Neurofibrillary Tangle Burden Research Articles

Learning precise segmentation of neurofibrillary tangles from rapid manual point annotations.

Accumulation of abnormal tau protein into neurofibrillary tangles (NFTs) is a pathologic hallmark of Alzheimer disease (AD). Accurate detection of NFTs in tissue samples can reveal relationships with clinical, demographic, and genetic features through deep phenotyping. However, expert manual analysis is time-consuming, subject to observer variability, and cannot handle the data amounts generated by modern imaging. We present a scalable, open-source, deep-learning approach to quantify NFT burden in digital whole slide images (WSIs) of post-mortem human brain tissue. To achieve this, we developed a method to generate detailed NFT boundaries directly from single-point-per-NFT annotations. We then trained a semantic segmentation model on 45 annotated 2400μm by 1200μm regions of interest (ROIs) selected from 15 unique temporal cortex WSIs of AD cases from three institutions (University of California (UC)-Davis, UC-San Diego, and Columbia University). Segmenting NFTs at the single-pixel level, the model achieved an area under the receiver operating characteristic of 0.832 and an F1 of 0.527 (196-fold over random) on a held-out test set of 664 NFTs from 20 ROIs (7 WSIs). We compared this to deep object detection, which achieved comparable but coarser-grained performance that was 60% faster. The segmentation and object detection models correlated well with expert semi-quantitative scores at the whole-slide level (Spearman's rho ρ=0.654 (p=6.50e-5) and ρ=0.513 (p=3.18e-3), respectively). We openly release this multi-institution deep-learning pipeline to provide detailed NFT spatial distribution and morphology analysis capability at a scale otherwise infeasible by manual assessment.

Distinct transcriptional alterations distinguish Lewy body disease from Alzheimer's disease.

Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy body disease (LBD) is characterized by alpha-synuclein aggregates in the form of Lewy bodies as well as the deposition of extracellular amyloid plaques, with many cases also exhibiting neurofibrillary tangle (NFT) pathology. In contrast, Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles. Both conditions often co-occur with additional neuropathological changes, such as vascular disease and TDP-43 pathology. To elucidate shared and distinct molecular signatures underlying these mixed neuropathologies, we extensively analyzed transcriptional changes in the anterior cingulate cortex, a brain region critically involved in cognitive processes. We performed bulk tissue RNAseq from the anterior cingulate cortex and determined differentially expressed genes (q-value < 0.05) in control (n = 81), Lewy body disease (n = 436), Alzheimer's disease (n = 53), and pathological amyloid cases consisting of amyloid pathology with minimal or no tau pathology (n = 39). We used gene set enrichment and weighted gene correlation network analysis (WGCNA) to understand the pathways associated with each neuropathologically defined group. Lewy body disease cases had strong up-regulation of inflammatory pathways and down-regulation of metabolic pathways. The Lewy body disease cases were further subdivided into either high Thal amyloid, Braak NFT, or low pathological burden cohorts. Compared to the control cases, the Lewy body disease cohorts consistently showed up-regulation for genes involved in protein folding and cytokine immune response, as well as down-regulation of fatty acid metabolism. Surprisingly, concomitant tau pathology within the Lewy body disease cases resulted in no additional changes. Some core inflammatory pathways were shared between Alzheimer's disease and Lewy body disease but with numerous disease-specific changes. Direct comparison of Lewy body disease cohorts versus Alzheimer's disease cases revealed strong enrichment of synaptic signaling, behavior, and neuronal system pathways. Females had a stronger response overall in both Lewy body and Alzheimer's disease, with several sex-specific changes. Overall, the results identify genes commonly and uniquely dysregulated in neuropathologically defined Lewy body disease and Alzheimer's disease cases, shedding light on shared and distinct molecular pathways. Additionally, the study underscores the importance of considering sex-specific changes in understanding the complex transcriptional landscape of these neurodegenerative diseases.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

Using an ex vivo MRI atlas of the human medial temporal lobe to characterize the 3D distribution of neurofibrillary tangle burden across histologically defined subregions

AbstractBackgroundAccumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer’s Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses.MethodWe combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion.ResultFig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3).ConclusionBuilding on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers

Targeted bisulfite sequencing analysis of Alzheimer’s disease candidate genes reveals differential methylation across neurofibrillary tangle burden in the prefrontal cortex.

AbstractBackgroundRecent epigenome‐wide association studies (EWAS) identified several loci in specific genes showing robust and reproducible alterations in DNA methylation in Alzheimer’s disease (AD) brain samples. Standardly, assessing methylation in EWAS is done using microarrays, which target a limited number of sites in each gene. Here, we performed targeted bisulfite sequencing of candidate genes associated with AD to determine the exact extent of methylation changes across neurofibrillary tangle burden (NFT) within these loci.MethodPrefrontal cortex brain samples from 58 individuals were grouped by Braak stage (control 0‐II; intermediate III‐IV; AD V‐VI). Following DNA extraction, 30 genomic regions were captured using Agilent SureSelect target baits. After next‐generation bisulfite sequencing, reads were aligned and the methylation status of cytosine residues called using the Bismark program. Differentially methylated positions (DMPs) were analyzed across the three groups. Furthermore, the presence of differentially methylated regions (DMRs), made up of several DMPs was assessed. Methylation levels in genomic features, such as promoters and gene bodies, of the target regions were also compared.ResultMethylation levels were quantified for each group. Linear regression controlled for co‐variation before differences were examined using a one‐way ANOVA, with Tukey’s post‐hoc test. Sites in several genes showed stepwise increases in DNA methylation across the groups. Interestingly, amongst the most robust sites, differences in methylation in the intermediate group when compared to the control and AD samples were observed. DMRs were observed in the groups, as were methylation differences between promotors and gene bodies in several targeted regions.ConclusionThis work provides further evidence that dysregulation of methylation is associated with pathological changes in AD prefrontal cortex. Differential methylation with intermediate NFT pathology, at sites showing no difference between control and AD samples, potentially indicates early pathological changes. As DNA methylation is reversible, this could present potential targets for pharmacological intervention.

Association between APOE‐ε4 allele and cognitive function is mediated by Alzheimer’s disease pathology: a population‐based autopsy study in an admixed sample

AbstractBackgroundApolipoprotein E ε4 allele (APOE‐ε4) is the main genetic risk factor for dementia. APOE‐ε4 is also associated with Alzheimer’s disease (AD) pathology, cerebrovascular disease, and non‐AD neurodegenerative pathologies. Although APOE‐ε4 may influence cognitive impairment through these pathways, less evidence is available from diverse populations, considering that APOE genotype associations seem to vary by race. Therefore, we aimed to evaluate the pathways linking APOE‐ε4 to cognition through AD and non‐AD neuropathology in an autopsy study with an admixed sample.MethodWe used data from the Biobank for Aging Studies of the University of Sao Paulo Medical School. Participants were classified into APOE‐ε4 carriers (at least one ε4 allele) and non‐carriers. Cognitive function was evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the APOE‐ε4 association with cognition through direct and indirect pathways. Indirect pathways included the following mediators: AD‐type pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA‐binding protein 43 (TDP‐43). We used immunohistochemistry to detect AD pathology, CAA, LBD, and TDP‐43. AD pathology was scored using the Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for AD criteria for β‐amyloid plaque. Lacunar infarcts and hyaline arteriosclerosis were evaluated microscopically using hematoxylin and eosin‐stained. All analyses were adjusted for demographic and clinical cofounders.ResultWe included 648 participants (mean age 75±12 y, 52% women, 69% white, and 28% APOE‐ε4 carriers). The association between APOE‐ε4 and cognitive abilities was mediated by the burden of neurofibrillary tangles (β = 0.78, 95% CI = 0.39; 1.22, p&lt;0.001) and β‐amyloid plaques (β = 0.87, 95% CI = 0.39; 1.40, p&lt;0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP‐43 were not mediators in the pathway from APOE‐ε4 to cognitive function. Direct pathways remained significant in the presence of all mediators except TDP‐43 (p = 0.09) and β‐amyloid plaques (p = 0.07).ConclusionThe influence of APOE‐ε4 on cognitive abilities was partially mediated by AD pathology. However, cerebrovascular lesions and non‐AD pathologies were not mediators in the pathway linking APOE‐ε4 to cognition.

Synaptic density is correlated with Aβ plaques and neurofibrillary tau tangles across the clinical and biologic Alzheimer’s disease continuum

AbstractBackgroundThe extent to which amyloid‐β burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐β plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer’s disease continuum.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer’s disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson’s r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR.ResultGlobal [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005).ConclusionBoth amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed.

Synaptic density is correlated with Aβ plaques and neurofibrillary tau tangles across the clinical and biologic Alzheimer’s disease continuum

AbstractBackgroundThe extent to which amyloid‐ß burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐ß plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer’s disease continuum.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer’s disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson’s r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR.ResultGlobal [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005).ConclusionBoth amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed.

Association between military service identified through public data tracing and Alzheimer’s disease neuropathology at autopsy

AbstractBackgroundMilitary veterans face increased risk of Alzheimer’s disease and related dementias (ADRD) compared to the general population, but the association between the military exposome and ADRD pathology is poorly understood. Existing biobanks rarely collect military service information, complicating efforts to characterize military risk factors. Public data tracing methods linking the military exposome to existing neuropathological data have the potential to catalyze research on the mechanisms driving brain health disparities.MethodSubjects were decedents from two Alzheimer’s Disease Research Center brain banks who died between 1986‐2018 and were characterized on neurofibrillary tangle burden (NFT‐B score, n = 1154). Military service was characterized through public data tracing (Figure 1): systematic extractions from public records including obituaries, newspapers, and enlistment records (Figure 2). NFT‐B score, per National Institute of Aging and Alzheimer’s Association guidelines for neuropathologic change, was extracted from the standardized Neuropathology Dataset form or from original autopsy reports. Generalized ordered logistic regression with site‐level clustered standards errors was used to model NFT‐B score, adjusting for age, sex, and year of death.ResultPublic data tracing identified 373 decedents (32% of the sample) with a history of military service. After adjusting for age, sex, and year of death, decedents with a history of military service had a 12% greater odds (OR = 1.12, 95% CI: 1.11–1.13) of a more severe NFT burden compared to those without a history of military service, which was proportional when comparing the odds at each increasing B score level (B score = (1,2, or 3), vs (0), B score = (2,3) vs (0,1) and B score = (3) vs (0,1,2)) (Table 1).ConclusionPublic data tracing offers a promising way to retrospectively add the military exposome into brain tissue biomarkers research. Military service was associated with more severe neurofibrillary tangle pathology, one of the primary neuropathological features of Alzheimer’s disease. Future research should explore the feasibility and validity of public data tracing for more detailed characterization of military service, such as length and branch of service, involvement in specific conflicts, or exposure to environmental toxins, which may elucidate mechanisms underlying its association with ADRD pathology.

Associations of Age and Sex with Levels of Tau PET in Screened Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease

AbstractBackgroundThe ongoing Autonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia with a CDR Global Score of 0.5 and who are tau PET positive. The Janssen plasma p217+tau assay is used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date we report on associations of age and sex with tau PET, a biomarker for neurofibrillary tangle (NFT) burden, and with plasma p217+tau levels.Method18F‐MK6240 Tau PET SUVRs for 355 screened participants (180 female) were quantified in Braak Regions Of Interest (ROI)[1] 1 through 6 using cerebellar gray as reference region. Associations were analyzed using a linear model of regional SUVR as a function of age and sex. Additionally, models of association for plasma p217+tau in log(pg/ml) were considered.ResultAge at baseline was not different (p&gt;0.5) for female (70.84 y) versus male (70.49 y) participants. For Braak 3 ROI, tau PET SUVRs showed significant negative association for age (R2partial = 16%, p&lt;10‐14), and increased levels in females (R2partial = 2%, p&lt;0.01). The results were qualitatively similar across Braak ROIs 1 through 4. For Braak ROIs 5, and 6, the effect of sex was no longer significant, although the trend remained in a consistent direction. For plasma p217+tau, we found significant negative association for age (R2partial = 7%, p&lt;10‐6) and a trend for higher levels in female participants (R2partial = 1%, p = 0.05).ConclusionIn early Alzheimer’s disease participants who were screened with tau PET for the ongoing Autonomy trial, higher SUVR was observed for younger versus older participants and in females versus males. The effect of age is likely due to the cohort’s cognitive uniformity whereby in younger participants, a higher tau burden as measured by PET is required for the same level of impairment as older participants[2]. The increased tau PET NFT levels observed in female participants is consistent with findings by Edwards et al. [3]. Associations of similar directions were also observed for plasma p217+tau. [1] Schöll et al., Neuron 2016. [2] Jack et al., Brain 2018. [3] Edwards L et al., Neurobiology of Aging 2021

Associations of Age and Sex with Levels of Tau PET in Screened Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease

AbstractBackgroundThe ongoing Auτonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia with a CDR Global Score of 0.5 and who are tau PET positive. The Janssen plasma p217+tau assay is used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date we report on associations of age and sex with tau PET, a biomarker for neurofibrillary tangle (NFT) burden, and with plasma p217+tau levels.Method18F‐MK6240 Tau PET SUVRs for 355 screened participants (180 female) were quantified in Braak Regions Of Interest (ROI)[1] 1 through 6 using cerebellar gray as reference region. Associations were analyzed using a linear model of regional SUVR as a function of age and sex. Additionally, models of association for plasma p217+tau in log(pg/ml) were considered.ResultAge at baseline was not different (p&gt;0.5) for female (70.84 y) versus male (70.49 y) participants. For Braak 3 ROI, tau PET SUVRs showed significant negative association for age (R2 partial = 16%, p&lt;10−14), and increased levels in females (R2 partial = 2%, p&lt;0.01). The results were qualitatively similar across Braak ROIs 1 through 4. For Braak ROIs 5, and 6, the effect of sex was no longer significant, although the trend remained in a consistent direction. For plasma p217+tau, we found significant negative association for age (R2 partial = 7%, p&lt;10−6) and a trend for higher levels in female participants (R2 partial = 1%, p = 0.05).ConclusionIn early Alzheimer’s disease participants who were screened with tau PET for the ongoing Auτonomy trial, higher SUVR was observed for younger versus older participants and in females versus males. The effect of age is likely due to the cohort’s cognitive uniformity whereby in younger participants, a higher tau burden as measured by PET is required for the same level of impairment as older participants[2]. The increased tau PET NFT levels observed in female participants is consistent with findings by Edwards et al. [3]. Associations of similar directions were also observed for plasma p217+tau.[1] Schöll et al., Neuron 2016. [2] Jack et al., Brain 2018. [3] Edwards L et al., Neurobiology of Aging 2021

Neurofibrillary tangle distribution in posterior cortical atrophy and early‐onset Alzheimer disease

AbstractBackgroundEarly onset sporadic Alzheimer’s disease (AD) sometimes presents with non‐memory symptoms attributed to relatively greater neocortical than hippocampal tau neurofibrillary tangle (NFT) density. Posterior cortical atrophy (PCA) is a variant of AD presenting with visuospatial deficits and atrophy of the occipital cortex, yet the pathologic underpinning is poorly understood.MethodWe examined brains of 50 patients with early onset (age&lt;65 y.), autopsy‐confirmed AD from the UCSD Alzheimer’s Disease Research Center, 12 of whom were clinically diagnosed with PCA. Immunohistochemistry for tau was performed in the hippocampus (HP), midfrontal cortex (MF), and occipital cortex (OC), and the density of NFTs was measured.ResultPCA and non‐PCA patients did not significantly differ in age (63.35±4.59 y. at death) or sex (40% female). The APOE ε4 allele was much less frequent in PCA (p = 0.002). While the PCA group was less impaired on the MMSE (p = 0.01), they performed comparably on the CDR sum‐of‐boxes. The OC NFT density did not differ between the groups; however, the OC/HP (p = 0.04) and OC/MF (p = 0.008) ratios demonstrate that PCA cases had relatively greater OC pathology than non‐PCA patients. Across the groups, age at symptom onset was inversely associated with OC NFT density (p = 0.01) and the OC/HP NFT ratio (p = 0.008), such that earlier onset was associated with greater OC NFT burden. Visuospatial performance, measured by the Block Design test, was associated with the OC NFT density (p = 0.006), as well as the OC/HP (p = 0.007) and OC/MF NFT ratios (p = 0.03), with the effects remaining significant when restricting to non‐PCA participants. In contrast, memory performance measured by the Logical Memory Immediate Recall measure was only associated with HP NFT density (p = 0.02).ConclusionDespite differences in the predominance of early visuospatial symptoms, PCA and non‐PCA patients did not differ in OC tangle density, with some of the highest densities in non‐PCA patients. However, the degree of visuospatial impairment was associated with the OC/HP NFT ratio across both groups. Results suggest that greater memory impairment in the non‐PCA patients associated with a higher HP tangle density may moderate the predominance of visuospatial impairment so that they do not receive a formal PCA diagnosis.

Cerebral amyloid angiopathy and neuritic plaques impact tangle burden and cognitive decline in a heterogeneous clinical population

AbstractBackgroundAlzheimer disease (AD) presents with two primary pathologies: neurofibrillary tangles (NFT) and neuritic plaques (NP). However, these hallmark pathologies typically co‐occur with pathologies from AD‐related dementias like cerebral amyloid angiopathy (CAA) [Godrich, 2022; PMID: 35142102]. While CAA is known to impact cognitive impairment, the role of CAA in AD dementia is still not well described [Rabin, 2022; PMID: 35759327]. Here we present an analysis of CAA, NP, and NFT to assess the interplay of these pathologies with cognitive decline and genetic risk factors for AD.MethodData come from 4,915 autopsied individuals from the National Alzheimer’s Coordinating Centers (NACC). NFT, NP, and CAA were measured ordinally. We used ordinal logistic regression to model and compare independent and interactive effects of CAA and NP on NFT and cognitive decline while adjusting for sex, AAD, and APOE. We also evaluate models with an APOE and NP interaction as a comparison to gauge whether it is more informative than CAA. Finally, we replicate causal mediation analysis from Rabin et al. and extend the path model to include APOE, stratifying both models by NP severity (Fig.1).ResultThe model with CAA and NP interactions best explained NFT burden outcome (per AIC, pseudo‐R2, and F‐test), even when compared to models with APOE. We replicated Rabin et al. findings that CAA does not directly affect cognitive decline but rather indirectly via NFT mediation, but only in individuals in the high NP group. We saw this in a larger clinical cohort with ordinal measures of neuropathology, which are more commonly obtained than linear ones. We also extended the mediation analysis to include APOE and findings held.ConclusionWe replicated the relationship between CAA, AD pathologies, and cognitive decline [Rabin, 2022] and extend the findings to a more heterogeneous clinical population. Even when accounting for APOE, CAA still had an indirect effect on cognitive decline in the high NP group as mediated by NFT severity, showing that the findings are likely not due to APOE confounding. These findings continue to underscore the importance of the consideration of co‐occurring neuropathologies like CAA when developing novel AD therapeutics.

Association of neuropathological lesions with body mass index by the time of death

AbstractBackgroundThe association between moderate/severe dementia and lower Body Mass Index (BMI) is well described, but the weight decline seems to also occur in cognitively normal individuals with preclinical dementia. Considering that up to one‐fifth of individuals with normal cognition might meet the criteria for a neuropathological diagnosis, autopsy studies are key detecting neurodegenerative and cerebrovascular diseases that could be underlining weight changes during the life course. Therefore, we investigated the association between dementia‐related brain lesions and BMI and evaluated whether cognitive function was a mediator of this association.MethodNeuropathological study in a population‐based sample of 1,170 Brazilians. Clinical variables and cognition evaluation were obtained through a post mortem interview with a proxy. Linear regression adjusted models were used to investigate the association between each neuropathologic lesion (independent variable) and the BMI (dependent variable). The direct and indirect (considering a mediation by cognitive abilities) effects of each neuropathologic lesion on BMI were evaluated through a mediation model.ResultIndividuals with lower body weight were more likely to have a higher burden of neuropathological lesions and worse cognitive abilities. Neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI. Mediation analyses showed these lesions were directly associated with BMI and indirectly through cognitive abilities. Despite having normal cognitive abilities, 25% of the sample had at least one neuropathologic diagnosis. High NFT burden was associated with lower BMI even in these participants.ConclusionNeurofibrillary tangles were associated with lower BMI independent of cognitive abilities.

Discovery of FERM domain protein–protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer’s disease

Proteomic studies have identified moesin (MSN), a protein containing a four-point-one, ezrin, radixin, moesin (FERM) domain, and the receptor CD44 as hub proteins found within a coexpression module strongly linked to Alzheimer's disease (AD) traits and microglia. These proteins are more abundant in Alzheimer's patient brains, and their levels are positively correlated with cognitive decline, amyloid plaque deposition, and neurofibrillary tangle burden. The MSN FERM domain interacts with the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) and the cytoplasmic tail of CD44. Inhibiting the MSN-CD44 interaction may help limit AD-associated neuronal damage. Here, we investigated the feasibility of developing inhibitors that target this protein-protein interaction. We have employed structural, mutational, and phage-display studies to examine how CD44 binds to the FERM domain of MSN. Interestingly, we have identified an allosteric site located close to the PIP2 binding pocket that influences CD44 binding. These findings suggest a mechanism in which PIP2 binding to the FERM domain stimulates CD44 binding through an allosteric effect, leading to the formation of a neighboring pocket capable of accommodating a receptor tail. Furthermore, high-throughput screening of a chemical library identified two compounds that disrupt the MSN-CD44 interaction. One compound series was further optimized for biochemical activity, specificity, and solubility. Our results suggest that the FERM domain holds potential as a drug development target. Small molecule preliminary leads generated from this study could serve as a foundation for additional medicinal chemistry efforts with the goal of controlling microglial activity in AD by modifying the MSN-CD44 interaction.

Association of short tandem repeats with neuropathological features in late‐onset of Alzheimer’s disease brains

AbstractBackgroundLate‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. Short tandem repeats (STRs), which are hyper‐mutable sequences in the human genome could explain some of the missing heritability in LOAD. STRs are involved in several neuro‐degenerative disorders. We systematically evaluated the impact of 31 disease‐associated STRs on neuropathological LOAD features.MethodFrom whole‐genome sequencing (WGS) data in for 1,134 unrelated individuals of European ancestry from Religious Orders Study (ROS) and Rush Memory and Aging project (MAP) cohorts, we identified known pathogenic STRs in 31 loci using ExpansionHunter. WGS was generated from DNA extracted from blood and brain tissues. We tested the association of STRs with a) neuropathological LOAD status, b) beta‐amyloid levels, c) neurofibrillary tangle (NFT) burden, d) global measure of pathology based on the scaled scores of 5 brain regions and e) estimated slope of global cognition using longitudinal measurements. Regression models adjusting for age, sex and first three principal components. Subsequently, we examined if STRs influenced gene expression in dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC) and the anterior cingulate (AC) and tested if the association of STRs with neuropathological traits were mediated by altered gene expression.ResultTGC repeat in ATXN1 was associated with cognitive decline (b = ‐0.007, p = 0.014) and risk of clinical AD (b = 0.126, p = 0.03). Variation in CAG repeats in ATN1 was associated with cognition (b = 0.004, p = 0.022) and risk of pathological AD (b = ‐0.069, p = 0.035). Longer Repeats at ATXN1 increased gene expression in DLPFC (b = 0.012, p = 0.049) and PCC (b = 0.019, p = 0.006) and repeats in ATN1 altered DLPFC (b = 0.01, p = 0.016) and PCC (b = 0.01, p = 0.026) expression. Mediation analysis determined that the effect of the CAG repeats in ATN1 on tau was mediated by gene expression in PCC (p = 0.004).ConclusionWe demonstrate that disease causing STRs influence the underlying gene expression in brain and are associated with neuropathological and cognitive endophenotypes of AD. This suggests that STRs could explain some of the missing heritability in LOAD.

Plasma and CSF concentrations of N-terminal tau fragments associate with in vivo neurofibrillary tangle burden.

Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal tau fragments (NTA-tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. CSF and plasma NTA-tau concentrations were specifically increased in cognitively impaired Aβ-positive groups. CSF and plasma NTA-tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA-tau are preferentially associated with tau pathology. Moreover, plasma NTA-tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. NTA-tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. An assay for detecting N-terminal tau fragments (NTA-tau) in plasma and CSF was evaluated. NTA-tau is more closely associated with tau PET than amyloid PET or neurodegeneration. NTA-tau can successfully track in vivo tau deposition across the AD continuum. Plasma NTA-tau increased over time only in cognitively impaired amyloid-β positive individuals.

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias

BackgroundChronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer’s disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).MethodsPost-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed.ResultsWe found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.

Disruption of DYRK1A-induced hyperphosphorylation of amyloid-beta and tau protein in Alzheimer's disease: An integrative molecular modeling approach.

Alzheimer's disease (AD) is a neurological disorder caused by the abnormal accumulation of hyperphosphorylated proteins. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual phosphorylation enzyme which phosphorylates the amyloid-β (Aβ) and neurofibrillary tangles (NFTs). A high throughput virtual screening approach was applied to screen a library of 98,071 compounds against DYRK1A using different programs including AutoDock Vina, Smina, and idock. Based on the binding affinities, we selected 330 compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Various pharmacokinetics parameters were predicted using the admetSAR server, and based on the pharmacokinetics results, 14 compounds were selected for cross-docking analysis using AutoDock. Cross-docking analysis revealed four compounds, namely, ZINC3843365 (-11.07kcal/mol-1), ZINC2123081 (-10.93kcal/mol-1), ZINC5220992 (-10.63kcal/mol-1), and ZINC68569602 (-10.35kcal/mol-1), which had the highest negative affinity scores compared to the 10 other molecules analyzed. Density functional theory (DFT) analysis was conducted for all the four top-ranked compounds. The molecular interaction stability of these four compounds with DYRK1A has been evaluated using molecular dynamics (MD) simulations on 100 nanoseconds followed by principal component analysis (PCA) and binding free energy calculations. The Gibbs free energy landscape analysis suggested the metastable state and folding pattern of selected docking complexes. Based on the present study outcome, we propose four antagonists, viz., ZINC3843365, ZINC2123081, ZINC5220992, and ZINC68569602 as potential inhibitors against DYRK1A and to reduce the amyloid-β and neurofibrillary tangle burden. These screened molecules can be further investigated using a number of in vitro and in vivo experiments.