bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebrospinal Fluid GFAP Mediates the Association of β2‐microglobulin with Tau Pathology
Authors: Sheng Ze‐Hu , Wang Lan‐Yang , Wang Xiao‐Qin , Guo Fan , Lü Yang
Published: January 2025

Background

Recent studies have demonstrated that β2 microglobulin is an important factor in β‐amyloid (Aβ) neurotoxicity and a potential target for the treatment of AD. Although β2 microglobulin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and Glial fbrillary acidic protein (GFAP) are involved in the neuroinflammatory response to promote the development of AD, their relationship in AD pathology remains to be studied.

Method

A total of a11 participants with cerebrospinal fuid (CSF) and Plasma β2 microglobulin, CSF sTREM2, GFAP, and AD biomarkers(Aβ42; phosphorylated‐tau, P‐tau; and total tau, T‐tau) were included from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We assessed the associations of CSF/Plasma β2 microglobulin with sTREM2/GFAP and AD biomarkers at baseline and in longitudinal study. The mediation models were used to explore the potential mechanism of how β2 microglobulin afects AD pathology.

Result

We found that T+ and N+ groups had higher CSF β2M levels (both p < 0.001), but there was no difference between A+ and A‐ groups. Meanwhile, Since stage 1, CSF β2M levels gradually increased in stage 2 and SNAP. We also found the elevated CSF β2M level was associated with the higher levels of Aβ42 (β = 0.230, p < 0.001), P‐tau (β = 0.564, p < 0.001) and T‐tau (β = 0.603, p < 0.001). There were also positive association between baseline CSF β2M and levels of GFAP (β = 0.552, p < 0.001) and sTREM2 (β = 0.641, p < 0.001). Nevertheless, plasma β2M was not cross‐sectionally correlated with CSF AD core biomarkers, GFAP and sTREM2. Furthermore, only higher CSF β2M was longitudinally associated with slower increase of T‐tau (β = ‐0.025, p = 0.025). Results of mediation analyses showed that the association of CSF β2M with CSF P‐tau (mediating ratio = 25.4%, p < 0.001) and T‐tau (mediating ratio = 26.7%, p < 0.001) was partially mediated by CSF GFAP in total participants. In addition, the mediation effects of sTREM2 were not significant.

Conclusion

Our findings provide evidence to suggest that CSF β2 microglobulin is associated with tau pathology and mediated by CSF GFAP.
Gait and speech analysis for predicting progression in memory clinic: A two‐year longitudinal follow‐up
Authors: Liu Yi‐Chien , Chou Chia‐Ju , Lee Chia‐Ying
Published: January 2025

Background

The clinical progression of AD exhibits significant heterogeneity among individuals. Early identification of individuals likely to experience disease progression holds paramount importance within the context of a memory clinic. In the present study, we endeavor to analyze gait and speech data as potential predictors of early AD progression.

Methods

Between 2021 and 2023, we conducted a prospective recruitment of 99 participants from a memory clinic in Taiwan. All participants underwent comprehensive assessments, including amyloid PET scans, brain MRI scans, a battery of neuropsychological tests, and serum tests aimed at excluding reversible causes of cognitive impairment. Over a two‐year longitudinal follow‐up period, participants received diagnoses ranging from subjective cognitive decline (SCD), mild cognitive impairment (MCI), to mild dementia. Additionally, based on changes observed in the Clinical Dementia Rating Scale, Sum of Boxes (CDR‐SB) scores during the follow‐up period, participants were categorized into ‘progressor’ (CDR‐SB change≧1) and ‘non‐progressor’ groups. We collected speech and gait data through picture description tests and the Short Physical Performance Battery (SPPB). Speech data was manually transcribed and subsequently analyzed, focusing on 16 linguistic features.

Results

In our cohort, 42.31% of individuals were categorized as progressors. The prevalence of amyloid positivity was notably higher among the progressors (84.09%) than in the non‐progressor group (29.63%). Our predictive modeling efforts involved logistic regression and the Receiver Operating Characteristic (ROC) curve analysis to forecast the progression of individuals within our dataset. Specifically, when we integrated gait speed and linguistic features as predictors, the Area Under the Curve (AUC) reached 0.8. In comparison, the AUC was 0.75 when we employed hippocampal volume as a predictor.

Conclusion

Gait and speech data have the potential to serve as indicators of baseline cognitive status within a memory clinic setting. When combined, these datasets allow us to predict clinical progression with comparable accuracy to that achieved using neuroimaging techniques.
Sex differences in microvascular and Alzheimer’s disease‐related pathology in the medial temporal lobe: a quantitative neuropathological study
Authors: Bax Francesco , van den Berg Marteen L. , Oltmer Jan , Auger Corinne A. , Melloni Alexandra N. , Connors Theresa , Serrano‐Pozo Alberto , Frosch Matt P. , Greenberg Steven M. , Hyman Bradley T. T , van Veluw Susanne J. , Perosa Valentina
Published: January 2025

Background

Alzheimer’s disease (AD) related pathologies (i.e., neurofibrillary tangles [NFTs], amyloid‐β plaques, and phosphorylated‐TAR‐DNA‐binding‐protein‐43 [pTDP‐43]) differ across sexes. However, the interaction between sex and cerebral small vessel disease (CSVD) (i.e., cerebral amyloid angiopathy [CAA] and arteriolosclerosis) on AD‐related pathologies has been less well characterized. The medial temporal lobe (MTL) is a crucial region in AD pathophysiology which harbors AD‐pathologies at an early disease stage and is vascularized by small vessels prone to CSVD. We therefore aimed to analyze the relationship between sex and CSVD on AD‐related pathologies in the MTL of a pathological AD cohort.

Methods

The study included autopsy cases from the Massachusetts AD Research Center. One hemisphere was formalin‐fixed, samples from pre‐defined regions (hippocampal body and entorhinal cortex) were stained for luxol fast blue with hematoxylin&eosin, amyloid‐b, At8, and pTDP‐43. Deep‐learning models (Aiforiaâ) were used to obtain quantitative measures for burden of CAA, NFTs, and pTDP‐43 inclusions. Arteriolosclerosis (grade 0‐3) was determined in vessels >20mm Ø. Mixed effect models explored age and sex (fixed terms) across regions of interest (ROIs: hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala) of the MTL on CSVD subtypes. Furthermore, interactions between sex and CSVD subtypes on AD‐related pathologies were tested. Finally, ApoE effect was evaluated in a subgroup with available genotyping.

Results

157 autopsy cases (80.8±12.6y, 91 females) were included, ApoE status was available in 66/157. Females had higher arteriolosclerosis severity (odds ratio for grade 2/3 = 1.56, 95% confidence interval [CI] 1.11; 2.20, p = 0.01) and lower CAA burden (b = ‐0.08, 95%CI ‐0.12; ‐0.04, p<0.001), when adjusting for age and ROIs. Moreover, females had lower burden of amyloid‐b plaques (b = ‐0.25, 95%CI ‐0.46; ‐0.04, p = 0.02) and higher density of NFTs (b = 5.16, 95%CI 1.90; 8.41, p = 0.002). Inclusion of ApoE‐status confirmed these findings with higher effect‐size, and ApoE4 genotype interacted with female sex predicting higher NFT density when adjusting for arteriolosclerosis and CAA respectively (b = 16.2, 95%CI 4.2; 28.2, p = 0.008 and b = 16.3, 95%CI 3.37; 29.22, p = 0.01). No interaction effect was found between sex and CSVD on AD‐pathology.

Conclusions

In this cohort, sex differentially affected microvascular and AD‐related pathologies in the MTL. ApoE4 genotype might act as an effect modifier of sex.
AD Pathology Spreading Detection Using Directional Motifs in Brain Connectomes
Authors: Bueichekú Elisenda , Diez Ibai , Úbeda Antonio , Kim Chan‐Mi , Jacobs Heidi I.L. , Sepulcre Jorge
Published: January 2025

Background

The accumulation of misfolded tau proteins, an Alzheimer’s disease (AD) hallmark, starts decades before the emergence of cognitive decline and clinical diagnosis. Autopsy studies support a predictable progression of tau pathology through large‐scale systems. However, less is known about the specific progression patterns. The use of connectomic metrics could enhance our understanding of the characteristics of pathology spread. We examined the spatiotemporal relationships of cortical tau accumulation using network motifs, directed graph metrics, which can reveal the underlying mechanisms governing the pathology progression routes in preclinical and clinical AD.

Methods

We used longitudinal tau‐PET data (1‐year follow‐up) from 40 adults with normal cognitive functioning and 33 adults with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐3) (Table 1). We used individual and group‐level whole‐brain voxel‐wise graph theory and motifs networks analyses to investigate AD‐related tau pathology directional spreading (Figure 1a). Directional relations are established by using group‐level association matrices and by assessing differences in between‐voxels temporal relations (Time1‐Time2; FDR‐corrected, p<0.001) (Figure 1b). Then, the resulting association matrix representing the human connectome is decomposed into motif networks, which are three‐node triangular fundamental relations (i.e., exact copies of every possible motif is searched at the voxel‐level) (Figure 1c). Finally, between‐group visual comparisons of each motif reveal similarities and differences in dominant pathology spreading patterns in preclinical vs. clinical AD stages (Figure 1d).

Results

Our results support that unidirectional and serial network motifs are behind misfolded tau protein spreading in AD (Figure 2). Feed‐forward loops, cascade, and regulated mutual networks drive tau propagation in medial and lateral temporal and medial prefrontal regions early in the disease. Through the disease, spread out from one region to another (i.e., fan out and regulating mutual networks) is a common characteristic of tau progression.

Conclusion

Our results suggest that the progression of toxic tau through the brain systems occurs mainly in a unidirectional and serial manner. AD is considered a dysconnectivity disease. Thus, serial motifs could indicate biological relations arising on a sequential spatiotemporal scale. Future developments will examine the role of amyloid accumulation in tau progression in the context of AD.
Glial and synaptic biomarkers as early indicators of mild cognitive decline
Authors: Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Zetterberg Henrik , Hanrieder Jörg , Blennow Kaj , Mroczko Jan , Krawczuk Daria , Doroszkiewicz Julia , Borawska Renata , Slowik Agnieszka , Mroczko Barbara
Published: January 2025

Background

Cognitive disorders are a growing cause of morbidity and mortality worldwide. Diagnostic approaches to improve early diagnosis of cognitive disorders are constantly being sought. The pathogenesis of cognitive impairment is multifactorial and complex. It is believed that microglial activation and synaptic disturbance are crucial mechanisms leading to disease progression thus study of the interrelationships of the proteins involved in these processes appears to be important. Chemokine CX3CL1 seems to play a pivotal role in the central nervous system and it is involved in microglia‐neuron communication, neuronal survival, synaptic plasticity, as well as neuronal excitability. Findings from preclinical studies on AD models have reported the crucial role of CX3CL1 in microglial activation, regulation of plaque load, and cognition. Neurogranin is considered, as a biomarker of early synaptic dysfunction in AD. Additionally, it may serve as a marker to predict disease progression. Therefore, we aimed to investigate and compare CX3CL1 and neurogranin (Ng) levels in CSF patients with mild cognitive decline (MCI) and cognitively normal subjects from the control group. We also assessed an association between CSF concentrations of CX3CL1, Ng, and neurochemical dementia biomarkers.

Method

The concentrations of CX3CL1, neurogranin as well as neurochemical dementia biomarkers, including amyloid beta 1‐42 (Aß‐42), amyloid beta 1‐40, Tau, as well as pTau181 were measured in cerebrospinal fluid patients with mild cognitive impairment and individuals without cognitive decline by multiplexing and enzyme‐linked immunosorbent techniques.

Result

Significantly higher CSF concentrations of CX3CL1 and neurogranin were found in MCI patients in comparison to subjects without cognitive decline. Furthermore, in the group of patients with MCI the CSF levels of CX3CL1 and Ng significantly correlated with Aβ‐42, and pTau181 proteins. Similarly, a significant association between neurogranin and Tau protein was observed. Additionally, a positive correlation between CSF levels of Ng and CX3XL1 was noticed.

Conclusion

Our findings indicate that both proteins CX3CL1, as well as neurogranin, could be applied as complementary early biomarkers for more accurate diagnosing and stratification of patients with cognitive decline.
Presynaptic toxicity of the AD susceptibility gene BIN1
Authors: Dourlen Pierre , Lambert Erwan , Freire‐Regatillo Alejandra , Gelle Carla , Leclerc Valentin , Barois Nicolas , Hermant Xavier , Malfoi Tommy , Verstreken Patrik , Amouyel Philippe , Lafont Frank , Kilinc Devrim , Lambert Jean‐Charles
Published: January 2025

Background

BIN1 is a major susceptibility gene for AD and BIN1 protein interacts with Tau. However, the contribution of BIN1 and its isoforms to AD pathogenesis remains unclear. We recently described that human BIN1 isoform1 (BIN1iso1) induces an accumulation of early endosome vesicles leading to neurodegeneration in Drosophila retina and that the early endosome size regulation was conserved in human induced neurons. This role was specific to BIN1iso1, as compared to BIN1iso8 and BIN1iso9. Because endosomal trafficking is essential for synapse, we further analyzed BIN1 isoforms neurotoxicity at the synaptic level.

Method

We first used electrophysiology, immunofluorescence and electron microscopy in vivo in transgenic Drosophila adult retina photoreceptor neurons and larval neuromuscular junction. We then tested a functional conservation in transduced rat primary neurons using tricompartment microfluidic devices, immunofluorescence and Multi‐Electrode‐Array to assess a presynaptic vs post‐synaptic role.

Result

We observed an early loss of synaptic transmission upon BIN1iso1 expression specifically, in Drosophila retina photoreceptor neurons. This was characterized by a strong accumulation of abnormally large vesicles in the presynaptic compartment. In addition, expression of BIN1iso1 in motoneurons of the neuromuscular junction altered the morphology of synaptic boutons, with an increase in their number and a decrease in their size, and the appearance of satellite boutons. BIN1iso1 synaptic toxicity could be partially rescued by modulating endosomal regulators, suggesting that an endosomal defect would be the cause of synaptotoxicity. Finally, we observed a functional conservation in rat primary neurons as shown by the loss of synaptic connectivity only when expressing BIN1iso1 in the presynaptic compartment.

Conclusion

Our results suggest that BIN1 has an isoform‐specific, deleterious effect on synaptic integrity when expressed in the presynaptic terminal. This effect could contribute to the synaptic loss observed early in AD.
A study of the efficacy of 500nm blue‐green light therapy on cognition, mood, and sleep in prodromal Alzheimer's disease
Authors: Feng Qiansen , Chen Lei , Li Linlin , Yang Junlan , Wu Jiajing , Yue Yuchuan , Wang Ziqi
Published: January 2025

Background

The study aimed to evaluate the effects of four weeks of 500 nm blue‐green light visual stimulation on cognition, mood, and sleep in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI).

Method

Eighty patients were recruited from the Memory Clinic. The experimental group comprised 42 cases (22 SCD and 20 MCI), while the control group comprised 38 cases (27 SCD and 11 MCI). The experimental group was treated with a 500nm blue‐green light (light spectrum intensity of 506 lux lm/m² and 230 µW/cm²) for 50 minutes in the morning for four weeks, while the control group received no treatment. General cognitive function was evaluated using the Mini‐mental State Examination (MMSE), Montreal Cognitive Assessment‐Basic (MoCA‐B), and Alzheimer’s Disease Assessment Scale‐cognitive subscale (ADAS‐cog), and mood was evaluated using the Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD). The Pittsburgh Sleep Quotient Index (PSQI) was used to assess the sleep quality. Paired t‐test and Wilcoxon signed‐rank test were used to compare the differences in cognition, sleep, and mood between the experimental and the control group before and after the intervention.

Result

There were no significant differences in baseline demographic information, cognition, mood, and sleep between the experimental and control groups (P>0.05). As shown in Table 1. After the intervention, the experimental group showed a significant reduction in the ADAS‐cog (P = 0.034), HAMA (P = 0.044), HAMD (P<0.001) and PSQI scores (P = 0.035). The control group showed a significant reduction in HAMA (P = 0.002) and HAMD (P = 0.018) scores. As shown in Table 2.

Conclusion

Four weeks of 500 nm blue‐green light therapy significantly improved overall cognitive function and sleep quality in SCD and MCI patients.
Rescue of impaired hippocampal consolidation in the APP/PS1 mouse model of Alzheimer’s disease after increasing cerebral blood flow
Authors: Berkowitz Laura E , Todorova Ralitsa , Harvey Ryan E , Shimizu Jean‐Luc , Dong Xuelai , Oliva Azahara , Fernandez‐Ruiz Antonio , Nishimura Nozomi , Schaffer Chris B
Published: January 2025

Background

Alzheimer’s disease (AD) manifests with early spatial memory impairment and is linked to the degeneration of hippocampal circuits. Hippocampal sharp wave ripples (SWRs) are high‐frequency population‐burst events that coordinate the reactivation of neural assemblies (groups of neurons that become correlated in their firing patterns during learning) in post‐learning sleep, which is the neural basis of memory consolidation. SWRs are reduced in the APP/PS1 mouse model of AD‐like pathology. Previously, we showed that cerebral blood flow (CBF) decreases and memory deficits were rescued following treatment with anti‐Ly6G antibodies. Here, we examine the potential normalization of hippocampal circuit activity with CBF increase.

Method

Male, 7‐14‐month‐old APP/PS1 mice and wild‐type controls were implanted with 64‐channel silicon probes in hippocampal area CA1. Neural activity was recorded during sleep before and after the exploration of an open field. Putative cell types were identified using feature‐based classification, and neural assemblies were detected using independent component analysis.

Result

APP/PS1 mice had reduced magnitude and duration of assembly reactivation in post‐task sleep SWRs. After treatment with anti‐Ly6G antibodies, which increase CBF and improve memory performance, we found increased reactivation of these assemblies in post‐task sleep SWRs, relative to no‐treatment controls (Figure 1).

Conclusion

We found that increasing CBF normalizes neural mechanisms of memory consolidation that are altered in AD mouse models, supporting the development of treatment approaches to increase CBF in AD.
NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS)
Authors: Saravanan Naveensri , Kuzma Amanda B , Valladares Otto , Nicaretta Heather Issen , Manuel Joseph , Gangadharan Prabhakaran , Katanic Zivadin , Kirsch Maureen , Ren Youli , Bass Lauren , Brettschneider Jascha , Wilk Andrew , Zhao Yi , Qu Liming , Moon Michelle K , Rose Alexis Lerro , Keskinen Peter , Cifello Jeffrey , Horng Wenhwai , Tate Sam , Robbins Flawless , White Heather , Carter Luke , Chou Shin‐Yi , Naj Adam C. , Greenfest‐Allen Emily , Kuksa Pavel P. , Leung Yuk Yee , Lee Wan‐Ping , Schellenberg Gerard D. , Wang Li‐San
Published: January 2025

Background

NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer’s Disease Sequencing Project (ADSP), and the Genome Center for Alzheimer’s Disease (GCAD) allow NIAGADS to lead the effort in managing large AD datasets that can be easily accessed and fully utilized by the research community.

Method

NIAGADS is supported by the National Institute on Aging (NIA) under a cooperative agreement. All data derived from NIA funded AD genetics studies are expected to be deposited in NIAGADS or another NIA approved site. NIAGADS manages a Data Sharing Service (DSS) that facilitates the deposition and sharing of genomic data and association results with approved users in the neurodegenerative research community. In addition, researchers are able to freely use the NIAGADS Alzheimer’s Genomics Database (www.niagads.org/genomics/) to search annotation resources that link published AD studies to AD‐relevant sequence features and genome‐wide annotations.

Result

As of January 2024, NIAGADS houses 105 datasets comprised of >183,000 samples including array data, sequencing, gene expression, annotations, deep phenotypes, summary statistics, among others. Qualified investigators can retrieve ADSP sequencing data with ease and flexibility through the NIAGADS DSS. To date, the ADSP and other contributing studies have completed whole exome sequencing (WES) of 20,499 samples and whole genome sequencing (WGS) of 36,352 samples. Raw WES and WGS files, quality controlled VCF files, and phenotype data files are available via qualified access. The next round of sequencing currently underway will generate around 30,000 additional genomes to be released in mid‐2024.

Conclusion

NIAGADS is a rich resource for AD researchers, with the goal of facilitating advances in Alzheimer’s genetics research. By housing datasets from many projects and institutions, NIAGADS enables AD researchers to meet their research goals more efficiently. Datasets, guidelines, and features are available on our website at https://www.niagads.org.
Hippocampal neuronal loss, LATE‐NC, Alzheimer’s disease pathology, and cognitive decline
Authors: Agrawal Sonal , Yu Lei , Leurgans Sue E. , Barnes Lisa L. , Bennett David A. , Schneider Julie A.
Published: January 2025

Background

Hippocampal neuronal loss (HNL), LATE neuropathologic changes (LATE‐NC), and Alzheimer’s disease (AD) are common neuropathological findings in older persons. However, the inter‐relationship between AD, LATE‐NC, HNL, and cognition is not well understood.

Method

Participants without known dementia (n = 420; mean age‐at‐death = 92 years, women = 72%) enrolled, in the Rush community‐based cohorts and underwent annual cognitive testing and autopsy. At autopsy, the severity of HNL in the CA1‐subiculum sector was semi‐quantitatively graded from 0 (none) to 5 (severe) on H&E stain without regard to AD or LATE‐NC pathology. Hippocampal sclerosis (HS) was defined as severe hippocampal neuronal loss (grade 5). Tau‐tangle density, β‐amyloid burden, LATE‐NC, and other age‐related pathologies were also recorded. Logistic regression and mixed‐effect models adjusted for demographics and neuropathologies were used to examine the association of HNL with AD (tangles/ β‐amyloid) and LATE‐NC, and separately with cognitive decline. Path analyses examined the extent to which the associations of LATE‐NC and tau tangles with cognitive decline was attributable to HNL.

Result

HNL was common: mild in 61%, moderate in 16%, and severe in 20% of participants. Advanced LATE‐NC stage 2/3 and tau‐tangles, but not β‐amyloid pathology, were associated with worse hippocampal neuronal loss. More HNL was associated with faster decline in global cognition and four cognitive domains: episodic, semantic, and working memory and perceptual speed. These associations remained robust even after excluding participants with HS. LATE‐NC and tangles were also associated with cognitive decline but the association between LATE‐NC and cognitive decline was lost while the association of tangles with cognitive decline was partially attenuated after adding HNL in the model. The result from path anlayses suggested that two‐thirds of the association between LATE‐NC and cognitive decline was attributable to HNL whereas only 5% of the association of tau tangles was through HNL.

Conclusion

Our results support that HNL and tangles are the major contributors of cognitive dysfunction. LATE‐NC is also associated with cognitive decline but may causes most dysfunction via HNL.
Differential Patterns of Gut and Oral Microbiomes in Patients with Mild‐cognitive Impairment
Authors: Ngouongo Yannick Joel Wadop , Mathews Julia J , Muhammad Jazmyn A , Pirela‐Mavarez Rosa P. , Mahaney Michael C , Maestre Gladys E. , Seshadri Sudha , Kautz Tiffany F. , Fongang Bernard
Published: January 2025

Background

Oral and gut microbiomes have been associated with Alzheimer’s disease and related dementias (ADRD). Although the role of the gut microbiome and gut dysbiosis in ADRD has been extensively studied, research on the oral microbiome is lacking. Moreover, the synergetic contribution of oral and gut microbiomes to ADRD is unexplored. This study aimed to assess the differential patterns of oral and gut microbiomes and their synergetic effects in patients with mild cognitive impairment (MCI) compared to normal cognition (NC).

Method

Gut and saliva microbiome abundance and diversity measurements were obtained using 16S rRNA gene sequencing of stool and saliva samples from 27 participants (12 MCI, 15 NC, %F = 66.7, Age = 70.2 ± 6.4) recruited in San Antonio, Texas, USA (Table 1). The indexes Chao1, ACE, Observe, Shannon, and Simpson were computed to assess the 〈‐diversity of samples. However, the ®‐diversity was investigated after carrying out the principal coordinates analysis (PCoA) based on Bray‐Curtis distances to visualize group separation in compositional data. We used linear discriminant effect size and differential abundant analysis to identify gut and saliva features statistically different between MCI and NC (adjusted p‐value < 0.005).

Result

No differences in bacteria 〈‐ and ®‐diversity between MCI and NC (Figure 1) were found. However, we found an increased abundance of oral pathogenic genera, including Anaeroglobus, Centipeda, Cardiobacterium, Dialister, Fretibacterium, Leptotrichia, Mycoplasma, Tannerella, and Treponema in patients with MCI (Figure 2). We also found that MCI patients have a decreased abundance of gut genera Butyricicoccus, Defluviitaleaceae, Lachnospira, Paludicola, Shuttleworthia, and Subdoligranulum. These differential abundant gut genera have been shown to harbor anti‐inflammatory properties. We did not find evidence of synergetic contributions of oral and gut genera to MCI.

Conclusion

Our results suggest that the saliva microbiome, like the gut microbiome, is disrupted as patients progress from NC to MCI. The pathogenic oral microbes we found were previously linked to periodontal and gingivitis pathogens. Further studies with larger sample sizes are needed to validate these findings.
DNA Methylation Drives Gene Networks Dysregulated in Alzheimer’s Disease
Authors: Wang Erming , Wang Minghui , Yu Gefei , Thorpe Abigail , Haroutunian Vahram , Zhang Bin
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that inflicts the elderly worldwide. Recent studies revealed the association of abnormal methylomic alterations in AD. However, a systematic and comprehensive study is needed to investigate the effects of methylomic changes on the molecular networks underpinning AD, in particular, in brain regions most vulnerable to AD neuropathology.

Method

We profiled genome‐wide methylomic variations in the parahippocampal gyrus across 201 postmortem control, mild cognitive impaired (MCI) and AD brains in the Mount Sinai Brain Bank (MSBB) cohort. We next investigated the influence of methylomic changes on both gene and protein co‐expression networks. We then integrated the methylomic, epigenomic (ATAC‐seq), transcriptomic and proteomic data to infer the regulatory relationships among DNA methylation, chromatin accessibility, transcription and translation. Finally, we validated our key findings using an independent cohort (Religious Orders Study/Memory and Aging Project (ROSMAP)).

Result

We first demonstrated the existence of significant AD‐associated variation in methylomic sites genome‐wide, which were subsequently summarized into distinct differentially methylated regions (DMRs) that are critical in AD. We then quantified the effect of the DMRs on each gene and each protein as well as gene and protein co‐expression networks. We found that DNA methylation had profound influences on not only the AD‐associated gene/protein modules but also their key regulators in the networks. With the integration of the matched multiomics data, we unveiled that DNA methylation likely influenced gene/protein expression via epigenomic peak domains in AD. Further integration of the matched bulk tissue methylation and single nucleus multiomics data revealed cell‐type specific methylomic regulation of transcriptomics in AD.

Conclusion

Our study is the most extensive genome‐wide investigation on the impact of methylation on AD pathology, and the first integrative survey on the complex interactions between methylation, chromatin accessibility, and multiscale transcriptomic and proteomics networks in AD.
From Normal Cognition to Dementia: Using Natural Language Processing to Identify Cognitive Stages from Clinical Notes
Authors: Amini Samad , Cheng You , Magdamo Colin G. , Paschalidis Ioannis , Das Sudeshna
Published: January 2025

Background

This study responds to the urgent need for automated and reliable methods to detect cognitive impairments on a large scale. It leverages natural language processing (NLP) techniques to predict dementia and mild cognitive impairment (MCI) using clinical notes from electronic health records (EHR).

Method

Our study used an EHR dataset from Massachusetts General Brigham, which included clinical notes from a 2‐year period (2017‐2018) covering 12 types of patient encounters. Sentence segmentation and keyword‐specific extraction were performed using the NLTK tool, focusing on dementia and activities of daily living, thus providing a comprehensive base for our analysis. Our analysis, designed for classifying cognitive stages into normal cognition, MCI, and dementia, involved three binary classification tasks. We employed two innovative NLP methods based on a transformer‐based language model, the Universal Sentence Encoder (USE). The first, Random Sampling, involved extracting and randomly batching sentences containing relevant keywords, each batch processed through the Universal Sentence Encoder (USE) to generate unique 512‐dimensional embeddings. The second method, Encounter‐based Sampling, grouped sentences by their corresponding note encounter types and keyword categories, creating 24 distinct embeddings for each patient. These methods, leveraging the USE’s deep learning capabilities, provided nuanced approach to classifying cognitive stages, enhancing the predictive accuracy of our model.

Result

We evaluated the performance of various classification tasks on the data containing 531 Normal, 153 MCI, and 229 Dementia subjects. These classifications include classifying between normal cognition and dementia (AUC 97.8% in random sampling, AUC 93.6% in encounter‐based sampling), normal cognition and MCI (AUC 81% in random sampling, AUC 74.6% in encounter‐based sampling), as well as normal cognition and cognitive impairment (i.e., merged MCI and dementia stages; AUC 92.4% in random sampling, AUC 85.4% in encounter‐based sampling). Our NLP‐based approaches also significantly outperforms the baseline model based on the number of relevant sentences by a margin of 6‐13% in AUC in these three classification tasks.

Conclusion

Our study harnessed NLP techniques for enhanced dementia staging accuracy using EHR clinical notes. We introduced a highly accurate, fully automated approach with scalability potential, promising to transform hospital practices in managing clinical notes.
Effects of menopause in a mouse model of Alzheimer’s disease and comorbid metabolic disease
Authors: Abi‐Ghanem Charly , Salinero Abigail E , Kelly Richard D , Rybka Krystyna A , Gannon Olivia J , Belanger‐Mayer Kasey M , Thrasher Christina A , Groom Emily , Smith Rachel , Brooks Heddwen L , Zuloaga Damian G , Zuloaga Kristen L
Published: January 2025

Background

About two‐thirds of those with Alzheimer’s disease (AD) are women, most of whom are post‐menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid‐life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well‐known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic, cognitive, and pathological outcomes in the AppNL‐F knock‐in mouse model of Alzheimer’s disease.

Method

To model menopause, we used an accelerated ovarian failure model (4‐vinylcyclohexene diepoxide, VCD). This ovary‐intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL‐F mice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age.

Result

Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). An interaction between HF diet and menopause led to an impaired episodic‐like memory. When examining the underlying pathology, we did not detect any changes in amyloid levels, however, we observe changes in neurogenesis and microglia response.

Conclusion

Menopause and HF diet have independent and synergistic effects on metabolic, cognitive and pathological aspects of AD. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.
Genotype specific microbiome divergence of humanized APOE 2, 3, and 4 mice after microbiome standardization
Authors: Aries Michelle L , Cook Makayla , Perez Anna , Gasvoda Hope , Gooman Ashley , Hensley‐McBain Tiffany
Published: January 2025

Background

Apolipoprotein E (ApoE) is a lipid cargo binding protein that has three variants in humans, ApoE 2, 3, and 4. The ApoE 4 allele is the greatest known genetic factor for sporadic Alzheimer’s Disease. The gut microbiome (GMB) is a key essential to health, and bacterial dysbiosis can lead to poorer outcomes for disease states and an increase in microbiota and their metabolites in the peripheral. The intersection of sex, ApoE, inflammation, and gut microbiota is incompletely understood. Previous studies in humans and humanized APOE mice have demonstrated APOE‐genotype differences in the GMB. However, the vast majority of these studies used methods unable to resolve the bacteria to the genus or species level. It remains unknown if APOE genotype is a driver of GMB divergence over time and how GMB changes with age and sex in the context of APOE genotype.

Methods

In this study, humanized targeted replacement mice with either APOE 2, 3, or 4 (APOE‐TR) were purchased from JAX. Each APOE‐TR male was bred with one of the same two C57BL/6 sisters to standardize microbiomes across lines and monitor divergence based on APOE allele inheritance. Stool samples were collected from the parents at breeder set up and 6 months old and from heterozygous pups at wean, and 6 months old and will be collected every 6 months, including from the homozygous F2 generation. Stool was assessed via shallow shotgun sequencing to increase the sequencing depth and enable species and strain level taxonomic resolution.

Results

The pup’s microbiome resembled each other at wean despite genotype. However, by 6 months old, GMB diverged based on sex and APOE genotype, with genotype‐specific alterations including changes in Lachnospiraceae (p<0.001 by PERMANOVA).

Conclusions

These are the first data demonstrating GMB divergence over time driven by APOE genotype. Studying genotype specific changes in GMB and how specific APOE‐specific bacteria impact inflammatory responses can aid in understanding and potentially treating some of the underlining diseases associated ApoE 4 allele including cardiovascular disease and Alzheimer’s Disease (AD).
ABCA7‐dependent Neuropeptide‐Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer’s disease
Authors: Tayran Huseyin , Yilmaz Elanur , Bhattarai Prabesh , Min Yuhao , Wang Xue , Ma Yiyi , Nelson Nastasia , Kassara Nada , Cosacak Mehmet I , Dogru Ruya M , Reyes‐Dumeyer Dolly , Reddy Joseph S. , Qiao Min N , Flaherty Delaney , Yang Zikun , Gunasekaran Tamil Iniyan , Teich Andrew F , Vardarajan Badri N. , Tosto Giuseppe , Is Ozkan , Ertekin‐Taner Nilüfer , Mayeux Richard , Kizil Caghan
Published: January 2025

Background

Genetic variations have emerged as crucial players in the etiology of Alzheimer’s disease (AD), and they serve for a better understanding of the disease mechanisms; yet the specific roles of these genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Therefore, we generated zebrafish models for AD variants to analyze the in depth molecular and biological functions of these variants.

Method

Using CRISPR/Cas9, we generated a knockout model for abca7, orthologous to human ABCA7. We performed single cell transcriptomics and analyzed the altered genes and molecular pathways in zebrafish. We leveraged data from multiethnic AD cohorts at Mayo Clinic and Columbia University, to perform genetic association studies, co‐expression analyses, in silico interaction mapping, family based variant segregation analyses and epigenetic association studies, and the functional and histological studies in zebrafish.

Result

The abca7± zebrafish reduced astroglial proliferation, synaptic integrity, and microglial response after Aβ42 toxicity. We found that the abca7 loss‐of‐function (LOF) reduced neuropeptide Y (npy) expression as well as Brain‐derived neurotrophic factor (bdnf) and Nerve growth factor receptor (ngfr). Human brain analysis showed reduced NPY in AD, regulatory interaction between NPY and BDNF, genetic variants in NPY associated with AD, and segregation of variants in ABCA7, BDNF and NGFR in families. ABCA7 variants altered the epigenetic codes in NPY, BDNF, and NGFR promoter regions. Human results paralleled with zebrafish findings to indicate an evolutionarily conserved disease mechanism through ABCA7‐NPY signalling axis. NPY administration to zebrafish rescued the phenotypes in abca7 knockout, suggesting a true biological relevance.

Conclusion

Our results demonstrate a previously unknown link between ABCA7 and NPY in regulation of synaptic integrity and neurogenesis in AD. We propose that ABCA7‐dependent NPY is a resilience factor in vertebrate brains, and this reserve mechanism is impaired in AD.
Uncovering hidden sensorimotor memories in mice with Alzheimer’s disease relevant pathology
Authors: Santi Andrea , Moore Sharlen , Wang Aaron , Lawlor Jennifer , Fogelson Kelly , Kuchibhotla Kishore
Published: January 2025

Background

Alzheimer’s disease is a progressive form of dementia where cognitive capacities deteriorate due to neurodegeneration. Interestingly, Alzheimer’s patients exhibit cognitive fluctuations during all stages of the disease. Though it is thought that contextual factors are critical for unlocking these hidden memories, understanding the neural basis of cognitive fluctuations has been hampered due to the lack of behavioral approaches to dissociate memories from contextual‐performance. Our previous work demonstrated that interleaving reinforced with non‐reinforced (‘probe’) trials in an auditory go/no‐go discrimination task, allows us to distinguish between acquired sensorimotor memories and their contextual expression.

Method

Here, we used this approach, together with two‐photon calcium imaging on behaving APP/PS1+ mice, to determine whether amyloid accumulation impacts underlying sensorimotor memories and/or contextual performance in an age dependent manner.

Result

Importantly, peripheral auditory function, measured using auditory brainstem responses, was similar between WT and APP/PS1+ mice. We found that while contextual‐performance is significantly impaired in 6‐8mo APP/PS1+ mice compared to age‐matched controls, these animals have preserved sensorimotor memories. However, 12mo APP/PS1+ mice show deficits in both domains. The impairment found in the young adults was accompanied by overall network suppression, compensatory disinhibition, reduced stimulus selectivity, and aberrant behavioral encoding in neurons of the primary auditory cortex that was partially restored in probe trials. These impairments were concentrated near Aβ plaques and were recapitulated with a reinforcement learning model that accounts for contextual signal changes. Model parameters affected were those governing contextual scaling and behavioral inhibition.

Conclusion

These results suggest that Aβ deposition impacts circuits involved in contextual computations before those involved in acquiring knowledge and that neural circuit interventions (modulating inhibition) may hold promise to reveal hidden memories.
Detection of differences between Amyloid‐Positive and Negative Participants based on Their Driving Behavior during On‐Ramp Merging
Authors: Danda Sai Santosh Reddy , Murphy Yi Lu , Maher Amanda Cook , Persad Carol C , Bross Jordan R , Flynn Emma , Koeppe Robert A. , Giordani Bruno
Published: January 2025

Background

Cognitive changes affecting performance are subtle in early stages of Alzheimer’s Disease (AD) and may emerge only with more complex tasks. Driving is a highly challenging instrumental activity of daily living, requiring higher order integration of cognitive skills. For example, driving on freeway entrance ramps requires heightened cognitive engagement such as rapid responses to fast‐emerging traffic and sudden speed changes, combining sensory processing and manipulative actions. This study analyzes quantitative attributes related to driving behaviors and physiological responses during freeway on‐ramp, merging, and post‐merge stages from fixed‐course drives taken by older amyloid‐positive and amyloid‐negative participants.

Method

We analyzed data from 21 amyloid‐positive (66‐81 years old) and 21 amyloid‐negative (65‐85 years old) consensus diagnosed cognitively normal participants in the University of Michigan’s Driving and Physiological Responses study. All 42 drivers navigated the same freeway on‐ramp, recording vehicle signals, physiological signals, and videos. Focus was on the on‐ramp, divided into ROI1 (On‐Ramp), ROI2 (Acceleration Lane), and ROI3 (10 seconds after merge). Nine driving attributes, including average speed, acceleration, and physiological signals (Heart Rate, Electrodermal activity, Blood Volume Pulse, and Skin Temperature), were assessed in each ROI. Group differences between amyloid‐positive and negative individuals were analyzed via independent sample t‐tests or Mann Whitney U tests, as appropriate.

Result

In ROI1 amyloid‐positive participants exhibited higher average speeds (T = 2.15, p = 0.03) and lower speed changes (U = 103, p = 0.003) compared to amyloid‐negative participants. ROI2 analyses revealed increased speed variability (T = 2.79, p = 0.007) and average acceleration (U = 138, p = 0.04) in amyloid‐positive participants. Amyloid positive participants also trended toward traveling further distance in the ROI2 acceleration lane (T = 1.73, p = 0.09) and toward having increased average heart rate in ROI3 (U = 152, p = 0.08).

Conclusion

These results offer insights into possible cognitive‐based decision‐making differences and potential physiological markers for early cognitive decline during challenging real‐world driving activities such as on‐ramp merging in persons at high risk for cognitive decline and AD. These findings deepen our understanding of the nuanced relationship between cognitive factors and driving behaviors. Future experiments aim to classify groups based on naturalistic drive on‐ramp merging using machine learning for more accurate classification.
Neuropathologic investigation of phospho‐threonine 217 provides neurobiologic insights into the intersection between amyloid‐β and tau
Authors: Murray Melissa E.
Published: January 2025

Background

Posttranslational modifications of tau occurs throughout disease progression in Alzheimer’s disease (AD) and non‐AD tauopathies. Phosphorylation of tau (p‐tau) in the proline‐rich region is a common target of immunohistochemical and fluid biomarker evaluation. P‐tau217 has emerged as a highly accurate fluid biomarker in AD, however elevated levels are not observed in non‐AD tauopathies.

Method

A neuropathologic overview of tau lesions immunopositive for phosphorylation at threonine 217 (pT217) in AD and non‐AD tauopathies will be provided in a didactic format with an emphasis on disease spectrum. The relevant biomarker literature with neuropathologic validation will be highlighted.

Result

Immunohistochemical evaluation of pT217 in AD demonstrates immunostaining in pretangles and mature tangles, but rarely observed in ghost tangles. Neuritic pathology in AD with pT217 immunopositivity include both neuropil threads and dystrophic neurites that cluster in neuritic plaques. Lesions in non‐AD tauopathies are also immunopositive for pT217, as exampled by immunolabelling of argyrophilic grains and tufted astrocytes. Digital pathology measures of pT217 and amyloid‐β will be compared with plasma p‐tau217 levels to contextualize the relationship. Additionally, the relationship between neurotransmitter hub vulnerability will be explored to consider upstream factors that may influence soluble tau release into plasma.

Conclusion

Neuropathologic insights discussed through visual and quantitative comparison of insoluble phospho‐tau accumulation and soluble levels of p‐tau217 may provide neurobiologic insights into the intersection between amyloid‐β and tau in the human brain.