bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi‐tissue profiling of RNA and DNA‐methylation signatures of progressive tau neuropathology in tau transgenic mice
Authors: Kulkarni Ameya S , Ideozu Justin , Vasanthakumar Aparna , Ammar Areej , Murphy Erin , Asque Elizabeth , Plaas Christian , Klein Corinna , Ried Janina S , Barghorn Stefan , Gasparini Laura
Published: December 2022

Background

Intracellular abnormal aggregation of hyperphosphorylated tau protein is a neuropathological hallmark associated with Alzheimer’s Disease (AD). The insoluble tau aggregates called neurofibrillary tangles lead to microtubule dysfunction and neurodegeneration with AD progression. The TG4510 transgenic mice overexpressing the P301L mutant human tau protein exhibit region‐specific tau inclusions, brain atrophy, and behavioral deficits, thereby serving as a widely used animal model of tauopathy in AD. This study aims to characterize the tissue‐specific transcriptomic and epigenomic signatures of progressive tau pathology in TG4510 mice as well as investigate the correlation of brain and blood expression and epigenomic changes.

Method

Using UMI‐based bulk RNA‐Sequencing and Reduced‐representation Bisulfite Sequencing (RRBS), we profiled the gene expression and DNA‐methylation changes respectively, in the cortex, hippocampus, cerebellum and pre‐sacrifice and terminal whole blood between three age groups (2‐3 months, 6‐7 months, 8‐9 months old; N=20/tissue/group) of male and female TG4510 mice.

Result

The cortex and hippocampus show the largest transcriptional differences between mice, recapitulating phenotype differences with loss of neurotransmission and increased inflammation in these tissues. Systems‐level co‐expression analysis reveals common gene modules in immune system, behaviour and cognition and ECM/synaptic pathways between cortex/hippocampus and blood. Furthermore, the genes correlated between brain regions and blood in these mice were prioritized as potential biomarkers of tau pathology, which can be further validated in preclinical animal models and ultimately human studies.

Conclusion

This study serves as one of the first evidence of multiomic molecular underpinnings in a tauopathy mouse model providing potential novel targets and biomarkers of progressive tau pathology in AD.

Disclosures

All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Dementia Research Engagement on Social Media: A Content Analysis
Authors: Hrincu Viorica , An Zijian , Joseph Kenneth A , Jiang Yu Fei , Shi Elaine , Robillard Julie M.
Published: December 2022

Background

Social media is a powerful tool for engaging diverse audiences in dementia research, especially healthy individuals who may not be actively seeking dementia research education or opportunities. However, there is little data summarizing current social media practices, content exchange, and ethical considerations in the context of dementia research. To inform ethical dementia research engagement on social media, we characterized current practices by analyzing public Facebook and Twitter posts.

Method

We searched for and downloaded from Facebook (2‐yr period) and Twitter (1‐yr period) all posts containing dementia research‐related keywords. We retrieved n = 7,990 Facebook posts after filtering for inclusion and exclusion criteria. The Facebook data aided the development of a machine learning model to search Twitter for dementia research‐related posts (n = 600,000). After filtering, we retrieved n = 10,000 top retweeted posts. We performed content analysis on a random sample (10%) of the Facebook and Twitter posts. Codebook development followed a qualitative manual coding strategy. Coding ceased when no new codes emerged from the data.

Result

The top 5 Facebook user spaces were Public groups (18%), Nonprofit organizations (18%), Medical & health (9%), Communities (8%), and Medical companies (7%). On Twitter, users with academic/research affiliations were the largest group. Sharing knowledge was the primary form of content exchange on Facebook (19%) and Twitter (21%); there were fewer research opportunities (<9%). Most posts contained linked or embedded media in the form of science news articles. Twitter likes (>100,000) were overall higher than Facebook reactions (>45,000). Although dementia ‘prevention/risk’ and ‘treatment’ were major topics for Facebook and Twitter, posts about ‘diagnostics’ had the most Facebook reactions (29%). Justice was a prominent ethics topic regarding inequalities related to race, ethnicity, culture, gender, and intersecting modes of marginalization in dementia research.

Conclusion

The results demonstrate the importance of social media as an engagement tool of current topics in dementia research and reveal areas of potential for increased engagement. More data is needed on the social media guidelines followed by dementia researchers, especially regarding their effectiveness and contextual application. The next project phase will use these data to inform the development of a consensus on best practices in this area.
Association of residential road proximity with cognitive decline and dementia: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Parker‐Allotey Naa Adoley , Bennett Erin E , Lynch Katie M , Xu Xiaohui , Whitsel Eric A , Smith Richard L , Stewart James D , Ying Qi , Park Eun Sug , Wei Jingkai , Power Melinda C
Published: December 2022

Background

Increasing evidence links higher midlife air pollution exposures to increased risk of cognitive impairment, and there is growing interest in the role of noise in cognitive aging. Although associations of incident dementia with risk factors are often strongest when values of risk factors in midlife are considered, few studies have considered such associations with mid‐life exposures to traffic‐related air pollution or road noise. Thus, our objective was to determine if midlife residential proximity to major roads, a proxy for traffic‐related air pollution exposure and road noise, is associated with increased risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) study.

Method

ARIC participants were enrolled from 4 US sites in 1987‐1989 at ages 45 to 65. We considered data from 12,135 participants who participated in ARIC Visit 2 (1990‐1992, study baseline). We calculated midlife residential Euclidean distance to a major (A1, A2, or A3) road based on geocoded residential addresses at Visit 2. We ascertained dementia status through 2019 via in‐person study visits with neurocognitive assessment, telephone cognitive interview, informant interview, and access to hospitalization and death records. We estimated the association between residential road proximity in midlife and incident dementia using adjusted Weibull models.

Result

At study baseline, the mean age of participants was 57 years, 22% were black, 56% were female, 48% lived within 200m of a major road, and 36% lived within 200 to 500m of a major road. 20% developed dementia during follow‐up. While residing closer to major roads in midlife was associated with increased risk of incident dementia in unadjusted models, this association did not persist in adjusted analyses.

Conclusion

Residence near a major road in midlife, which may lead to higher exposure to traffic‐related air pollution and noise, does not appear to increase risk of dementia.
Sex‐specific Biomarkers in Alzheimer's Disease Progression: Framingham Heart Study
Authors: Liu Chunyu , Li Yi , Ang Ting Fang Alvin , Liu Yulin , Devine Sherral A. , Au Rhoda , Doraiswamy P. Murali
Published: December 2022

Background

Research shows that women have a higher risk of developing Alzheimer’s disease (AD) than men. This study seeks to identify sex‐specific risk profiles linked to the development of AD.

Method

We analyzed multiple blood biomarkers for risk of development of AD as well as with cognitive decline in the community‐based longitudinal Framingham Heart Study Offspring Cohort. A total of 2962 participants (mean age 60 year, 55% women) without any type of dementia were followed up to a median of 12 years with cognitive testing, blood sampling and dementia assessments. This study analyzed participants 60 years and older. Proportional hazards models were performed to investigate associations between biomarkers and the time to incident AD. Linear models were used to quantify the associations between biomarkers and annualized, domain‐specific cognitive decline. Covariates included age, sex, education, and baseline cognitive measurement.

Result

During the follow‐up, 7.3% (119/1631) women and 4.7% (63/1331) men developed AD; 8.6% (141/1631) women and 7.1% (94/1331) men developed all‐cause dementia. We found that women were 41% more likely than men to be diagnosed with AD (P = 0.029) while found no gender differences in the time to develop all‐cause dementia (P = 0.16). We found that lower plasma amyloid‐beta42 level was significantly predictive for the future risk of AD in women (P = 0.0018) and not in men (P = 0.069), while the hazards ratio were not significantly different between men and women (Pdiff = 0.92). Further, lower plasma amyloid‐beta42 was significantly associated with annualized memory decline in women (P = 0.00023) but not in men (P = 0.55) (Pdiff = 0.026 between men and women for regression estimates). Several vascular risk factors, such as fasting glucose levels, were predictive of AD/dementia in both men and women.

Conclusion

Our study may offer new insights into how blood tests can be better personalized for predicting future AD risk in women versus men.
Association of ambient air pollutants and cognitive impairment in a community‐dwelling elderly population: A four‐year cohort study
Authors: Kuo Emily , Chen Jen‐Hau , Yu Hwa‐Lung , Chiou Jeng‐Min , Chen Ta‐Fu , Chen Yen‐Ching
Published: December 2022

Background

Long‐term ambient air pollution has known to affect cognitive function. However, limited studies investigated the relationship between co‐exposure to ambient air pollutants and cognitive functions in non‐demented older adults. Therefore, this study aimed to explore this association in a community‐based prospective cohort study.

Method

This four‐year prospective cohort study is part of the ongoing Taiwan Initiative Geriatric Epidemiological Research (TIGER, 2011‐present) and included 286 non‐demented older adults between 2015‐2019. Ambient air pollution data were collected from 29 monitoring stations from Taiwan Environmental Protection Administration (TEPA) between 1994 and 2019. Global and domain‐specific (memory, attention, executive function, and language) cognitive functions were assessed using the Taiwanese version of Montreal Cognitive Assessment (MoCA‐T) and a battery of neuropsychological tests. The generalized linear mixed models were used to evaluate the association of co‐exposure to air pollutants with cognitive function adjusting for important covariates. Furthermore, we conducted stratified analyses by olfaction, known as an early marker of dementia.

Result

Except for PM2.5, the annual average exposure of the other five pollutants was below the TEPA standards. A 25‐year high‐level exposure of NO2 (≥ 27.7 ppb) was associated with good performance executive function (β = 0.25) over four years. For joint effect, high‐level (the highest tertile) PM2.5 with low to medium concentration level of NO2, CO, or SO2 were significantly associated with the poor performance of memory (β = ‐0.39 to ‐0.35). Similarly, high‐level PM2.5 with low to medium concentration level of NO2, PM10 with O3 were significantly associated with poor executive function (β = ‐0.28 to ‐0.19). In participants with normal olfaction, high co‐exposure level to PM2.5 and PM10, with CO, SO2, O3, and NO2 was significantly associated with poor memory and executive function (β = ‐0.55 to ‐0.30). No significant associations were found in participants with abnormal olfaction.

Conclusion

Long‐term low to medium‐level co‐exposure to NO2, CO, or SO2 and high‐level PM2.5 was associated with poor memory; co‐exposure to O3 with PM10 and co‐exposure to NO2 with PM2.5 was associated with poor executive function. A revision on exposure standards shall be considered to protect older adults at the preclinical phase of dementia.
CSF Proteome Changes Depend on APOE Genotype in Prodromal AD
Authors: Vromen Eleonora M. , Wesenhagen Kirsten E. J. , van der Kant Rik , Gobom Johan , Scheltens Philip , Teunissen Charlotte E. , Dobricic Valerija , Bertram Lars , Zetterberg Henrik , Visser Pieter Jelle , Tijms Betty M.
Published: December 2022

Background

APOE Ɛ4, the major genetic risk factor for sporadic Alzheimer’s disease (AD), has a dose‐dependent effect on the risk of development of AD. It remains unclear how APOE Ɛ4 dose affects different pathophysiological processes in AD, and therefore we studied APOE genotype effects on the CSF proteome of prodromal AD individuals.

Method

CSF proteomics was performed using TMT‐MS in 77 prodromal AD individuals (mean age 70±7 years, 42 (55%) female, n=25 Ɛ3Ɛ3, n=38 Ɛ3Ɛ4, n=14 Ɛ4Ɛ4) and 41 cognitively normal individuals used as a reference group (mean age 64±7 years, 21 (51%) female, biomarker A‐T‐, all Ɛ3Ɛ3) from the EMIF cohort. APOE Ɛ2‐carriers were excluded due to the low number. In total, 2535 proteins were detected, of which we selected 1143 observed in at least 70% of the individuals. APOE genotype effects on CSF protein concentrations were tested with linear regressions adjusting for age and sex in comparison to our reference group.

Result

In total, 134 (12%) proteins showed APOE genotype dependent differences in prodromal AD individuals compared with the reference group (P < 0.05, Fig. 1). Of these, 6 proteins, including SMOC1 and YWHAB, showed differences in all prodromal AD individuals, reflecting general disease processes. Comparing each genotype to the reference group, 23 proteins differed in Ɛ3Ɛ3 prodromal AD, of which 21 showed higher concentrations, without enrichment for any specific biological pathways; 54 proteins differed in Ɛ3Ɛ4 prodromal AD, of which 51 proteins, enriched for glucose metabolism, showed higher concentrations; and 110 proteins differed in Ɛ4Ɛ4 prodromal AD, of which 98 proteins, enriched for glucose metabolism, (oxidative stress‐induced) apoptosis and interleukin‐12 signaling, showed higher concentrations and 12 proteins, enriched for complement activation, showed lower concentrations. Comparing APOE Ɛ4 dose within prodromal AD, 21 proteins showed differences between Ɛ3Ɛ4 and Ɛ4Ɛ4, of which 7 proteins, enriched for complement activation, showed downregulation in Ɛ4Ɛ4.

Conclusion

The CSF proteome of prodromal AD individuals showed APOE genotype dependent alterations, which were associated with distinct biological processes, including glucose metabolism, apoptosis and complement activation. Most of these alterations were Ɛ4 dose‐dependent. These differences should be considered in selection of future therapy targets.
Examining the effects of sex and age on tau PET binding in the absence of beta‐amyloid pathology
Authors: Gordon Brian A. , Flores Shaney , Dincer Aylin , Keefe Sarah J. , McKay Nicole S. , Hobbs Diana A. , Wisch Julie K. , Hornbeck Russ C. , Franklin Erin E. , Jack Clifford R. , Koeppe Robert A. , Xiong Chengjie , van Dyck Christopher H , McDade Eric , Klein Gregory , Pariente Jeremie , Bateman Randall J. , Morris John C. , Ances Beau M , Benzinger Tammie L.S. , Perrin Richard J.
Published: December 2022

Background

Tau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown.

Methods

Cross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and sub‐threshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT.

Results

There were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or sub‐threshold levels of amyloid.

Conclusions

Tau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease.
Age Differences in Heritability of a Latent Dementia Index Score in Men and Women
Authors: Luczak Susan E , Beam Christopher R. , Tureson Kayla , Reynolds Chandra A. , Panizzon Matthew S. , Lee Teresa , Sachdev Perminder S. , Gatz Margaret ,   IGEMS Consortium
Published: December 2022

Background

Heritability estimates of dementia are ∼50‐60% of the total variance across older adulthood. Earlier age of onset, however, might be associated with greater genetic influence whereas older age of onset might be associated with greater environmental influences. The categorical nature of dementia diagnosis outcomes has made testing the relative importance of genetic and environmental influences on dementia difficult due to low statistical power. To overcome this methodological limitation, we tested linear and quadratic effects of age on genetic and environmental variance underlying a continuous measure of dementia likelihood in men and women.

Method

The analytic sample was 5,670 (53% female) pairs of twins from 10 studies in the Interplay of Genes and Environment Across Multiple Studies (IGEMS) consortium. Dementia likelihood is quantified continuously using a latent dementia index measure that is estimated from twins’ available cognitive, memory‐specific, and functional ability measures. Linear and quadratic age differences in genetic and environmental influences on dementia likelihood were tested by modeling univariate correlation between twins’ dementia scores as a linear function of zygosity and age in Mplus. Separate models were estimated for male and female twin groups.

Results

Age moderated genetic and environmental influences on dementia likelihood scores. Both genetic and nonshared environmental variance increased as a function of age, whereas common environmental variance declined. Sex significantly moderated the effect of zygosity on the twin correlations (monozygotic male: .57, monozygotic female: .51, dizygotic male: .19, dizygotic female: .25). Notably, MZ twin correlations were consistent with previously reported heritability estimates for dementia. The pattern of age moderation was the same in men as women, although the linear effect of age on both genetic and common environmental influences was greater in men than women (see Figure 1).

Conclusion

Age linearly moderated genetic and environmental variance underlying dementia likelihood similarly for both men and women, despite quantitative genetic and environmental sex differences in dementia likelihood. Genetic variance accounted for similar proportions of total variance at younger ages, whereas genetic variance accounted for greater variance in men than in women at older ages.
Quantitative proteomic analysis reveals apoE4‐dependent phosphorylation of the actin regulating protein VASP
Authors: Cakir Zeynep , Polacco Benjamin , Krogan Nevan J , Mahley Robert W , Swaney Danielle L
Published: December 2022

Background

Apolipoprotein E4 (APOE4) is the major genetic risk factor for Alzheimer’s disease (AD). Current evidence suggests that neuronal expression of apoE4 is sufficient to promote neuropathology via a gain‐of‐function mechanism; however, the precise molecular mechanisms mediating this process are still unclear. To elucidate specific protein targets and cellular pathways dysregulated due to apoE4 expression, we performed global proteomic profiling of ubiquitylation and phosphorylation signaling in Neuro‐2a cells stably expressing either apoE3 or apoE4.

Method

Neuro‐2a cells (apoE3 or apoE4) were lysed and proteins digested into peptides. Peptides were enriched for either phosphorylation or ubiquitylation post‐translational modifications, and the resulting peptides were detected and quantified using a label‐free quantitative proteomics workflow. Modification sites were detected by MaxQuant, and statistical analysis was performed using MSstats to identify significantly regulated modification sites (p<0.05) between apoE3 and apoE4‐expressing cells. Immunoblotting was performed to validate protein phosphorylation sites of interest.

Result

The expression of apoE3 versus apoE4 in Neuro‐2a cells results in the differential regulation of thousands of ubiquitylation and phosphorylation sites. Gene ontology and pathway analysis of these regulated sites reveal an enrichment for a variety of cellular processes, including proteasomal biology, redox homeostasis, spindle organization, as well as cytoskeletal regulation. Accordingly, among the most differentially regulated phosphorylation sites is the vasodilator‐stimulated phosphoprotein, VASP, in which there is a 14‐fold increase in phosphorylation at position S235 in Neuro2a‐apoE4‐expressing cells (p=5.5e‐10) as compared to Neuro2a‐apoE3. This phosphorylation was reduced upon siRNA knockdown of APOE4, as well as by pharmacological inhibition of PKA, indicating that VASP S235 is phosphorylated by PKA in an apoE4‐dependent manner. VASP S235 phosphorylation results in reduced filopodia and cytoskeletal filament formation. Thus, we hypothesize that phosphorylation of VASP at S235 represents a mechanism regulating the well‐established defects in neurite outgrowth and dendritic spine formation in apoE4‐expressing neurons.

Conclusion

Our data demonstrate that VASP S235 is highly phosphorylated by PKA in apoE4‐expressing neurons compared to apoE3. Future experiments will evaluate the effect of VASP S235 phosphorylation on actin cytoskeleton remodeling and neurite outgrowth and will be extended to the evaluation of PKA inhibitors as a therapeutic opportunity in apoE4‐associated AD.
Discovery of DA‐7503 as a Novel Tau‐targeted Therapeutic Candidate for the Treatment of Alzheimer’s Disease
Authors: Pae Ae Nim , Lim Sungsu , Lim Sang Min , Lee Hyangsoo , Lee Min Jung , Kim Yun Kyung
Published: December 2022

Background

Alzheimer’s disease (AD) is a late‐onset, progressive, age‐dependent neurodegenerative disorder. The load of neurofibrillary tangles correlates strongly with clinical progression of the disease. Although tauopathy has been extensively studied as a key hypothesis in AD, there are currently no clinical tau‐targeted drugs that produce a noticeable improvement. Therefore, we studied and developed novel tau‐targeted therapeutic drug candidates for the treatment of AD; in particular, tau aggregation inhibitors.

Method

We performed high‐content screening based on a Tau‐BiFC cell‐based assay platform and identified novel tau aggregation inhibitors. Lead optimization was subsequently performed to improve potency and ADME/Tox properties, resulting in the production of DA‐7503. In vivo efficacy of the candidate was validated by demonstration of memory impairment restoration in two transgenic animal models of P301L Tau‐BiFC and rTg4510. The non‐clinical GLP‐Tox studies of DA‐7503 is ongoing in order to proceed to clinical studies.

Result

DA‐7503 exhibited excellent tau aggregation inhibitory activities (cell‐based IC50, 0.02 mM, in vitro IC50, 0.96 mM) with good cell viability (MTS IC50, 77.8 mM). DA‐7503 reduced tau oligomerization and protected against neuronal cell death. It restored memory impairment in P301L Tau‐BiFC and rTg4510 Tg mouse models (NOR, Open Field, and Morris Water Maze test) with reduction of tau pathology. The mode of action of DA‐7503 was confirmed by MALDI‐TOF Mass Spectrometric Analysis, 2D HSQC NMR and TR‐2 competition study to show reversible covalent inhibition of disulfide‐dependent oligomer formation.

Conclusion

DA‐7503, a highly potent inhibitor of tau aggregation, significantly improved memory impairment and reduced tau pathology in P301L Tau‐BiFC and rTg4510 Tg mouse models with good pharmacological properties. Currently, the GLP‐Tox safety profile of DA‐7503 as a non‐clinical candidate is being evaluated, and early results are promising enough to proceed to clinical studies.
A novel neurofilament light chain Simoa assay that can quantify age‐dependent changes in control plasma samples over small time periods
Authors: Das Shreyasee , Dewit Nele , Blennow Kaj , Zetterberg Henrik , Vanmechelen Eugeen
Published: December 2022

Background

Neurofilament light chain (Nf‐L) is an established biomarker for axonal degeneration, and it is well documented that Nf‐L shows an age‐ dependent increase in plasma. Currently, all highly sensitive immunoassay formats to quantify Nf‐L in plasma are based on one antibody pair alone, i.e., the commercial UmanDiagnostics monoclonal antibodies.

Methods

In the novel Nf‐L Simoa, we have used Fab fragments of ADx206 as the capture antibody coupled to paramagnetic beads and biotinylated NfL23 as the detector antibody. Routine plasma and serum samples were collected according to established preclinical guidelines at baseline (BL) and after 7‐8 months of follow‐up (FU) for 23 individuals. The age range of these individuals was between 22 and 70 years.

Results

All plasma and serum samples could be quantified and the lower limit of quantification (LLOQ) of the novel immunoassay was 2.2 pg/mL. The average coefficient of variation for plasma Nf‐L concentrations was 8% and that for serum was 13%. The plasma and serum concentrations correlated significantly with concentrations obtained using the commercial Quanterix Nf‐L Simoa kit (Plasma: Spearman’s rho= 0.93, p<0.0001; Serum: Spearman’s rho= 0.92, p<0.0001). However, in contrast to the Quanterix assay, Nf‐L concentrations detected in serum were lower than in plasma. Since the age range of the individuals were between 22 to 70 years, we were able to observe a significant age‐dependent increase of Nf‐L at BL in plasma as well as in serum. Furthermore, a positive 5% average annual rate of change in the Nf‐L plasma concentrations can be discriminated from BL to FU with the current assay format. Therefore, in this cohort, Nf‐L plasma concentrations increase from BL to FU, consistent with data reported from other cohorts.

Conclusion

The novel Nf‐L Simoa is precise and can be used to quantify small scale changes in Nf‐L plasma concentrations. Our assay measured lower concentrations of Nf‐L in serum than in plasma, although quantification of serum samples using this assay format probably requires further optimization.
Ageing‐associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease
Authors: Depp Constanze Martha , Nave Klaus‐Armin , Lab Klaus‐Armin Nave
Published: December 2022

Background

The prevalence of Alzheimer’s disease (AD), the leading cause of dementia, shows a strict age‐dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing markedly affects oligodendrocytes and the structural integrity of myelin sheaths which is associated with secondary gliosis. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing‐associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid‐β (Aβ) deposition, the primary neuropathological hallmark of AD.

Method

We used AD mouse models and combined them with genetic myelin dysfunction models (CNP−/−, PLP−/y, Emx‐Cre MBPfl/fl forebrain shiverer) as well as mouse models of acute demyelination (Cuprizone, EAE) and investigated the effect of myelin defects on amyloid deposition using in toto quantitative light sheet microscopy. Bulk and single cell transcriptomics, immunohistochemistry and biochemical approaches were used to investigate the potential mechanism of action.

Result

We identified myelin defects as potent drivers of amyloid deposition in vivo. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque‐corralling microglia but show a disease‐associated microglia (DAM)‐like signature. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques.

Conclusion

Our data suggest a working model, in which age‐dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.
White matter associated microglia in Alzheimer’s disease
Authors: Simons Mikael
Published: December 2022

Background

White matter is composed of mostly myelinated axons that connect neurons from different brain regions into functional circuits. Aging results in both grey and white matter degeneration, but the specific microglial responses to the damage is unknown. Strikingly, in Alzheimer’s disease white matter alterations occur early in the disease course. Here, we analyzed microglia responses in the white matter in aging rodents and models of Alzheimer’s disease.

Method

We dissociated grey and white matter tracts and isolated microglia from young and aged mice and performed single cell RNA sequencing. To compare aging and neurodegeneration effects on microglia, we isolated microglia from a transgenic Alzheimer’s disease mouse model, and to study signaling pathways we included aged Trem2 and Apoe knockout mice into the analysis. Validation and characterization of the phenotypes occurred by in situ hybridization, immunohistochemistry, correlated light and electron microscopy.

Results

Using single‐cell RNA sequencing from white and grey matter separately, we identified white matter associated microglia, which shared distinct parts of the disease‐associated microglia (DAM) gene signature. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin, depending on Trem2 signaling. In the aged brain, white matter associated microglia form independently of ApoE, which is in contrast to mouse models of Alzheimer’s disease, in which microglia with white matter associated microglia gene signature are generated prematurely and in an ApoE‐dependent pathway similar to DAM.

Conclusion

We propose that white matter associated microglia represent a protective metabolic response, required to clear the increasing amounts of myelin debris that accumulate during aging and AD. We speculate that premature formation of white matter associated microglia in AD may contribute to the development of neurodegenerative disease, possibly by attrition of microglia function leading to accumulation of toxic protein or lipid species within the brain.
An Innovative Approach to Empowering Care Partners Living with A Loved One Diagnosed with Younger‐Onset Alzheimer’s
Authors: Cose Diana Shulla
Published: December 2022

An Innovative Approach to Empowering Care Partners Living with A Loved One Diagnosed with Younger‐Onset Alzheimer's Our innovative approach at Lorenzo's House, a nonprofit in Chicago, empowers care partners living with a loved one with younger‐onset Alzheimer's. Lorenzo's Angels is a proven model designed to create one‐on‐one mentor matches between care partners. This personalized match offers connection with someone who shares a similar profile and understands. Families living with a younger‐onset diagnosis are often underserved and under‐discussed in the Alzheimer's community. With this diagnosis comes a dramatic shift in a younger family's dynamic and they are often alienated from popular Alzheimers' resources geared towards people who are diagnosed later in life. These care partner spouses are in a uniquely important and difficult position as they are responsible for being the primary care partner to their spouse, breadwinner for the household, and for parenting independently ‐ all while navigating the complexities of the diagnosis.

A family culture changes after a younger‐onset Alzheimer's diagnosis, and there is a need for innovative care and personal connection. We recognize that the best guidance and support for care partners often comes from people who have or are still walking the path. We empower families by cultivating a care partner‐to‐care partner mentor model, building an International network of care partners matches. Our framework emphasizes social emotional wellness, practical information and resourcefulness so that families turn isolation to connectedness and darkness to light, living this journey together ‐ never alone. By creating this framework through digital and in‐person platforms, we provide sustenance to care partners everywhere living with a loved one with younger‐onset Alzheimer's.
Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s
Authors: Rowan Matthew JM , Olah Viktor Janos , Goettemoeller Anne M
Published: December 2022

Background

In Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD.

Method

We used an interneuron‐enhancer AAV labeling technique to specifically target PV interneurons for whole‐cell and outside‐out patch clamp recordings in young 5xFAD mice. Our findings were complemented by PV dyanmic clamp recordings, PV‐specific qPCR, quantitative proteomics, and NEURON modeling.

Result

We report a novel mechanism responsible for cortical PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K+ channels, but not changes in mRNA expression, are responsible for dampened excitability. These K+ conductances could efficiently regulate near‐threshold AP firing, resulting in gamma‐frequency specific network hyperexcitability.

Conclusion

Our findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.
Quantitative myelin imaging with MPnRAGE‐derived R1 mapping: Applications to Alzheimer’s disease
Authors: Kohli Akshay , Kecskemeti Steven R , Yang Kao Lee , III Doug C Dean , Asthana Sanjay , Johnson Sterling C. , Alexander Andrew L , Bendlin Barbara B.
Published: December 2022

Background

Post‐mortem observations of Alzheimer’s disease (AD) brain suggest that developmental patterns of myelin and AD pathology are inversely related (Braak and Braak, 1996). Myelin injury and repair processes have also been implicated in the amyloid cascade hypothesis (Bartzokis, 2004; Depp et al., 2021). While diffusion‐weighted imaging has been widely applied to examine white matter abnormalities in AD, there remains a dearth of high resolution and high contrast imaging methods that allow for accurate and precise measurement of brain myelin in vivo. Here, we leveraged a novel imaging sequence—MPnRAGE (Kecskemeti et al., 2016; 2018)—to derive R1 maps, a myelin sensitive metric, and assessed the potential of R1 to identify myelin abnormalities in relation to cognitive impairment in AD.

Method

791 cognitively unimpaired older adults, 30 with dementia, and 43 with MCI enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center clinical core study underwent T1‐weighted (T1w) MPnRAGE with motion‐correction. T1w images and R1 maps were reconstructed at 1mm isotropic resolution. Preprocessing steps are outlined in Figure 1. As the T1w image and R1 map are inherently coregistered, no additional preprocessing was applied to the R1 map.

Result

A whole‐brain vertex‐wise cortical R1 map for a single participant and bilaterally averaged group mean parcellations for both cortical and WM R1 can be seen in Figure 2. Notably, densely‐myelinated regions are typically spared in AD, while thinly‐myelinated regions are vulnerable to AD pathology. In the cortex, sensory/motor regions exhibited the highest R1 (indicative of greater myelin content) and frontal/temporal regions had the lowest R1. In shallow WM, pericingulate WM exhibited the highest R1 and visual‐adjacent WM had the lowest R1. Participants with dementia and MCI had substantially reduced cortical adjacent WM R1 compared to unimpaired individuals (Figure 3).

Conclusion

This is the largest study to date to examine R1 maps among older adults with and without AD. These R1 maps are expected to facilitate analyses between myelin content and regional AD pathology accumulation as indexed by tau and amyloid PET, as well as testing the role of longitudinal myelin injury and repair in disease progression.
Investigating P2×7R‐mediated inflammatory signalling in Alzheimer’s disease
Authors: Lobo Paula Beltran , Hughes Martina M , Kassiou Michael , Perez‐Nievas Beatriz G. , Noble Wendy
Published: December 2022

Background

Alzheimer’s disease (AD) is pathologically characterised by the presence of amyloid plaques and neurofibrillary tangles accompanied by a marked neuroinflammation which contributes to the onset and progression of AD. Astrocytes and microglia recognize danger‐associated molecular patterns (Aß, ATP) through a myriad of sensors including the purinergic receptor P2×7 (P2×7R). These interactions lead to the release of inflammatory mediators that could participate in damaging inter‐cellular cascades. Inhibition of P2×7R in AD models ameliorates cognitive deficits and supports a neuroprotective effect of P2×7R blockade in vivo. However, the cell type‐specific inflammatory signals downstream of P2×7R in AD are not fully understood.

Method

We used biochemical and histological methods, including in situ RNA detection (RNAscope), to examine P2×7R expression and localization relative to disease hallmarks and local inflammatory features in temporal and prefrontal cortex at different Braak stages. A series of P2×7R antagonists were used to study P2×7R‐mediated responses to inflammatory stimuli in primary glial cells and to assess the effects of P2×7R blockage on tau and synapse health in brain slice cultures.

Result

We found elevated levels of P2×7R in AD relative to control brain together with an increased amyloid burden, synapse mislocalization of tau and loss of synaptic markers. P2×7R was detected in human astrocytes as well as other neural cell types and its increased abundance was accompanied by an upregulation of inflammatory cytokines including CCL2 and IL‐1ß. In cultured astrocytes, P2×7R activation contributes to the production of the inflammatory cytokines CCL2, IL‐6 and the synaptotoxic molecule lipocalin‐2, whereas microglial P2×7R activation induces IL‐1ß secretion through the NLRP3 inflammasome pathway. Treatment of organotypic brain slice cultures with specific P2×7R antagonists suggests that P2×7R inhibition modulates glial function in response to neurodegenerative disease relevant stimulation.

Conclusion

These data show that P2×7R expression is elevated in AD prior to marked synapse loss and point towards distinct P2×7R‐mediated responses in astrocytes and microglia. Ongoing work aims to determine if pharmacological blockade of P2×7R‐inflammatory signals has benefits for tau‐associated neurodegeneration in AD.
Single‐nucleus open chromatin accessibility landscape of Pick’s and Alzheimer’s disease
Authors: Shi Zechuan , Das Sudeshna , Morabito Samuel , Miyoshi Emily , Head Elizabeth , Swarup Vivek
Published: December 2022

Background

Pick’s disease (PiD), a behavioral variant of frontotemporal dementia, is one of the common neurodegenerative dementia that is characterized by tau lesions. Despite the distinct tau aggregation observed in Pick’s disease compared with the tauopathy of Alzheimer’s disease (AD), the similarity in cognitive and behavioral impairments during the progression of the disease make their diagnosis challenging. What determines the differences and similarities between PiD and AD progression, especially at the epigenetic level, are largely unknown. We believe that recent advancement in single‐cell epigenomic profiling methods, Assay for Transposase‐Accessible Chromatin (ATAC) combined with high throughput sequencing, will enable us to map the chromatin‐regulatory landscapes of disease brains at a single‐cell resolution and enable us to understand underlying molecular changes in these diseases.

Method

In the present study, we have isolated single nuclei from the frontal cortex region and performed single‐nucleus ATAC sequencing (snATAC‐seq) of 198,722 nuclei to generate cell‐type specific chromatin accessibility profiles of postmortem brains of PiD and AD patients and to uncover their cellular heterogeneity and similarity. We used cellranger to process the paired‐end FastQ reads of each sample to obtain its chromatin accessibility count matrix. Next, we utilized ArchR and Signac pipelines to generate 501‐bp fixed‐width peak regions and performed downstream differential accessible regions analysis. Quality control was also performed to remove the contribution of low‐quality nuclei.

Result

We constructed chromatin accessibility profiles from 19,690 nuclei from PiD patients, 59,148 nuclei from AD patients, and 119,884 nuclei from healthy controls. We applied UMAP dimensionality reduction and clustered nuclei through open chromatin region to the batch‐corrected epigenomic datasets. We identified seven distinct cell types, including astrocyte, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, OPC, and pericyte/endothelial cells, and we applied pseudotime trajectory analysis to characterize disease‐associated cell state in both AD and PiD at the epigenomics level.

Conclusion

Our data identified the cell‐type‐specific open chromatin accessible regions in AD and PiD brains. Although the causative molecular mechanisms of AD and PiD remain unknown, our work helps to identify shared epigenomic changes in AD and PiD, especially in regards to cell‐type‐specific genomic loci with disease risk.
Longitudinal Changes in P3 Event‐related Potential among Older Adults with Preclinical Alzheimer’s Disease: A 1‐year Follow‐Up
Authors: Estes Bradley J , Gustafson Kathleen , Liao Ke , Martin Laura E , Ahmadnezhad Pedram , Kuhlmann Emily , Brooks William M , Mahnken Jonathan D , Burns Jeffrey M. , Devos Hannes
Published: December 2022

Background

The third positive peak of the event‐related potential (ERP P3) is understood to reflect neural resource utilization during working memory. We previously showed lower P3 ERP amplitude of the task effect in older adults with preclinical Alzheimer’s disease (AD). The aim of this study was to compare changes from baseline to 1‐year follow‐up in P3 ERP between older adults with and without preclinical AD.

Method

Cognitively normal, beta‐amyloid positive (CNAβ+, n = 14) participants and beta‐amyloid negative (CNAβ‐, n = 15) controls completed a working memory task (n‐back) with three levels of difficulty (0, 1, 2) at baseline and 1‐year follow‐up. ERP P3 peak amplitude and latency of the task effect (non‐target minus target) were extracted from continuous electroencephalography recording. The frontal midline channel Fz was identified a priori as the main channel of interest. Aβ accumulation was characterized with [18F] Florbetapir positron emission tomography scans. Independent t‐tests, Fisher’s Exact, or Mann‐Whitney U tests were employed to compare baseline characteristics between groups. Linear mixed models with random intercept were used to compare changes in P3 peak amplitude and latency. Group (CNAβ+ vs CNAβ‐), time (baseline, 1‐year), and n‐back (0, 1, 2) were entered as main effects. The main analysis of interest was the interaction between group and time.

Result

Baseline age, sex, MOCA scores, and n‐back accuracy and response times did not differ (p>0.11) between CNAβ+ and CNAβ‐ groups [Table 1]. Additionally, no longitudinal changes in MOCA scores or n‐back performance were observed between groups (p>0.41). A significant group by time interaction effect in P3 peak amplitude at Fz was found between CNAβ+ and CNAβ‐ participants (p = 0.049). The P3 peak amplitude increased by 48% in CNAβ+ participants, whereas only a 19% increase was observed in CNAβ‐ participants.

Conclusion

The ERP revealed significant changes over time in P3 amplitude for the CNAβ+ participants compared to the CNAβ‐ controls. The greater increase of CNAβ+ task effect amplitude likely represents a growing imbalance in task specific resource allocation. Further investigation of this phenomenon is warranted to evaluate neuronal activity of preclinical AD and the use of P3 ERP as a potential screening tool.