT expression (p < 0.0001). MGMT promoter methylation was not significantly associated with PFS or OS. PDGFRA alterations (n = 13) were associated with inferior OS (p = 0.0035). Post-radiation local (± distant) recurrence occurred in 81.0% (17/21) of patients. Our findings reaffirm the dismal outcomes of pediatric H3 G34-mutant DHG, which exhibits radiation resistance, frequent widespread disease, and a novel mechanism of MGMT regulation. Our data support the use of frontline TMZ in pediatric patients and underscore the importance of GTR when feasible.
Laroche VT, Cavill R, Kouhsar M
… +16 more, Müller J, Reijnders RA, Harvey J, Smith AR, Imm J, Koetsier J, Weymouth L, MacBean L, Pegoraro G, Eijssen L, Creese B, Kenis G, Tijms BM, van den Hove D, Lunnon K, Pishva E
Acta Neuropathol
· 2026 Feb · PMID 41733741
·
Full text
Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease (LOAD) contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances...Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease (LOAD) contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This underscores the need to expand subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation (DNAm) data from three independent postmortem brain cohorts (N = 826) to identify epigenetic subtypes of LOAD. We used unsupervised clustering to define subtype-specific DNAm patterns and validated them across cohorts. We then mapped subtype signatures to brain cell types using purified-cell DNAm profiles and integrated bulk and single-nucleus RNA-seq to assess each subtype's impact on gene expression. Finally, we examined clinical and neuropathological correlates to evaluate biological and clinical significance. We identified two distinct epigenomic subtypes of LOAD, consistently observed across three cohorts. Both subtypes exhibit significant yet distinct microglial methylation enrichment. Bulk transcriptomic analyses highlighted distinct biological mechanisms underlying these subtypes: subtype 1 was enriched for immune-related processes, while subtype 2 was characterized by neuronal and synaptic pathways. Single-nucleus transcriptional profiling of microglia indicated that both subtypes share AD-associated innate-immune remodeling, with subtype differences emerging primarily as state-dependent transcriptional shifts rather than large changes in state abundance. Overall, subtype 1 showed a relative weighting toward more inflammatory microglial programs, whereas subtype 2 showed stronger transcriptional remodeling in specific microglial states alongside relatively greater engagement of regulatory and clearance-associated features. These findings reveal distinct epigenetic and functional microglial states underlying LOAD subtypes, advancing our understanding of disease heterogeneity. This work lays the groundwork for targeted therapeutic strategies tailored to specific molecular and cellular disease profiles.
Acta Neuropathol
· 2026 Feb · PMID 41739230
·
Full text
Flortaucipir PET imaging has significantly advanced our ability to visualize tau pathology in vivo. However, off-target Flortaucipir signal remains a considerable challenge for interpreting of imaging results, particular...Flortaucipir PET imaging has significantly advanced our ability to visualize tau pathology in vivo. However, off-target Flortaucipir signal remains a considerable challenge for interpreting of imaging results, particularly in non-Alzheimer's tauopathies and non-tau pathologies. To better understand this off-target signal, we used an innovative voxel-to-voxel correlation approach, analyzing thousands of histology-Flortaucipir pairs from individual cases. This allowed us to quantitatively assess the relationship between Flortaucipir PET signal and three key biological factors: histological tau burden (CP-13 phospho-tau), ferric iron (Perls' Prussian blue), and monoamine oxidase B (MAO-B). Our study included individuals with Alzheimer's disease (AD), various non-AD tauopathies, and a case of FTLD-TDP-43 type A. In AD, Flortaucipir signal showed a significant but moderate correlation with histological tau pathology, suggesting that while tau is a major contributor, other biological factors also influence Flortaucipir binding in AD. Conversely, in non-AD tauopathies and FTLD-TDP-43, correlations between Flortaucipir signal and tau pathology were weak or negligible. Instead, Flortaucipir signal correlated more strongly with ferric iron and MAO-B. However, these factors did not fully explain all the off-target signals, implying other unknown contributors are likely involved. These findings underscore the complexity of interpreting Flortaucipir PET scans. A thorough understanding of off-target binding mechanisms is crucial for improving the diagnostic accuracy of Flortaucipir PET and its specificity.
Ono D, Kondrakunta S, Mak E
… +27 more, Przybelski SA, Fought AJ, Schwarz CG, Murray ME, Nguyen A, Reichard RR, Senjem ML, Gunter JL, Jack CR, Miyagawa T, Forsberg LK, Fields JA, Savica R, Ramanan VK, Jones DT, Botha H, Louis EKS, Knopman DS, Graff-Radford NR, Day GS, Ferman TJ, Kremers WK, Lowe VJ, Petersen RC, Boeve BF, Dickson DW, Kantarci K
Acta Neuropathol
· 2026 Feb · PMID 41708563
·
Full text
Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been r...Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been reported in Lewy body disease and other parkinsonian disorders, but from existing literature it remains unclear whether these findings are driven by neurodegeneration-related iron deposition or other neuropathologic features. We studied 59 autopsied participants who underwent antemortem 3 T MRI with QSM (median age at death, 78.5 years; MRI-to-death interval, 2.0 years), including clinical diagnoses of 18 with Alzheimer's-type dementia, 15 cognitively unimpaired, 9 with mild cognitive impairment, and 9 with dementia with Lewy bodies. A machine learning-incorporated digital histopathology pipeline quantified tau burden, iron deposition, and neuronal densities. The SN was divided into geometric quadrants, and QSM values were analyzed in relation to corresponding neuropathologic measures within each quadrant. Iron deposition correlated with QSM in all quadrants (ρ = 0.41-0.56, all P < 0.005). Tau burden correlated with QSM in the ventromedial (VM) quadrant (ρ = 0.45, P = 0.002), whereas lower pigmented neuron density was associated with higher QSM in the dorsomedial quadrant (ρ = - 0.35, P = 0.007). Rank regression analysis confirmed iron as the strongest predictor of QSM across all quadrants (β = 0.35-1.06, P ≤ 0.026), with tau independently associated with QSM in the VM (β = 0.45, P = 0.015). Mediation analysis demonstrated that tau exerted direct (0.45, P = 0.018) and indirect effects via iron (0.12, P = 0.046) on QSM in the VM, with 80% of the effect being direct. These findings underscore the contributions of tau pathology, pigmented neuron density, and iron deposition to nigral magnetic susceptibility and highlight the potential for QSM to serve as a sensitive biomarker for diverse neuropathologies.