Dennis W. Dickson

Tau A152T risk variant drives distinct cell type transcriptional signatures in AD and PSP

The A152T point mutation is a rare genetic variant in the tau gene (MAPT) that is linked to risk of Alzheimer's disease (AD) and frontotemporal dementia spectrum disorders, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). To uncover mechanisms through which the A152T variant contributes to risk of tauopathy, we performed single-nucleus RNA sequencing (snRNA-seq) on postmortem brain tissue collected from A152T carriers and pathology-matched non-carriers with either AD or PSP, along with age-matched controls. These efforts revealed that despite similar cell type composition across groups, A152T carriers exhibited distinct cell type-specific transcriptional changes in both AD and PSP. Differential expression analysis identified excitatory neurons, oligodendrocytes, and astrocytes as the most affected cell populations in AD and PSP, and these same cell types showed the strongest A152T-specific changes. These findings identify transcriptional alterations that differentiate sporadic AD and sporadic PSP from AD-A152T and PSP-A152T, as well as shared molecular signatures unique to A152T carriers in both PSP and AD. Donor-level pseudo-bulk analyses showed broad directional support with the single-nucleus findings although the proportion of donor-supported genes varied across cell type and comparison. Importantly, merging sporadic and A152T cases into a single disease group was found to mask transcriptional differences in several cell types in both AD and PSP, indicating divergence in transcriptional signature and highlighting the importance of screening for genetic risk variants like A152T in snRNA-seq data from human cohorts.

Comparative neuropathological evaluation of pT217 immunoreactivity in human and transgenic mouse tauopathies

Tau phosphorylation at threonine 217 (pT217) has been increasingly recognized as a biomarker for Alzheimer disease (AD), but its neuropathological distribution and the performance of available antibodies remain to be fully characterized. In this study, we performed a comparative evaluation of a recombinant rabbit monoclonal anti-pT217 antibody (mAb) using immunohistochemical and biochemical analyzes in human and transgenic mouse tauopathies and compared results to those of a commercially available anti-pT217 antibody and the AT8 antibody. In rTg4510 mice, the anti-pT217 mAb detected pathological tau aggregates with high sensitivity, including hyperphosphorylated tau species identified by biochemical fraction. In human postmortem brain tissues (AD, Pick disease, progressive supranuclear palsy, corticobasal degeneration), quantitative image analysis demonstrated labeling of a broad range of tau lesions, including neurofibrillary tangles, neuropil threads, tufted astrocytes, astrocytic plaques, and Pick bodies. The overall detectability was comparable to that of AT8 and similar to or modestly > that of a representative commercial anti-pT217 antibody. These findings indicate that pT217 is widely present across tauopathies and suggest that the recombinant anti-pT217 mAb provides a sensitive and reproducible tool for neuropathological assessment. Together, these results provide a framework for evaluating anti-pT217 antibodies in neuropathological studies.

Serine-65 phosphorylated ubiquitin associates with soluble tau and seeding activity in Alzheimer’s disease

Tau propagation is a key driver of Alzheimer’s disease (AD), yet selective markers of seeding-competent tau remain elusive. Ubiquitin phosphorylated at Serine-65 (pS65-Ub) is a PINK1-derived cellular stress signal that accumulates in AD with elevated tau pathology, but its relationship to tau seeding is unknown. Here, using postmortem brain tissue from female and male donors, we show that a subset of tau is covalently modified by pS65-Ub in AD brain. The pS65-Ub-associated tau population is elevated in AD and is enriched in soluble, high-molecular-weight, oligomeric, and hyperphosphorylated tau species. Across AD cases, soluble pS65-Ub-associated tau levels strongly correlate with tau seeding activity. Tau species isolated with pS65-Ub antibodies exhibit seeding activity, whereas removal of pS65-Ub-associated material markedly reduces seeding from AD brain extracts. Together, these findings identify pS65-Ub as a disease-enriched molecular feature of a seed-competent tau population and link cellular stress signaling with pathological tau propagation in AD. Not all selective markers of seeding-competent Tau are known. Here, the authors identify pS65-Ub-associated tau linked to pathological Tau spreading and elevated in Alzheimer’s disease. Removal of pS65-Ub reduces tau seeding activity.

APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease

The apolipoprotein E ( APOE ) gene is the strongest genetic risk factor for Alzheimer’s disease (AD), influencing amyloid-β (Aβ) aggregation, clearance, and glial function. While APOE4 promotes Aβ pathology and APOE2 is protective, how these opposing alleles interact in the heterozygous APOE2/4 state remains unknown. Here, using littermate-controlled heterozygous APOE mice ( APOE2/3 , APOE3/4 , and APOE2/4 ) alongside APOE3/3 controls crossed with 5xFAD mice, we show that APOE3/4 mice exhibit increased Aβ deposition, maladaptive microglial activation, and reduced microglial interactions with plaques. These changes were attenuated in APOE2/4 mice, accompanied by a brain proteomic profile more similar to those of APOE3/3 and APOE2/3 mice. Increased myelin basic protein (MBP) abundance was observed in APOE2/3 but not APOE2/4 mice. Plasma lipidomics revealed shared alterations in APOE3/4 and APOE2/4 mice, with distinct signatures in APOE2/3 mice. These findings define allele interaction-dependent effects of APOE on brain and systemic phenotypes and provide a framework for understanding the biological consequences of the APOE2/4 genotype.

Plasma eMTBR‐tau243 as a disease biomarker across Alzheimer's disease clinical phenotypes

INTRODUCTION: The concentration of endogenous tau microtubule-binding region containing residue-243 in plasma (eMTBR-tau243) has been proposed to be a sensitive biomarker of tangle pathology in Alzheimer's disease (AD). We assessed eMTBR-tau243 and phosphorylated tau217 (p-tau217) with tau and Aβ-positron emission tomography (PET) across different AD clinical phenotypes. METHODS: Plasma eMTBR-tau243, p-tau217, and the ratio of non-phosphorylated to phosphorylated tau217 (%p-tau217) were measured in 20 Aβ-PET positive AD patients representing four clinical phenotypes and 10 cognitively unimpaired controls. Plasma levels were correlated with PET, demographic and cognitive variables. RESULTS: Plasma eMTBR-tau243, p-tau217, and %p-tau217 levels were greater in AD than controls, with greatest levels observed in motor-predominant AD. Plasma biomarker levels correlated with cortical flortaucipir-PET uptake; eMTBR-tau243 correlations were strongest. In AD, eMTBR-tau243 levels were undetectable in patients with mild/focal flortaucipir-PET uptake (45%). Only eMTBR-tau243 correlated with cognition. DISCUSSION: Plasma eMTBR-tau243 may be an excellent biomarker for tau deposition and cognition in AD across different phenotypes.

SEP 23JosephsiScience

Neurofibrillary tangle deposition in primary idiotypic isocortices using flortaucipir PET in histopathologically confirmed Alzheimer’s disease

Tau deposition in Alzheimer's disease (AD) spreads throughout the brain in a stereotypical pattern captured by the Braak neurofibrillary tangle staging scheme. While involvement of primary isocortex defines the highest stage, it is unclear whether flortaucipir PET uptake differs among primary isocortical regions. We determined relationships between flortaucipir uptake in primary visual, auditory, motor, and somatosensory isocortices and Braak stage in 155 autopsy-confirmed participants with AD. Flortaucipir uptake was observed starting at Braak stage V, with visual and auditory isocortices showing greater and faster increases in uptake than somatosensory and motor; age and APOE ε4 influenced uptake. Flortaucipir uptake and change in primary isocortices were similar in the lateral temporal cortex but different in the entorhinal cortex. Findings suggest that tau deposition in primary isocortices in AD occurs earlier than currently emphasized, although there are differences among them. Given these findings, clinical correlations of primary isocortical involvement in AD need to be evaluated.

Distinct and shared multimodal neuroimaging patterns in clinical frontotemporal dementia syndromes

Observational study uncovers distinct neuroimaging covariance patterns across frontotemporal dementia syndromes, highlighting the diagnostic utility of structural and metabolic brain imaging.

Cell type- and tau lesion-specific accumulation of phospho-Ser65 ubiquitin in primary tauopathies

Postmortem brain analysis reveals disease- and cell-specific phospho-Ser65 ubiquitin accumulation in primary tauopathies, highlighting its utility for differential diagnosis.

Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer’s disease

Post-mortem multiomic study reveals widespread tau-related transcriptomic dysregulation in Alzheimer's disease brains, highlighting dynamic gene expression networks tracking disease progression.

APOE2 attenuates APOE4-associated amyloid pathology and related toxicity

Preclinical animal study demonstrates that APOE2 mitigates APOE4-driven amyloid pathology in mice, indicating protective molecular mechanisms against neurodegeneration.

The UNC13A cryptic exon associates with cognitive impairment in Alzheimer’s disease

Cohort study reveals UNC13A cryptic splicing associates with accelerated cognitive decline in Alzheimer disease, indicating a specific RNA mis-splicing driver of cognitive impairment.

TAF15 amyloids propagate via defined motifs in a prion-like fashion

TATA-box binding protein–associated factor 15 (TAF15) is an RNA-binding member of the FET family recently identified as the primary fibrillar constituent in a subset of frontotemporal lobar degeneration (FTLD-FET) cases. Although TAF15 is also linked to amyotrophic lateral sclerosis (ALS), the molecular basis and propagation behavior of its aggregates remain unknown. In this work, we show that recombinant TAF15 forms amyloid fibrils under physiological conditions and developed a single-fluorophore TAF15 biosensor to quantitatively monitor their cellular propagation. Using this system, we demonstrate that both recombinant TAF15 fibrils and pathological aggregates extracted from atypical FTLD with ubiquitin inclusions (aFTLD-U) patient brains seed aggregation efficiently and transmit serially between cells, demonstrating hallmark features of prion-like propagation. Seeding was specific to TAF15 and absent for other amyloidogenic proteins, including the homologous protein fused-in-sarcoma (FUS), revealing an unexpected cross-seeding barrier. Occasional colocalization of FUS within TAF15 inclusions was observed upon transient co-expression, suggesting that FUS can be passively recruited rather than acting as an inducer of pathology in FTLD-FET brains. Computational and peptide-based experimental mapping identified multiple aggregation-prone regions within the TAF15 low-complexity domain that coincide with hotspots stabilizing the core of ex vivo TAF15 amyloid fibrils. These short motifs encode the propagation propensity of TAF15 aggregation in vitro and in cells. Together, these findings establish TAF15 as a bona fide amyloid-forming, prion-like protein and define the sequence grammar underlying its self-assembly, providing a mechanistic framework for its role in FTLD-FET and ALS and offering tractable molecular targets for therapeutic intervention.

Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick’s disease

Phosphorylated ubiquitin is a secondary messenger and an epigenetic mark mediating mitochondria to nucleus signaling

Parkinson's disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

Herpesvirus genome integration in whole‐genome sequences of dementia and control cohorts

Analysis reveals herpesvirus genome integration in dementia patients, suggesting a link to specific conditions.

Predicting pattern and spread of brain atrophy and tau deposition in progressive supranuclear palsy

BACKGROUND: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy characterized by clinicopathological heterogeneity. The complex interplay between tau deposition, structural changes, and disease spread are unclear. OBJECTIVES: To investigate the temporospatial patterns of tau propagation and neurodegeneration using multimodal imaging with MRI and flortaucipir (FTP) PET, and determine relationship with clinical heterogeneity. METHODS: 150 PSP patients (n = 66 Richardson's syndrome [PSP-RS], n = 26 parkinsonism [PSP-P], n = 25 speech-language [PSP-SL], n = 13 progressive gait freezing (PSP-PGF), n = 10 corticobasal syndrome [PSP-CBS], n = 3 frontal, n = 1 oculomotor and n = 6 postural instability) underwent 3 T-MRI and FTP-PET. Forty-three patients died and underwent autopsy. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that separates data-driven disease phenotypes distinguished by diverse temporal progression patterns, was applied to both MRI and FTP-PET W-scores (adjusted for age, sex and scanner, using 102 controls). Longitudinal MRI (n = 76) and FTP (n = 56) data, analysed with linear mixed models, were used to assess regional progression patterns and compared with the machine learning predictions. RESULTS: Two subtypes emerged across modalities. Subtype 1 exhibited initial subcortical involvement, mainly included PSP-RS and PSP-P patients and mostly featured PSP pathology, while subtype 2 exhibited early cortical involvement, PSP-SL patients and CBD pathology. FTP-PET stages preceded MRI stages, suggesting tau deposition anticipates atrophy. MRI stages were better in capturing clinical progression and predicting longitudinal disease evolution. CONCLUSIONS: These findings suggest the existence of subcortical and cortical subtypes of PSP, with distinct clinicopathological features. Tau PET and MRI provide complementary insights into disease progression, with MRI more closely reflecting clinical evolution.

Identification of common variants influencing risk of the three-repeat tauopathy Pick’s disease: a genome wide association study

Pick’s disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Pick’s disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Mapping and Annotation of GWAS (FUMA) platform, followed by co-localisation analyses using the METABRAIN dataset and statistical finemapping using FINEMAP and SuSiE. After exclusion of 3 cases of MAPT mutations, no variants were associated with risk of PiD at genome-wide significance ( p < 5 × 10 -8 ). The strongest association was on chromosome 4 (4p13, lead SNP rs112161979, OR = 7.53, 95% Confidence Interval (CI) = 3.62-15.65, p = 6.37 × 10 -8 ) followed by chromosome 11 (11p15.4, lead SNP rs66481907, OR = 2.10, 95% CI = 1.54-2.84, p = 1.83 × 10 -6 ). rs112161979 is an intronic SNP in the KCDT8 gene, encoding a potassium channel tetramerization domain that acts as an auxiliary subunit for GABA B receptors, whilst rs66481907 is an intronic SNP in TRIM22 , encoding an E3 ubiquitin-protein ligase. Our GWAS provides the first evidence of possible genetic risk for PiD that implicate the modulation of GABA B receptor signalling and inflammation, in disease pathogenesis. Replication of these findings will be important, but our results suggest that, if present, the genetic risk of PiD beyond MAPT mutations is low.

White matter hyperintensities in the deep cerebral venous territory differ between subcortical and cortical 4-repeat tauopathies

BACKGROUND: Progressive supranuclear palsy (PSP) syndromes and corticobasal syndrome (CBS) are atypical parkinsonian disorders resulting from 4-repeat (4R) tauopathies. They target a common network of brain regions, although relative involvement of cortical and subcortical regions differs. White matter hyperintensities (WMHs) are explicit in neurodegenerative disorders, however, little is known about their distribution in 4R-tauopathies. OBJECTIVES: To evaluate the distribution of WMHs in the cortical and subcortical predominant 4R-tauopathies using venous territory-based and the derivative layer designed atlases. METHODS: Ninety-five participants with clinical variants of PSP or CBS were recruited by the Neurodegenerative Research Group, Mayo Clinic, and were classified as cortical (n = 64) or subcortical (n = 31) predominant. WMH volume was calculated for superficial, deep cerebral venous territory, and the periventricular (PV) region. Additionally, a layered atlas was created to assess WMH volume from the lateral ventricles (LV) to the brain surface. WMH volumes, clinical tests, and vascular-relevant histories were compared across groups and to 50 age-matched controls. RESULTS: Compared to the cortical group, the subcortical group had greater WMHs in the deep venous territory (p = 0.04). The major WMHs in the subcortical group distributed in layers 5-10 (12-30 mm from the LV) (p ≤ 0.01). The subcortical group had more histories of old strokes, chronic kidney disease, and headache. CONCLUSIONS: The distribution of WMHs in the deep cerebral venous territory and the presumed watershed zone suggests that dysfunction of the venous system may play a role in the pathomechanism of 4R-tauopathies, particularly subcortical variants.

Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.

TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD

Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.