Neurofibrillary Tangle Stage Research Articles

Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis

BackgroundALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS. MethodsWe investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43–positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed. ResultsOf the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms. ConclusionPsychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).

A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology.

Creating a mouse model that recapitulates human tau pathology is essential for developing strategies to intervene in tau-induced neurodegeneration. However, mimicking the pathological features seen in human pathology often involves a trade-off with artificial effects such as unexpected gene insertion and neurotoxicity from the expression system. To overcome these issues, we developed the rTKhomo mouse model by combining a transgenic CaMKII-tTA system with a P301L mutated 1N4R human tau knock-in at the Rosa26 locus with a C57BL/6J background. This model closely mimics human tau pathology, particularly in the hippocampal CA1 region, showing age-dependent tau accumulation, neuronal loss and neuroinflammation. Notably, whole-brain 3D staining and light-sheet microscopy revealed a spatial gradient of tau deposition from the entorhinal cortex to the hippocampus, similar to the spatial distribution of Braak neurofibrillary tangle staging. Furthermore, [18F]PM-PBB3 positron emission tomography imaging enabled the quantification and live monitoring of tau deposition. The rTKhomo mouse model shows potential as a promising next-generation preclinical tool for exploring the mechanisms of tauopathy and for developing interventions targeting the spatial progression of tau pathology.

Very low levels of ABCA7 in the cerebrum and Alzheimer's disease onset between the ages of 60 and 80 independently of APOE.

This cross-sectional study addressed the ABCA7-Alzheimer's disease (AD) association. ABCA7 protein levels were quantified in 3 cerebral regions of brain donors with Braak neurofibrillary tangle (NFT) stages 0-V. Ordinal regression models were implemented to estimate the effect of ABCA7 on stopping in an earlier Braak NFT stage versus progressing to the later stages in 2 prespecified age segments. In the final model, high ABCA7 levels in the parietal cortex increased the odds of remaining cognitively healthy (ie, in stages 0/I) versus experiencing AD onset (ie, progressing to stages II-V) in the 61-80 age segment (OR = 2.87, adj 95% CI = 1.41-7.86, adj P = .007, n = 109), after controlling for APOE and other covariates. No ABCA7-AD association was found in the 81-98 age segment (n = 113). Parietal ABCA7 levels in 61-80-year-old with stages II-V were very low, even significantly lower than in 81-98-year-old with stages II-V. ABCA7 levels in the prefrontal cortex and hippocampus predicted AD onset in the 61-80 age segment after adjustment for APOE. ABCA7 levels were also the lowest in 61-80-year-old with frequent neuritic plaques. Thus, very low ABCA7 levels in the cerebrum are associated with AD onset in the 7th-8th decade of life.

Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease.

Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90 min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.

Role of GBA variants in Lewy body disease neuropathology.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n=1175; Lewy body pathology [LBP], n=316; and mixed AD and LBP [AD-LBP], n=893). We used logistic regression to evaluate age, sex, education,APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Multiple system atrophy with amyloid-β-predominant Alzheimer's disease neuropathologic change.

Multiple system atrophy is a neurodegenerative disease with α-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer's disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-β phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped α-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-β peptides between multiple system atrophy and Alzheimer's disease. In addition, we performed α-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE, MAPT, PSEN1, PSEN2 and APP. We refer to the four multiple system atrophy cases with discrepancy between amyloid-β and tau pathology as 'amyloid-β-predominant Alzheimer's disease neuropathologic change-multiple system atrophy' to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer's disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-β-predominant Alzheimer's disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE ɛ4 allele. The extent and severity of neuronal loss and α-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-β peptides revealed more premature amyloid-β plaques in amyloid-β-predominant Alzheimer's disease neuropathologic change-multiple system atrophy compared with Alzheimer's disease. α-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-β and α-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential α-synuclein-based therapies might be influenced by the co-presence of amyloid-β in regions where α-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to α-synuclein-targeted therapies.

Toward a generalizable machine learning workflow for neurodegenerative disease staging with focus on neurofibrillary tangles

Machine learning (ML) has increasingly been used to assist and expand current practices in neuropathology. However, generating large imaging datasets with quality labels is challenging in fields which demand high levels of expertise. Further complicating matters is the often seen disagreement between experts in neuropathology-related tasks, both at the case level and at a more granular level. Neurofibrillary tangles (NFTs) are a hallmark pathological feature of Alzheimer disease, and are associated with disease progression which warrants further investigation and granular quantification at a scale not currently accessible in routine human assessment. In this work, we first provide a baseline of annotator/rater agreement for the tasks of Braak NFT staging between experts and NFT detection using both experts and novices in neuropathology. We use a whole-slide-image (WSI) cohort of neuropathology cases from Emory University Hospital immunohistochemically stained for Tau. We develop a workflow for gathering annotations of the early stage formation of NFTs (Pre-NFTs) and mature intracellular (iNFTs) and show ML models can be trained to learn annotator nuances for the task of NFT detection in WSIs. We utilize a model-assisted-labeling approach and demonstrate ML models can be used to aid in labeling large datasets efficiently. We also show these models can be used to extract case-level features, which predict Braak NFT stages comparable to expert human raters, and do so at scale. This study provides a generalizable workflow for various pathology and related fields, and also provides a technique for accomplishing a high-level neuropathology task with limited human annotations.

Spatiotemporal characterization of tau pathology and dendritic atrophy in the human locus coeruleus

AbstractBackgroundTau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age‐related neurodegenerative disorders, including Alzheimer’s disease. However, comprehensive neuropathological examination of the LC is difficult due to its small size and rod‐like shape.MethodTo investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease‐associated tau in a large‐scale and high resolution three‐dimensional view, we applied the state‐of‐the‐art volume immunostaining and optical clearing technology iDISCO+, combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0 to 6.ResultWe demonstrate a high morphological complexity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle‐bearing neurons. Irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer’s disease, like the hippocampus or neocortical areas. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro‐dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT‐bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT‐bearing LC neurons that target the 4th ventricle wall.ConclusionOur study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans‐neuronal spreading of hyperphosphorylated tau.

Associations of Antemortem Cerebrospinal Fluid Biomarkers with Alzheimer’s Disease Neuropathologic changes at Autopsy

AbstractBackgroundCerebrospinal fluid (CSF) amyloid‐beta 42 (Aβ42) and tau phosphorylated at threonine 181 (p‐tau181) have been widely used as biomarkers for Alzheimer’s disease (AD). AT(N) classification even proposes each substance as a direct biomarker of amyloid (A) and tau (T) pathologies, respectively. However, recent studies suggest that increased CSF p‐tau181 may rather be associated with amyloid pathology. Although neuropathological evaluation at autopsy is the gold standard for assessing these changes, studies evaluating the association between CSF biomarkers and AD neuropathologic changes are limited.MethodWe retrospectively studied patients who underwent antemortem CSF AD biomarker measurement and neuropathological evaluation at autopsy at our institution from 1995 to 2021. CSF biomarkers were measured by ELISA (Fujirebio, Belgium). Neuropathological evaluation of AD was performed routinely regardless of diagnosis and Thal phase, Braak neurofibrillary tangle (NFT) stage, and CERAD score were assessed according to current guidelines.ResultThe mean age of the 119 patients was 76.2 ± 8.9 years; 49 were women. The duration from lumbar puncture to autopsy was median 2 years (0‐13 years). AD pathology was observed in 29 patients (24%). Other common pathologies were Lewy body disease and frontotemporal lobar degeneration. Antemortem CSF Aβ42 and p‐tau181 results were obtained in 119 and 68 patients, respectively. As expected, CSF Aβ42 decreased with increasing Thal phase and CERAD score. CSF p‐tau181 increased with increasing Thal phase, Braak NFT stage, and CERAD score. Even when the analysis was restricted to patients with Braak NFT stage 3 or less (n = 48), CSF p‐tau181 increased mildly with increasing Thal phase and CERAD score. In patients with moderate or severe amyloid pathology by Thal phase or CERAD score (n = 34), CSF p‐tau181 increased more highly at Braak NFT stage 5 or more.ConclusionThe results of this study, which directly compared antemortem CSF biomarkers with AD neuropathologic changes at autopsy, support the current theories that increased CSF p‐tau181 is caused by both amyloid and tau pathology related to AD while decreased CSF Aβ42 is associated with amyloid pathology.

Omics analysis of Alzheimer’s disease stratified by the microglial polygenic effect

AbstractBackgroundRecent single‐cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia‐centred pathological mechanism may be considered one of the pathologies of Alzheimer’s disease (AD). However, a single gene mutation, such as a TREM2 mutation, can rarely explain the pathology of AD. Therefore, polygenic effects involving multiple gene mutations have been proposed. In this study, we propose a polygenic risk score (PRS) to quantify the microglial polygenic effect. We stratified patient groups by this PRS and examined differences in pathogenesis based on omics analysis using postmortem brains.MethodWhole‐genome sequencing and bulk brain tissue RNA‐seq of the frontal cortex were performed using postmortem brain samples from 100 subjects with Braak senile plaque (SP) and neurofibrillary tangle (NFT) staging information. In addition, single‐nuclei RNA‐seq (snRNA‐seq) was performed on 15 of these subjects (healthy subjects: 8 subjects, AD patients: 7 subjects).ResultWe divided AD patients into low and high groups by microglial PRS and performed bulk brain tissue RNA‐seq analysis. We identified 112 differentially expressed genes and found that those genes were related to autophagy and inflammation. To further validate these findings at the single‐cell level, we identified cell clusters containing microglia based on snRNA‐seq. Gene expression analysis of microglia in 3 AD patients with low PRS and 4 AD patients with high PRS suggested altered transcriptional profiles of immune cells and phagocytosis. The expression of APOE and TYROBP, signature genes of reactive microglia, was significantly upregulated in the AD patients with low PRS compared to the AD patients with high PRS and healthy subjects. In contrast, CX3CR1 and P2RY12, signature genes of homeostatic microglia, were downregulated.ConclusionThe stratification analysis of AD by PRS suggests that microglial reactivity differs among AD patient groups. Future detailed microglial observations in postmortem brains from AD patients with low PRS and those with high PRS will further elaborate our results.

Single nucleotide polymorphisms linked to Alzheimer’s disease are associated with distinct neuropathological phenotypes

AbstractBackgroundNeurodegenerative brain diseases (NBDs) ultimately result in neuronal loss and subsequent cognitive decline. In Alzheimer’s disease, tau neurofibrillary tangles (NFT) and amyloid plaques are considered as the hallmark lesions, but there are a number of other distinct features that are not exclusive to AD and do occur to a certain extent in other NBDs.MethodWe extracted DNA from a cohort of 382 post‐mortem brains of NBD patients and controls with detailed neuropathological characterization. Genotyping of 85 genetic loci, previously found to be associated with AD, is ongoing using an in‐house developed oxford nanopore technologies (ONT) multiplex assay, allowing simultaneous sequencing of all variants on an ONT Flongle platform. Base‐ calling, alignment to Hg38 and variant calling were performed followed by QC on the data and regression analysis.ResultAssociation testing has currently been performed for 59 of the total 85 SNPs in the assay using either linear or logistic regression. This revealed significant association for an AD risk variant in the SIGLEC11 locus and Braak NFT staging (p = 0.003) and NIA_AA score (p = 0.002). Significance was also found for a risk variant in the EPHA1 locus and Hirano body score (p = 0.008). Furthermore, we found numerous nominally significant associations between risk loci and TDP43 LATE, granulovacuolar degeneration, phases of amyloid plaque distribution and CAA severity.ConclusionThese results possibly highlight biological pathways involved in generating these additional features. Our ongoing work is currently focusing on increasing our sample size to further validate the associations we discovered and optimizing our ONT assay.

White matter hyperintensities associate with pathological stages of neurodegenerative disease.

AbstractBackgroundWhite matter hyper‐intensities (WMH) are observed on FLAIR MRI, increase with age and are more prominent in neurodegenerative diseases such as in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The aim of this study was to assess the association between WMH and neuropathological staging of amyloid‐beta, neurofibrillary tangles (NFT) and α‐synuclein (α‐syn).MethodIn‐situ 3T‐MRI 3DT1‐weighted and 3D‐FLAIR data were collected for 77 clinically defined and pathologically‐confirmed brain donors; 31 AD, 21 PD and PD dementia (PDD), and 25 controls. WMH were segmented on FLAIR using an in‐house developed multiview convolutional neural network, followed by manual checking, and volume was obtained with FSL. Fifteen brain regions were dissected at autopsy, immunostained and evaluated for neuropathological diagnosis, including Thal amyloid phase, CAA type, and Braak stages for NFT and α‐syn. Group differences were assessed with linear models (corrected for age, gender, post‐mortem delay), and associations with Spearman and Pearson partial correlations.ResultCompared to controls, WMH load was higher in AD (p&lt;0.001), specifically amnestic AD (p = 0.003) rather than non‐amnestic AD (p = 0.053), and higher in PD (p = 0.016), specifically non‐demented PD (p = 0.015) rather than PDD (p = 1.0). No difference in gender was observed (p = 0.38). Without the influence of pathology (in controls), WMH was associated with age (r = 0.49,p = 0.016).In the whole cohort, WMH was associated with Fazekas score (r = 0.67; p&lt;0.001), normalized brain volume (NBV; r = ‐0.31,p = 0.007), gray matter volume (NGMV; r = ‐0.36,p = 0.002), Thal phase (r = 0.24,p0.034), Braak NFT stage (r = 0.33,p = 0.004), and Braak α‐syn stage (r = 0.27, p0.018).Across controls and AD, WMH associated with NBV (r = ‐0.39,p = 0.004), NGMV (r = ‐0.42,p = 0.002), left and right hippocampal volume (r = ‐0.36,p = 0.008 and r = ‐0.32,p = 0.022), Braak NFT (r = 0.41,p&lt;0.001), Thal phase (r = 0.41,p = 0.002), and CAA (r = 0.34,p = 0.01). Amnestic and non‐amnestic AD showed similar results, except for CAA, which was associated with WMH in non‐amnestic AD only (r = 0.33,p = 0.04).Across controls and PD(D), WMH associated with Braak NFT stage (r = 0.39,p = 0.008) and Braak α‐syn stage (r = 0.60,p&lt;0.001), but not with MRI outcome measures. In this respect PD and PDD showed different results; in PD WMH associated with NGMV (r = ‐0.37,p = 0.031), in PDD with left and right hippocampal volume (r = ‐0.44,p = 0.014 and r = ‐0.44,p = 0.015).ConclusionWMH associate with pathological stages of AD and PD(D), and contributes to MRI atrophy.

The limbic‐predominant hypometabolic subtype of AD is not enriched for comorbid TDP‐43 pathology or hippocampal sclerosis

AbstractBackgroundPrevious research has identified distinct subtypes of AD that differed with respect to the distribution of neurofibrillary tangles (NFT). One of them, a limbic‐predominant subtype, was enriched for comorbid TDP‐43 pathology. Our previous data‐driven analysis used FDG‐PET to identify a limbic‐predominant subtype of AD that may correspond to the limbic‐predominant NFT subtype. In the current study, we tested the expected associations between measures of neuropathology such as TDP‐43 pathology, hippocampal sclerosis, and Braak stages of NFT accumulation, and the limbic‐predominant hypometabolic subtype.MethodWe analyzed ante‐mortem FDG‐PET and neuropathological data of 74 individuals from the autopsy cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 7 cognitively normal participants, 12 participants with MCI, and 55 with dementia (as assessed at the last available clinical evaluation). Severity of TDP‐43 pathology was operationalized as the number of brain areas with TDP‐43 immunoreactive inclusions (including amygdala, hippocampus, entorhinal/inferior temporal cortex and neocortex). Hippocampal sclerosis was operationalized as a binary variable. We measured similarity of individual FDG‐PET profiles to the limbic‐predominant subtype. For that, we used Euclidean distances from each individual profile to the mean profile of the limbic‐predominant AD subtype identified previously in a larger ADNI sample using a data‐driven hierarchical clustering approach (Fig.1). Lower Euclidean distances indicated higher similarity to the subtype. Bayesian linear regressions in JASP were used to assess associations between neuropathological markers and similarity to the limbic‐predominant FDG‐PET pattern, controlling for Thal phase of amyloid accumulation, age, sex, and time delay between the FDG‐PET scan and death in the null model. We assessed Bayes factors representing evidence for a given model in comparison to the null model (BF10).ResultOur results suggest that similarity of individual FDG‐PET profiles to the limbic‐predominant FDG‐PET pattern was not related to severity of TDP‐43 pathology (BF10 = 0.449), presence of hippocampal sclerosis (BF10 = 0.544), or Braak NFT stages (BF10 = 0.525).ConclusionContrary to the expected effects, our current analysis indicates a lack of reliable associations between neuropathological markers such as TDP‐43 pathology, hippocampal sclerosis, or global NFT accumulation and the limbic‐predominant hypometabolic subtype. Future analyses will assess potential alternative contributors, such as region‐specific patterns of NFT distribution.

Genetic associations with mixed neuropathologies in the aging brainGenetic associations with mixed neuropathologies in the aging brain

AbstractBackground““Mixed” neuropathologies (NPs) are common in aged brains. Classic Alzheimer’s disease neuropathologic change (ADNC) proteinopathies are amyloid‐β plaques and tau neurofibrillary tangles (NFTs). In addition, α‐synuclein and TDP‐43 are also key proteinaceous disease markers, and cerebrovascular diseases (CVDs) often coexist. Although the scientific problems regarding mixed NPs are increasingly recognized, genetic associations with mixed NPs have not been well‐investigated. In this study, we applied item response theory (IRT) to optimize the clustering and combination of mixed NPs and examined the genetic associations.MethodNP data were drawn from the National Alzheimer’s Coordinating Center (NACC) NP v10‐11 forms through the March 2022 data freeze, including Thal phase ratings (A score); Braak NFT stage (B score); CERAD neuritic plaque scores (C score); Lewy bodies (LBs); TDP‐43; hippocampal sclerosis (HS); cerebral amyloid angiopathy (CAA); infarct and lacunes; microinfarcts; atherosclerosis of the circle of Willis; and brain arteriolosclerosis. We determined dominant pathology patterns in 1,228 participants who had no missing data using a multidimensional graded response model within the IRT framework. The NACC NP data were linked to the U.S. Alzheimer’s Disease Research Centers genetic data provided by the Alzheimer’s Disease genetic Consortium.ResultFrom the leave one out cross validation simulation, the model fitness tests showed that the 4‐factor model had fewer differences from the data than the other models. As shown in Figure, the predominant NPs were TDP‐43 and HS for factor 1 (F1), CVDs other than CAA for factor 2 (F2), A, B, and C scores and CAA for factor 3 (F3), and LBs for factor 4 (F4). The TMEM106B locus was genome‐wide significant with F1 (TDP‐43/HS) and the APOE locus was genome‐wide significant with F3 (ADNC/CAA) after adjusted for age at death, sex, and other factor scores. The SDK1 and FMNL2 loci were not genome‐wide significant, but had noteworthy associations with F2 (CVDs).ConclusionOur new approach to create mixed NP scores could detect the TMEM106B and APOE loci as TDP‐43/HS related and ADNC related regions, respectively. Although previous studies reported SDK1 as an ADNC related gene, we showed that the gene may be associated with CVDs.

Hyperspectral analysis of amyloid beta (Aβ) evolutional changes in preclinical to late‐stage Alzheimer’s disease using matched brain and retinal tissue

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, degenerative brain disorder that leads to cognitive impairment and eventually death. It is marked by buildup of abnormal amyloid aggregates (Aβ) in the brain. This study aimed to elucidate the neuropathologic sequence and corresponding [RetiSpec] hyperspectral signals of Aβ evolutional changes in preclinical to late‐stage AD using retinal and brain samples.MethodWe used brain‐ and retina‐matched human tissue samples from the NIH Brain Bank at Johns Hopkins. Study groups included: No AD neuropathologic change with negative AD neuropathology (n = 15); Low‐level AD neuropathologic change with positive AD neuropathology (n = 15); High level AD neuropathologic change with positive AD neuropathology (n = 15). To validate retinal hyperspectral imaging (rHSI) detection of Aβ in these retinal samples, we quantified Aβ oligomers (AβOs) in human retinal tissue. Immunohistochemistry was performed. We used humanized, affinity‐matured, IgG2 mAβ selective biotinylated antibody (ACU‐193) to detect soluble AβOs in retinal and brain tissues followed by objective quantification of ACU193 retinal staining by performing annotations and data extraction using QuPath software. One‐way ANOVA and t‐tests were performed to compare between controls and AD stages.ResultWhen assessing ACU193 staining present from retinal tissue samples, we observed 29‐53% retinal tissue area positivity in controls and 15‐72% retinal tissue area positivity in the AD group. Level of AD pathology demonstrated an effect on the rHSI spectra (450‐600nm) in regions near the optic disc and the ventral periphery: intermediate AD pathology showed the strongest rHSI signature (decrease in optical transmittance) followed by high, then low AD pathology samples. Correlation of the Braak neurofibrillary tangle stage and ΔOD offered a Pearson r score of 0.79 (p = 0.004).ConclusionThis study was the first to assess and quantify AβOs in clinically, neuropathologically, and hyperspectrally characterized postmortem matched brain and retinal tissues. Progression of well‐established neuropathologically classified AD stages (e.g Braak) may correlate with retinal AβO levels measured using rHSI. Certain retina regions that share nervous tissue with the brain (optic disc, periphery) are likely more sensitive to rHSI‐mediated detection of AD pathology. Larger samples are needed to comprehensively assess and quantify retinal AβOs.

Predictors of Successful Brain Aging: An Autopsy Study

AbstractBackgroundThe neuropathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques and neurofibrillary tangles, also accumulate in the brains of aging individuals. However, some individuals are able to age successfully without significant degenerative neuropathology or cognitive impairment, a phenomenon referred to as “successful aging”. The predictors of successful “neuropathologic” and “cognitive” aging are not fully understood, creating a critical knowledge gap. Factors such as resistance, resilience, and reserve are believed to play important roles. Furthermore, the relationship between neuropathological changes, such as tau pathology and amyloid pathology, and cognitive impairment in the oldest old population remains unclear, and the concept of amyloid plaques causing tau pathology may not be universally valid. The association between amyloid plaques and dementia also continues to be debated.MethodsIn this study, we utilized a collection of 414 post‐mortem brain tissues (171 female, 241 male) from aged individuals (average age 90, range 80‐108) with neuropathological and clinical data (215 without cognitive impairment and 161 with cognitive impairment) to perform a cross‐sectional analysis. Our cohort included subjects who had cognitive assessments available and included those with no amyloid plaque pathology or mild burden based on neuropathological criteria. Variables (including new traits derived from A.I. based feature extraction) associated with the cognitive measures were determined using multivariable logistic regression.ResultsOur results revealed that age of death and Braak neurofibrillary tangle stage were significant predictors of cognitive impairment (p&lt;0.05), while amyloid positivity was not. These findings suggest that tau pathology may have a stronger association with cognitive impairment in the oldest old population compared to amyloid plaques.ConclusionUnderstanding the neuropathological factors associated with successful brain and cognitive aging will contribute to our knowledge of the underlying mechanisms and may pave the way for the development of interventions to promote successful aging and prevent cognitive decline in old age. Further research in this area is warranted to elucidate the complex relationship between neuropathology, cognitive function, and aging in the oldest old population.

An Epigenome‐wide association study of psychosis in Alzheimer’s disease dorsolateral prefrontal cortex

AbstractBackgroundPsychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving aetiology. In this study, we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of post‐mortem brain samples.MethodBrain samples were obtained from the University of Pittsburgh Alzheimer’s disease Research Centre (PITT‐ADRC). AD pathology was assessed and classified using CERAD neurotic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. We used the presence or absence of delusions and hallucinations, Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) to categorise our samples into AD with Psychosis (AD+P) and AD without Psychosis (AD‐P) groups. DNA was extracted, bisulfite‐treated and profiled on the Illumina Methylation EPIC Array and genotyping was carried out on the Illumina Global Screening Array (GSA).ResultAfter data quality control, 153 samples (40 AD‐P, 113 AD+P) remained for further analysis. The normalized beta values and the effect estimate values were used to extract Differentially Methylated positions (DMP) and differentially methylated regions (DMRs), respectively. To identify methylation quantitative trait loci (mQTLs) in both cis and trans, SNP‐CpG pairs with a p‐value threshold of &lt;1e‐5 were calculated. We performed a colocalization analysis for the most significant DMPs and mQTLs, using publicly available summary statistics of relevant genome‐wide association studies (GWAS).ConclusionThe development of effective therapies for AD+P is an urgent priority and requires a better understanding of the molecular mechanisms underlying this syndrome. To address this, we have collated a well‐powered study cohort to interrogate the epigenetic basis of AD+P in the brain and have identified several loci of interest that require further study.

ASSOCIATION BETWEEN ALZHEIMER DISEASE AND CANCER: A POSTMORTEM CROSS‐SECTIONAL STUDY IN BRAZIL

AbstractBackgroundA biological mechanism in cancer promotion may have a protective role against AD1. Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described2, most previous studies were based only on the clinical diagnoses for both diseases. Therefore, we aimed to investigate the association between AD and cancer in a large autopsy study from a racially diverse sample.MethodThis cross‐sectional study analyzed data with postmortem brain tissue from participants over 55 years of age from the Biobank for Aging Studies. Data from the full‐body autopsy reports and a Functional Clinical Questionnaire (FCQ) applied to an informant were used to determine the presence of cancer. The association between AD and cancer was investigated using logistic and linear models adjusted for sociodemographic and clinical variables and APOE allele 4.Result689 subjects were included (mean age 74.2 ± 10.8 years old, 47.5% women, 68% White) (Table 1). 18% of the sample had cancer. The frequencies of cancer types and neuropathological post‐mortem diagnoses are shown in Figure 1. Cancer was not associated with AD (OR = 0.56, 95% CI = 0.21;1.39), or CERAD neuritic plaque score [ b = 0.057, 95% CI = ‐0.31; 0.41], but was associated with lower Braak neurofibrillary tangle staging (b = ‐0.49, 95% CI = ‐0.98; ‐0.03] (Table 2).ConclusionIn a large autopsy study, we found an association between cancer and Braak neurofibrillary tangle staging, which is in accordance with previous research suggesting a protective role of cancer in AD risk3.1. Ospina‐Romero M, Glymour MM, Hayes‐Larson E, Mayeda ER, Graff RE, Brenowitz WD, Ackley SF, Witte JS, Kobayashi LC. Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Metaanalysis. JAMA Netw Open. 2020 Nov 2;3(11):e2025515.2. Landefeld CS, Chren MM, Myers A, et al. Diagnostic yield of the autopsy in a university hospital and a community hospital. The New England Journal of Medicine. 1988 May;318(19):1249‐1254.3. Nakamura M, Kaneko S, Dickson DW, Kusaka H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. J Neuropathol Exp Neurol. 2020 Jan 1;79(1):22‐33.