bluuebunny/crossref_metadata_2025 huggingface dataset:
Studying Alzheimer’s‐Related Neuronal Dysfunction Using a New Tool: Characterizing a Neurodegenerative Animal Model with Increased Neuronal‐specific miR34
Authors: Pursell India A , Freitas Raul , Wegrowski Laura , Blahusiak Gabrielle , Barahona Natasha B , Engler‐Chiurazzi Elizabeth
Published: January 2025

Background

Alzheimer’s Disease (AD) is a prevalent age‐related neurodegenerative condition leading to dementia, yet factors regulating its polygenomic etiology and progression remain elusive. MicroRNAs (miRNAs), small RNA molecules regulating protein expression, play a role in neurodegeneration. MicroRNA‐34a (miR‐34a) is a crucial regulator of numerous genes associated with neurodegenerative disorders, protein aggregation and synaptic transmission genes. However, the lack of effective tools for in vivo study impedes comprehensive research in this area. We developed a global miR‐34a overexpressing mouse line in which cognitive deficits, altered amyloid and tau protein processing, and synaptic reorganization were noted.

Method

We generated a CaMKIIα driven, excitatory neuron‐specific Tet‐inducible miR‐34a overexpressing mouse model. Male and female miR‐34a± mice aged 28‐46 weeks were treated with water or Doxycycline to induce miR‐34a overexpression for up to 90 days cognitive and neurobiological consequences were assessed. In this pilot study, we assessed the expression of predicted miR‐34a target genes and associated proteins (SIRT1, NMDAR2B). A subset of mice underwent sequencing analysis in one hemisphere to identify novel miR‐34a targets.

Result

At 30 days of miR‐34a overexpression, we observed trends towards reduced levels of miR‐34a target genes (NMDAR2B, SHANK3) in the hippocampus of mice. However, these findings were non‐significant, likely attributed to the limited power or insufficient exposure duration. With 90 days of exposure, mice exhibited subtle behavior changes, characterized by a decreased percent of spontaneous alternations; no differences observed at 30 days. Distinct nervous system cell populations were isolated for miRNA analysis, hinting at region‐specific changes. Whole brain hemisphere bulk RNA sequencing of Doxy‐treated animals revealed upregulation of the genes Gh and Prl and downregulation of Avp and Drd1 compared to control.

Conclusion

The inducible global miR‐34a overexpression mouse model exhibited modest dementia‐like characteristics and warrants further characterization. Further interrogation of contributions from other neural or peripheral cell types in the AD phenotype induced by global miR‐34a overexpression. The cell‐specific nature of our model provides valuable insights into miR‐34a’s role in AD pathology. These findings contribute to understanding the complex, polygenomic mechanisms underlying neurodegeneration in AD and may reveal novel miR‐focused therapeutic targets.
The Impact of Cognitive Reserve on Cognitive Functions in the Elderly: A Neuropsychological Investigation
Authors: Gasparre Daphne , Ricciardi Elisabetta , Abbatantuono Chiara , Prontu Laura , Marocchino Federica , Biasi Madia Marika , Paparella Giulia , Introna Alessandro , Caffò Alessandro , De Caro Maria Fara , Taurisano Paolo
Published: January 2025

Background

Cognitive reserve (CR) represents the susceptibility to age‐related brain changes or Alzheimer’s disease‐related pathology. It is the ability to withstand the effects of aging and neurological damage. Several factors influence CR, including education, work, activites, mental activity, and social networks, which play a crucial role in an individual’s ability to preserve the global cognitive functioning and counteract cognitive decline. Boosting cognitive reserve has become a relevant focus in our efforts. In this study, we aim to investigate how cognitive reserve could influence the cognitive decline in the elderly.

Method

Targeted neuropsychological assessment were administered to patients with Mild cognitive Impairment and dementia. We analyse through software R 4.3.2., the relationship between of cognitive reserve and other cognitive functions such as attention and memory capabilities.

Results

Our preliminary findings suggest a clear correlation between higher cognitive reserve and improved performance on these tests. This connection appeared particularly significant in the early stages of deterioration (Mild Cognitive Impairment). In other words the notion of cognitive reserve posits the prospect of interventions capable of mitigating cognitive aging or diminishing the susceptibility to dementia.

Conclusions

CR has a key role across the aging. In particular individuals with MCI could prevent and contrast cognitive decline boosting their CR, for example doing more activities, learning new language, gaining new skills, doing physical activities. Further research is needed to fully grasp this relationship and devise methods to extend cognitive reserve in order to promote cognitive health.
Clinical profile of Amnestic Early‐Onset Alzheimer’s disease in Peru: Case Series from a Neurological Care Center
Authors: Castro‐Suarez Sheila , Guevara‐Silva Erik Alberto , Alvarez‐Toledo Kelvin , Caparo‐Zamalloa Cesar , Zegarra‐Valdivia Jonathan Adrian , Meza‐Vega Maria
Published: January 2025

Background

Early‐onset Alzheimer’s disease (EOAD) is a rare and devasting form of Alzheimer disease that represents 5‐10% of the total number of Alzheimer disease (AD). It is significantly less well studied than the late‐onset form of AD. The clinical presentation is heterogeneous, the amnestic variant is the most frequent (75%). Clinical aspects of EOAD in Admixed Latin American population are lacking in the literature. We aim to describe clinical features of amnestic EOAD patients followed‐up at a Neurological healthcare center in Peru.

Method

We reviewed medical records of patients with diagnosis of probable EOAD during January‐December 2023. All patients were evaluated by trained neurologists from a dementia outpatient clinic at a specialized neurologic center in Lima, Peru. Relevant information about neurocognitive, neuropsychiatric, and functional assessments were extracted from medical records with further descriptive analysis. IRB approval from local institution was obtained for this study.

Result

A total of 45 patients (73% female, age at onset = 56 [50‐61] years) met the selection criteria. The 71% of the cases have more than 6 years of education. The delay for diagnosis in this group was between 2 and 5 years. A first‐degree relative with dementia was present in 15.5% of patients. Clinical and cognitive assessment profile included: MMSE average score was 13.2±6.8. The clinical manifestation characterized by anterograde episodic memory impairment were accompanied by executive disfunction (97.8%), attention and calculation impairment (84.4%), and visuospatial impairment (71%); impaired repetition of phrases and anomia were present in 67 and 44% respectively. Based on NPI the most frequent neuropsychiatric symptoms were depression (57%) irritability (51%), and anxiety (38%). Severity of dementia was CDR = 3 for 31.1%, CDR = 2 for 35.6%, CDR = 1 for 33.3%.

Conclusion

The clinical features of our Peruvian amnestic EOAD cohort are mostly consistent with previous reports. There is a significant delay of EOAD diagnosis. Implementing training strategies for clinicians, neurologists, and no‐neurologists, will improve a timely and accurate diagnosis of EOAD.
The association between cognitive tests and stages of cognitive decline in Caribbean Hispanics
Authors: McInerney Katalina F , Zaman Andrew F , Prough Michael B. , Mena Pedro R. , Adams Larry D. , Sanchez Jose Javier , Rodriguez Vanessa C , Valladares Glenies S , Celis Katrina , Hamilton‐Nelson Kara L. , Rajabli Farid , Beecham Gary , Feliciano‐Astacio Briseida E. , Vance Jeffery M. , Pericak‐Vance Margaret A , Cuccaro Michael L.
Published: January 2025

Background

The utility of neuropsychological measures commonly used to diagnose individuals with suspected MCI or AD was recently explored in European cohorts, however their utility in Caribbean Hispanic (CH) populations is not well understood.

Method

Our sample consisted of 507 CH individuals from ongoing studies of Puerto Rican and Cuban American older adults (74%% Female, mean age = 74.1, mean education = 12.7 years, 209 Unaffected, 185 MCI, 113 with AD) who completed cognitive measures from the NACC UDS2 battery (Logical Memory, Semantic Fluency [animals and vegetables], and Digit Span). Participants were clinically adjudicated as unaffected, MCI, or AD, and had a CDR global score ≤1. Individuals with disorders known to affect cognition were excluded. An ordinal regression explored which cognitive tests were most strongly associated with clinical diagnoses. We ran this analysis again on a subset of participants who also completed the Trails Making Test (n = 242, 103 unaffected, 97 MCI, 42 AD). We examined both the log‐odds estimate and Wald value.

Result

An ordinal regression on the full sample showed that the tests associated with differences in clinical diagnosis in order of their predictive value are Delayed Logical Memory (log‐odds = 1.29, Wald = 40.1, p<0.001), Digit Span Backwards (log‐odds = 0.70, Wald = 25.2, p<0.001), Animals (log‐odds = 0.44, Wald = 12.0, p<0.001), Vegetables (log‐odds = 0.32, Wald = 7.3, p<0.01), and Digit Span Forwards (log‐odds = 0.24, Wald = 6.3, p = 0.012). On the subset that completed the Trails Making Test, Trails B emerged as most predictive (log‐odds = 0.70, Wald = 26.8, p <0.001), but Vegetables (p = 0.26), Logical Memory Immediate (p = 0.43), and Trails A (p = 0.70) were not significant predictors of differences in clinical diagnosis in this smaller group.

Conclusion

In our sample of CH individuals, we found performance on measures of delayed contextual memory (Logical Memory), working memory (Digit Span Backwards and Trails B) and semantic fluency (Animals) to be most useful in differentiating individuals clinically diagnosed as unaffected, MCI, or AD. These results highlight possible performance patterns specific to CH that can inform adjudication efforts with this population.
Transmission of Alzheimer’s disease‐associated microbiota dysbiosis and its impact on cognitive function: evidence from mice and patients
Authors: Zhang Yiying , Shen Yuan , Li Wei , xie zhongcong
Published: January 2025

Background

Spouses of Alzheimer’s disease (AD) patients are at a higher risk of developing incidental dementia. However, the causes and underlying mechanism of this clinical observation remain largely unknown. One possible explanation is linked to microbiota dysbiosis, a condition that has been associated with AD. However, it remains unclear whether gut microbiota dysbiosis can be transmitted from AD individuals to non‐AD individuals and contribute to the development of AD pathogenesis and cognitive impairment.

Method

We, therefore, set out to perform both animal studies and clinical investigation by co‐housing wild‐type mice and AD transgenic mice, analyzing microbiota via 16S rRNA gene sequencing, measuring short‐chain fatty acid amounts, and employing behavioral test, mass spectrometry, site‐mutations and other methods.

Result

The present study revealed that co‐housing between wildtype mice and AD transgenic mice or administrating feces of AD transgenic mice to wild‐type mice resulted in AD‐associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment in the wild‐type mice. Gavage with Lactobacillus and Bifidobacterium restored these changes in the wild‐type mice. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. The underlying mechanism of these findings includes that the butyric acid‐mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation.

Conclusion

This initial proof‐of‐concept study demonstrated the potential transmission of microbiota from AD patients or ADTg mice to non‐AD controls or WT mice housed together. This transmission may contribute to the development of AD‐associated microbiota dysbiosis and metabolite alterations, ultimately leading to AD pathogenesis and cognitive impairment. However, these findings should be validated in future studies. The results of this study are expected to drive further research to explore gut microbiota dysbiosis and its connection to AD in both preclinical and clinical contexts.
DAP12 deficiency increases resilience to tau toxicity by modulating oligodendrocyte state and myelination in tauopathy mice despite elevated tau inclusions
Authors: Luo Wenjie , Chen Hao
Published: January 2025

Background

DAP12 (DNAX‐activation protein 12 or TYROBP) functions as a pivotal adaptor, facilitating signal transmission from surface immune receptors on microglia, including TREM2—a known risk gene for Alzheimer’s disease (AD). Previous studies showed that DAP12‐deficient mice exhibit resistance to tau toxicity in a tauopathy model, manifesting reduced brain inflammation and improved cognition, despite increased tau pathology. However, the precise mechanism underlying how DAP12 deficiency enhances resilience to tauopathy remains elusive.

Method

We conducted bulk transcriptomic analysis of the cortex and single‐nuclei RNA sequencing (snRNAseq) of the hippocampi from female homozygous P301S tauopathy mice at six months of age. Subsequent analysis involved various immunohistochemical and biochemical assays, such as multiplex bead‐based immunoassays, western blotting, and immunostaining.

Result

Deletion of DAP12 led to an increase in tau inclusions but remarkably prevented tau‐induced neuroinflammation and synapse loss. DAP12 deletion disrupted the transition of microglia from a homeostatic to a disease‐associated state induced by tau, reversing neuronal transcriptomic changes. SnRNAseq analysis unveiled a tau‐inducible cluster of oligodendrocytes characterized by gene signatures resembling an intermediate state, marked by a comprised myelination function. Strikingly, DAP12 deletion significantly impeded tau‐induced formation of intermediate oligodendrocytes and promoted increased myelination in tauopathy mice.

Conclusion

Our findings reveal a critical role of microglial DAP12 signaling in mediating tau toxicity, enhancing our understanding of the intricate interactions among neurons, microglia, and oligodendrocytes in AD and tauopathy. Future studies will delve into dissecting the specific ligands and receptors mediating microglial interactions with other cell types.
Kv1.3 regulation of brain immune function in vitro and in vivo
Authors: Bowen Christine A , Nguyen Hai Minh , Lin Young Qingyang , Bagchi Pritha , Natu Aditya , Xiao Hailian , Espinosa‐Garcia Claudia , Kumar Prateek , Wulff Heike , Seyfried Nicholas T , Rangaraju Srikant
Published: January 2025

Background

In neurodegenerative disease such as Alzheimer’s disease and stroke, the brain transitions to pro‐inflammatory profile, where microglia and T‐cells in the brain have increase inflammatory profiles, along with increased Kv1.3 potassium channel abundance. Pharmacological blockade of Kv1.3 in vivo reduces Aβ pathology and dampens pro‐inflammatory function. To identify Kv1.3 channels regulation of neurodegenerative models, we examined the protein‐protein interactome of Kv1.3 channels in vitro, and Kv1.3 deletion in vivo.

Method

TurboID, a biotin ligase, was fused to N‐term or C‐term of Kv1.3 and stably‐transduced in BV2 microglial cells and Jurkat T‐cells. Mass spectrometry (MS) of biotinylated proteins, under resting and lipopolysaccharide (LPS)‐treated conditions, was performed to identify N and C‐terminal interactomes. Kcna3(Kv1.3)‐floxed mice were generated and crossed to CMV‐Cre mice to produce a Kv1.3 KO mouse. Kv1.3 KO mice were then exposed to an LPS challenge for 4 days or (middle cerebral artery occlusion) MCAO. Changes in transcriptomic levels were evaluated via RNA‐seq of microglia and brain.

Result

Proximity‐based proteomics of BV2‐Kv1.3‐TurboID microglia identified distinct N‐term (n = 991) and C‐term Kv1.3 (n = 849) interactors. Kv1.3 N‐terminus interacts with plasma membrane proteins (e.g. Cars1, Psma2) and mitochondrial trafficking proteins (TIMM23 and 50). The C‐terminal interactors are modified by LPS‐stimulation (C3, STAT1, OASL1) (n = 36), and dependent on a PDZ‐binding motif (SNX3, ND3, n = 70). Jurkat T‐cell N‐terminal interactors are ER‐processing and plasma membrane (e.g. TXNL1, ACTN3, CASP3), whereas C‐terminal interactors are protein processing (e.g. EHD1, VAMP2). About 400 proteins are shared between the T‐cell and microglial Kv1.3 interactors. Kv1.3 KO mice have reduced Kv1.3 mRNA and channels in brain and microglia. PCA and differential expression highlight microglial inflammatory LPS response and an MCAO, which is reduced in brain overall. Further analysis comparing Kv1.3 KO and WT will be evaluated.

Conclusion

We identified novel N and C‐terminal domain‐specific and context‐dependent interactors of Kv1.3 channels in immune cells. While the N‐terminus regulates protein processing and localization, the C‐terminus regulates immune signaling during LPS‐stimulation. Some interactions are dependent on the PDZ‐binding domain. KO of Kv1.3 impacts microglial signatures under neuroinflammatory states. microglial transcripts. Identifying microglial Kv1.3 influence in AD may provide knowledge on future biomarkers and treatments.
Glial changes as result of cerebral amyloid angiopathy progression
Authors: Krick Katelynn E. , Johnson Sherika N. , Rogers Colin B , Sudduth Tiffany L. , Weekman Erica M. , Wilcock Donna M.
Published: January 2025

Background

Cerebral Amyloid Angiopathy (CAA) occurs at the intersection of Alzheimer’s disease and vascular contributions to cognitive impairment and dementia (VCID). In the human brain it occurs when amyloid beta (Aβ) aggregates in small/medium‐sized cerebral blood vessels, which contribute to hypoperfusion and cognitive decline by altering vascular function and integrity. The current study seeks to track the progression of CAA and associated neuroinflammation and glial cell changes in Tg2576 mice.

Method

Tg2576 mice were aged to 8‐, 14‐, 20‐, and 27‐months and assessed for CAA pathology via histology. Gene expression was evaluated in hippocampal tissue by qPCR and posterior cortex by nanostring (ncounter Mouse Neuroinflammation and Mouse CVD Pathophysiology panels; in progress) to compare 8‐ and 20‐month APP and wildtype groups. Protein expression was evaluated via digital spatial profiling in the same APP mice, grouped by age or CAA presence compared to wildtype controls. CAA presence was defined as Aβ surrounding lectin‐positive vessels. Regions of interest were categorized as either positive or negative for CAA based on this criterion.

Result

Congophillic plaque deposition along the vasculature increased in width, length, and area in a time dependent manner in both the frontal cortex and hippocampus. Astrocyte marker GFAP and proinflammatory receptor TNFR1 gene expression both increased at 20 months compared to 8 months in the APP group. Of the protein profile assessed (Mouse Neural Cell Profiling and Mouse Glial Cell Subtyping), the most consistent changes were found in astrocyte markers. Both Aldh1l1 and S100B were increased at 20 months compared to 8 months of age in both APP and WT mice. GFAP protein expression was found to increase with both age and CAA.

Conclusion

This study showed increased vascular amyloid deposition and astrocyte gene and protein expression over time, further supporting a role for astrocytes in etiology and/or reaction to CAA.
The prefrontal cortex of homozygous ε3 APOE carriers with local African ancestry has fewer transcripts compared to individuals with local European ancestry
Authors: Santos Nascimento , Naslavsky Michel Satya , Haddad Luciana Amaral , Suemoto Claudia Kimie , Ferretti‐Rebustini Renata Eloah de Lucena
Published: January 2025

Background

he APOE gene has been identified as a major risk factor for late‐onset Alzheimer’s disease (AD) and has three most common alleles: ε2, ε3, and ε4. The presence of the ε4 allele confers a dose‐dependent increased risk for the disease (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer’s disease has a multifactorial etiology where factors such as age and sex and the ancestry around the APOE gene is relevant to the disease’s risk. Individuals of African‐American local ancestry have a reduced risk of developing AD compared to European whites and Asians.

Method

this project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 49 post‐mortem frontal cortex tissues with different genotypes and local ancestry combinations (ε3ε3 European‐European, African‐African and ε3ε4 European‐European, African‐African, European‐African, African‐European) and to associate them with the expression of this gene using allele‐specific and non allele‐specific molecular markers and RT‐qPCR techniques.

Result

Within the heterozygous groups, we observed a constant reduced mean expression of the ε4 allele compared with ε3, but these differences did not achieve statistical significance, as didn’t the total APOE expression between these groups with different ancestries. Although we identified a significant difference (p‐value = 0.039) between the homozygous individuals of different ancestry (ε3 European ε3 European versus ε3 African ε3 African), the total expression of individuals of European local ancestry was twice superior to that of African ancestry (European mean: 0.416; African mean: 0.218).

Conclusion

These data support the hypothesis that the lower expression of APOEε3 may be part of the explanation for the reduced African risk of DA in homozygous individuals.
Associations between brain metabolism and financial capacity in Alzheimer’s disease
Authors: Michel Luca Marie , Borelli Wyllians Vendramini , Schlickmann Thomas Hugentobler , Gehres Sarah Wehle , De Bastiani Marco , Bieger Andrei , Povala Guilherme , Machado Luiza Santos , Zimmer Eduardo R.
Published: January 2025

Background

Individuals with early stages of cognitive decline face a significant stagnation in their financial capacity, leading to a decrease in quality of life. However, whether changes in brain function are associated with financial capacity remains unclear. Here, we evaluate the association between financial capacity and brain glucose metabolism.

Method

Individuals across the Alzheimer’s disease (AD) clinical continuum with complete FCI‐SF total scores and FDG‐PET imaging data were selected from the ADNI dataset. We performed a Pearson correlation with 79 brain regions of interest, extracted using the ICBM152 atlas, and the total FCI score. A multiple linear regression model was fitted to assess the relationship between FCI and different brain regions, corrected for age, gender, and education. Analyses were adjusted by Bonferroni, with p considered significant if < 0.05.

Result

A total of 1364 individuals were analyzed in this study (44% female, mean age 73.4). There were 26 brain areas in which glucose metabolism significantly correlated with FCI scores (adjusted p < 0.05, Figure 1A). The highest correlation coefficients were bilaterally located in the Caudate Nucleus and Fornix (r > 0.3, Figure 1A). The regression model demonstrated multiple significant brain regions (adjusted p < 0.05, Figure 1B). The left Fornix (β = 14.8, Figure 1C) and right Fornix (β = 13.7, Figure 1D), as well as the left Caudate Nucleus (β = 14.15, Figure 1E) and right Caudate Nucleus (β = 12.66, Figure 1F), had the highest significance (adjusted p < 0.001).

Conclusion

We observed positive associations between regional brain glucose metabolism and the FCI‐Score. Thus, our findings suggest a relationship between metabolic patterns, serving as an index of brain function, and the financial capacity of individuals.
Anti‐Amyloid Immunotherapy for AD: A Potential Link between ARIA and Complement
Authors: Bathini Praveen , Schilling Stephan , Lemere Cynthia A.
Published: January 2025

Background

Anti‐amyloid antibodies have been associated with amyloid‐related‐imaging‐abnormalities (ARIA) in AD patients, causing vasogenic edema and microhemorrhages, especially in ApoE4 carriers. Here, we compared recombinant 3D6‐L, a murine version of bapineuzumab, and an isotype control IgG2a monoclonal antibody (mAb) to investigate potential mechanisms, including complement activation, involved in these side effects (ARIA‐H or microhemorrhages) following passive immunization.

Method

Plaque‐rich 16.5‐mo‐old APP/PS1dE9; hApoE4 mice were treated weekly (i.p.) for 13 weeks with ∼15 mg/kg (500 µg) 3D6‐L or IgG2a (n = 5 per group). amyloid‐beta (Aβ), ApoE, and complement C3 levels from the brain homogenates were determined using ELISA and microhemorrhages with Prussian‐blue staining. Additionally, 20‐month‐old APP/PS1dE9;hApoE4 mice underwent a shorter 7‐week passive immunization (500 µg/week 3D6‐L or IgG2a, n = 3 per group) followed by RNAseq to evaluate differentially expressed genes (DEGs) in the brain and FACS sorted CD31+ vascular endothelial cells. Pathological analyses are underway.

Result

In the 13‐week study, 3D6‐L significantly reduced guanidium‐HCL‐soluble Aβx‐42 and Aβx‐40; ApoE levels showed a trend for reduction. Soluble C3 levels rose significantly, correlating with increased microhemorrhages in leptomeninges and large blood vessels in the cortex and cerebellum. In the shorter immunization study, brain transcriptome revealed significant upregulation of many genes related to complement activation (C1qa, C1qb, Cq1qc, C4b, C3), glial activation (GFAP), IgG receptor activity (Fcgr1, Fcgr2, Fcgr3), lysozyme (Lyz2) and Galectin‐3 (LGALS3). Endothelial cell transcriptome revealed increased expression of genes involved in inflammation and lipid metabolism. Some of these include IL1r1, Cxcl12, Lcn2, Abca1, CH25H, vWf, and Cfh. Notably, 3D6‐L induced microhemorrhages, microbleeds, and our preliminary analysis indicate an increase in cerebral amyloid angiopathy (CAA)‐associated complement activation and endothelial inflammation. Based on our RNAseq data, we are investigating potential markers including, iC3b, C5b‐9, MMP‐9, and vWf involved in immunotherapy‐associated microhemorrhages.

Conclusion

Passive immunization against Aβ using 3D6‐L amplified CAA‐associated complement activation and altered expression of genes related to extracellular matrix degradation and vascular inflammation. The observed microhemorrhages appear to result from complement‐mediated vascular inflammation induced by the binding of 3D6‐L to vascular amyloid. These findings suggest potential biomarkers or targets for therapeutic interventions in the context of anti‐Aβ immunization.
Identifying partial haplotypes that are associated with late‐onset Alzheimer disease
Authors: Climer Sharlee
Published: January 2025

Background

Haplotypes are patterns of nucleotides in close proximity along a chromosome that are passed together across time and space. These patterns dictate the specific properties of proteins produced and the regulation of this production. General haplotype inference methods phase all provided genotypes within the region of interest into two haplotypes without regard for the ages or evolutionary impact of each mutation, thus force the inclusion of more recent and/or neutral mutations. Alternatively, BlocBuster (www.blocbuster.org) identifies partial haplotypes that include only highly correlated nucleotides using a unique correlation metric that anticipates heterogeneity of the individuals and an expanded network scaffolding. Given the heterogeneous nature of late‐onset Alzheimer disease (AD), we utilize BlocBuster to identify genetic risk patterns.

Method

We analyzed WGS_Omni2.5M_20140220 data for chromosome 19 provided in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database(adni.loni.usc.edu). The data were arbitrarily split into 70% Discovery (42 AD, 69 MCI, 87 control) and 30% Validation (18 AD, 29 MCI, 37 control). BlocBuster builds a network model using AD, MCI, and control individuals (without labeling), where nodes represent SNP alleles and edges represent pairwise correlations between alleles, extracts clusters of inter‐correlated SNP alleles representing a partial haplotype, then tests the pattern for association with the given phenotype.

Result

BlocBuster identified two patterns that are significantly associated with AD in both the Discovery and the independent Validation datasets(Table 1). The first represents a variant of the RUVBL2 gene and the second is a large allelic combination beginning upstream from DIRAS1 and spanning across SLC39A3, SGTA, and THOP1(Table 2).

Conclusion

The network model was created blindly using all individuals in the Discovery dataset, yet two of the clusters were significantly associated with AD risk in both the Discovery and Validation data. Interestingly, THOP1 is a zinc‐activated oligopeptidase that is capable of cleaving beta‐amyloid precursor protein into amyloidogenic peptides. Furthermore, SLC39A3 is predicted to enable zinc transport across the membrane, SGTA is suggested to play a role in aggregate formation in neurodegenerative diseases, and methylation of DIRAS1 is associated with AD risk. These results identify interesting signatures that may pinpoint specific AD biological pathways, motivating further validation efforts.
Deterioration of neuronal primary cilia in Alzheimer’s disease
Authors: Miller Emiko , Bambakidis Peter , Reitsch Niklas , Templin Phoebe , Vázquez‐Rosa Edwin , Bud Zea , Yu Youngmin , Fujioka Hisashi , Cheng Feixiong , Bykova Marina , Koh Yeojung , Sridharan Preethy , Cintrón‐Pérez Coral , Franke Kathryn , Pieper Andrew A.
Published: January 2025

Background

Emerging evidence links Alzheimer’s disease (AD) to dysfunction of the primary cilium, a historically overlooked organelle that serves as the neuron’s antenna. All neurons harbor a single primary cilium that projects from the membrane to sense changes in the extracellular environment. Primary cilia dysfunction leads to a group of diseases called ‘ciliopathies’, which are associated with reduced hippocampal and cortical mass, as well as neurocognitive impairment. Ciliopathies place individuals at higher risk for dementia, and genetic defects in primary cilia proteins in mice lead to a phenotype resembling AD.

Method

To establish whether primary cilia are disrupted in AD, we conducted unbiased analysis of differentially expressed genes (DEGs) in postmortem brains from AD subjects, compared to age‐matched non‐AD controls. Using the DAVID bioinformatics platform, we performed a gene ontology analysis on the significantly changed genes related to the primary cilia. Additionally, we performed immunohistochemical and electron microscopy analysis of primary cilia in the brains of 5xFAD mice, a mouse model of AD. Primary cilia were visualized with antibodies to adenylate cyclase 3 (AC3).

Result

Our systematic survey of the published literature in AD revealed very few studies to date of cilia, compared to other organelles. Our analysis of DEGs in postmortem human AD brains revealed a high prevalence of DEGs intricately linked to processes that maintain primary cilia structure and function. Furthermore, the proportion of DEGs related to the primary cilia was comparable to that observed in other heavily implicated organelles in AD, such as mitochondria. Additionally, we found that the gene ADCY3, which encodes for primary cilia‐specific adenylate cyclase 3 (AC3), is significantly downregulated in human AD brains. Primary cilia are dependent on AC3, and loss of functional AC3 in primary cilia reveals consequences reminiscent of symptoms associated with AD. We observed reduced levels of AC3 throughout the hippocampus of 5xFAD mice. Additionally, electron microscopy analysis of primary cilia revealed shortened primary cilia length in advanced stages of disease in 5xFAD mice.

Conclusion

AC3 loss and primary cilia deterioration may drive progression of AD pathology and provide a basis for development of a new neuroprotective therapy for AD.
White blood cell types and tau deposition in the medial temporal lobe of cognitively normal older adults
Authors: Braskie Meredith N , Lee Noelle , Davison Marylan , Tennant Victoria R , Wheeler Koral V , Tubi Meral A , Terner Jamie , Hand Maxwell W , Toga Arthur W. , O'Bryant Sid E. , Yaffe Kristine
Published: January 2025

Background

Alzheimer’s disease (AD) and other dementia risk may be influenced by the immune function and associated with several white blood cell type counts. In cognitively normal Black, Hispanic, and non‐Hispanic white older adults we related three white blood cell types previously associated with AD risk to tau positron emission tomography (PET) values in the medial temporal lobe (MTL), where tau accumulates early. We assessed whether amyloid positivity moderated this relationship.

Method

We evaluated 430 cognitively normal older adults (Table 1) from the Health & Aging Brain Study‐Health Disparities (HABS‐HD) study who had: 1) MTL tau PET values 2) counts for three types of white blood cells: absolute monocytes, lymphocytes, and neutrophils and 3) global brain amyloid values. Tau was assessed using [18F]PI‐2620 PET standardized uptake value ratios (SUVR; inferior cerebellar gray matter reference region). The MTL region included FreeSurfer‐derived hippocampus, amygdala, and entorhinal cortex. Global amyloid ([18F]Florbetaben PET) was calculated as mean SUVR in frontal, cingulate, lateral parietal, and lateral temporal cortex using a whole cerebellar reference region. Multiple linear regression related log‐transformed absolute counts of white blood cell types to MTL tau, covarying for age, sex, education, ethnicity (Hispanic or non‐Hispanic) and race (Black or white) with white blood cell type by amyloid positivity (global amyloid SUVR >1.08) interactions modeled on MTL tau.

Result

Amyloid‐positivity interacted with lymphocytes on MTL tau (p = 0.02); in amyloid‐positive participants there was a stronger relationship between higher lymphocytes and more MTL tau (β = 0.21) than in amyloid‐negative participants (b = 0.02). There was a trend level interaction between amyloid positivity and monocytes on MTL tau (p = 0.06); in amyloid‐positive participants there was a stronger relationship between lower monocytes and more MTL tau (β = ‐0.23) than in amyloid‐negative participants (β = ‐0.10). Older age (β = 0.40, p<0.001), female sex (β = 0.11, p = 0.02), Black race (β = 0.20, p<0.001), and Hispanic ethnicity (β = 0.22, p<0.001) also were associated with greater MTL tau.

Conclusion

Higher lymphocyte and lower monocyte values were associated with more MTL tau, particularly in amyloid‐positive older adults suggesting a complex relationship between the peripheral immune system and early AD neuropathology.
Linking Cognitive Function Index Item‐Level Responses to Tau Pathology in Amyloid Positive Cognitively Unimpaired individuals: Findings from The A4 Study
Authors: Demirsoy Idris , Petersen Kellen K. , Nallapu Bhargav Teja , Ghanbarian Elham , Lipton Richard B. , Rabin Laura , Ezzati Ali
Published: January 2025

Background

The Cognitive Function Index (CFI) is a validated test used to assess changes in self‐perceived cognitive and functional status as reported by an individual and their study partner. Previous studies have demonstrated an inverse correlation between higher amyloid‐beta (Aβ) burden and CFI, with certain CFI items exhibiting stronger associations than others. However, there is limited understanding of the association between declines in cognition and function, as assessed by CFI, and Tau levels measured by PET.

Methods

Participants were 339 cognitively unimpaired, Aβ positive, individuals enrolled in the Anti‐Amyloid Asymptomatic Alzheimer’s (A4) Study who underwent tau‐PET imaging. Participants were classified as tau‐PET positive (T+) or negative (T‐) based on tau levels in the medial temporal lobe (TMTL+/TMTL‐). Participants and their study partners assessed subjective changes in cognition and function over the past year using a 15‐item CFI questionnaire. For each CFI item, the relationship between Tau and CFI reports (Yes/Maybe vs No) was investigated using logistic regression models.

Results

Participants were on average 72.38(SD = 4.87) years old, 58.1% were female, and 23.6% was TMTL+. Table 1 summarizes the sample characteristics. Higher TMTL was significantly associated with participant report of decline on six items, seeing a doctor about memory concerns (OR = 1.746, p = 0.002) and getting lost while travelling to another city (OR = 1.557, p = 0.003) showing the highest odds ratios. By contrast, Higher TMTL was associated with study partner report of decline on only one item: needing help from others to remember appointments/occasions (OR = 1.592, p = 0.002).

Conclusion

Unique CFI items were associated differentially with higher TMTL for participants and their study partners. The value of the CFI questionnaire with participant as the source of information may be higher than responses provided by informant in terms of the association with Tau‐PET positivity. This is consistent with the idea that self‐awareness of cognitive decline might precede the observations made by others.
Identification of USP16 cryo‐EM protein structure and development of a small molecule inhibitor to restore compromised neural stem cell regeneration in a mouse Alzheimer’s model
Authors: Ho William Hai Dang , Djomehri Sabra I. , Alford Vincent M. , Chen Elizabeth Y. , Reinitz Felicia , Gottlieb Sydney , Igboabuchi Francie I. , Chung Grace Yuna , Fernandez Daniel , Montabana Elizabeth , Singal Bharti , Qi Zhen , Kuo Angera H. , Qian Dalong , Clarke Michael F.
Published: January 2025

Background

Hallmark pathologies of Alzheimer’s Disease (AD) include the accumulation of both extracellular amyloid and intracellular tau proteins. While a significant body of knowledge exists surrounding the role of the protein aggregates in the context of AD, research supporting these as targets for therapeutic development have yielded inconsistent findings. One significant barrier is the inability to restore cognitive function despite the successful clearance of these proteins. In our recently published paper, we discuss a novel target for AD, USP16, which has been shown to promote ubiquitination of histones allowing for transcription of CDKN2A, a cell cycle regulator. We demonstrated that knockdown of USP16 improved neurosphere initiating capacity in mouse neural stem cells. Moreover, reduction of USP16 expression via heterozygosity resulted in improved cognition in 12‐month‐old mice. From these findings, our lab aims to identify the full‐length protein structure of USP16 using cryogenic electron microscopy (cryo‐EM) and develop a small molecule drug to inhibit its activity for end‐use as a viable AD therapeutic option.

Methods

Truncated regions corresponding to the active and zinc‐finger (ZnF) domains of USP16 were expressed in both HEK293T and SF9 cells. Whole cell lysates were purified using affinity chromatography and identity was verified using Western blot. The purified protein products were submitted for cryo‐EM to determine their respective structures. Focusing on the ZnF domain, we utilized both a previously published proton NMR‐derived structure as well as AlphaFold‐predicted USP16 protein structure to serve as model scaffolding onto which we could perform in silico small molecule drug screening. Libraries were obtained from Schrodinger, MilliporeSigma, Emanine, MolPort, Thermo Fisher, MedChemExpress, Life Chemicals, ChemDiv, and Mcule.

Results

Chromatogram from affinity chromatography and Western blot imaging together indicate successful isolation of truncated USP16 domains expressed in HEK293T and SF9 cells. Preliminary findings from cryo‐EM on the WT SF9 construct recapitulates the major domains predicted by AlphaFold. Over 9.5 million small molecule hit interactions against the ZnF domain have been identified.

Conclusion

Cryo‐EM was successful in generating a course model of USP16. In silico protein modeling and drug screening was able to identify potential ligands against the ZnF domain of USP16.
Multi‐Ethnic Analysis of Expression Quantitative Trait Loci (eQTL) in Alzheimer’s Disease: A Focus on Health Disparity Populations
Authors: Wheeler Nicholas R. , Mews Makaela , Gu Tianjie , Gomez Lissette , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Sanchez Jose Javier , Adams Larry D. , Mena Pedro R. , Starks Takiyah D. , Silva Concepcion , Illanes‐Manrique Maryenela , Cuccaro Michael L. , Vance Jeffery M. , Cornejo‐Olivas Mario , Byrd Goldie S. , Feliciano‐Astacio Briseida E. , Haines Jonathan L. , Beecham Gary , Pericak‐Vance Margaret A. , Griswold Anthony J. , Bush William S.
Published: January 2025

Background

Despite its high heritability, the genetic mechanisms influencing Alzheimer’s Disease (AD), particularly in health disparity populations like African Americans (AA) and Hispanics (HI), are not fully understood. The lack of ancestral diversity in genetic datasets, notably in eQTL studies that associate genetic variation with gene expression, exacerbates these disparities. Our study seeks to address this gap by comparing the AD interactions of racially and ethnically diverse expression Quantitative Trait Loci (eQTL) effects to investigate the genetic influence on AD in underrepresented populations.

Method

We investigated the impact of AD status on multi‐ethnic eQTLs across 3 diverse ancestral cohorts: AA, HI, and Non‐Hispanic White (NHW). Genotype and gene expression data were collected from samples of each genetic ancestry (AA = 224, HI = 293, NHW = 235), all with known AD status, with a focus on generating whole blood RNAseq data. We modified the TensorQTL pipeline to incorporate an interaction term for AD status to identify eQTL effects potentially induced by disease. We examined the top eQTL association per gene to assess the impact of AD status across the three ancestral cohorts.

Result

Our preliminary analysis reveals striking variations in the impact of AD status on gene expression across AA, HI, and NHW cohorts. Several genes in each ancestry show statistically significant (pv<10e‐8) interaction effects (G X AD) (AA = 11, HI = 5, NHW = 9), indicating that genetic variation within those genes influences gene expression in an AD‐status dependent manner. A number of genes displayed interesting interaction patterns, where the most significant eQTL‐AD interaction was identical in two of the three ancestries studied, suggesting a potential ancestrally‐shared connection to AD risk (AA+HI = 4, AA+NHW = 3, HI+NHW = 5, AA+HI+NHW = 0), though notably there were no genes with induced eQTLs across all three ancestries.

Conclusion

Our study highlights the impact the AD disease process has on genetic variants that alter whole‐blood gene expression. We also highlight differences by population, prompting the development of ethnically diverse gene expression panels that pave the way for more accurate genetic studies in health disparity populations. Our findings also underscore the potential for discovering novel genetic mechanisms influencing AD risk, which could lead to more effective and inclusive therapeutic strategies.
Relationship between cortical diffusivity and neuropathological substrates in Alzheimer’s disease
Authors: Debatisse Justine , Leng Fangda , Edison Paul
Published: January 2025

Background

Pathological alterations in Alzheimer’s disease (AD) begin several years before the onset of symptoms. Grey matter mean diffusivity (MD) may be used as a measure of early grey matter damage in AD as it reflects the breakdown of microstructural barriers, which precede volumetric changes and affect cognitive function. In this study, we investigated the changes in MD early on in the disease trajectory, and relate them to the amyloid and tau deposition.

Method

We analysed multimodal PET, DTI and MRI data of 90 participants, stratified into amyloid‐β negative and positive, cognitively normal (CN), mild cognitive impaired (MCI) and AD patients.

Result

We found that MD was significantly increased in Aβ‐positive MCI and AD compared with CN in frontal, parietal, temporal cortex, hippocampus, and medial temporal lobe. We also found that cortical MD is significantly correlated with cortical thickness only in patients without amyloid deposition and is not significant in Aβ‐positive patients.

Conclusion

Our results suggest that cortical MD is an early marker of neuronal damage as it is observed simultaneously as Aβ deposition and as it is correlated with cortical thickness when there is no Aβ deposition. This suggests that cortical MD provides information about early microstructural changes before macrostructural changes.
Sex Differences in Cerebrovascular Reactivity to Hypercapnia in Older Adults
Authors: Engstrom Allison C , Kapoor Arunima , Dutt Shubir , Alitin John Paul M , Gaubert Aimée , Lohman Trevor , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Shao Xingfeng , Wang Danny JJ , Nation Daniel A.
Published: January 2025

Background

Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function defined by blood flow changes in response to vasoactive stimuli, which may represent a valuable indicator of risk for vascular brain injury and cognitive decline. Understanding of sex specific CVR patterns is limited, yet likely important for understanding vascular risk. Previous research on sex differences in CVR is mixed, and has predominantly focused on younger adults and utilized Transcranial Doppler ultrasound approaches that focus on large intracranial artery flow. We sought to determine sex differences in CVR responses in older adults using MRI approaches focused on microvascular vasodilatory responses.

Method

Independently living older adults, (N = 127, mean age = 69.9 years; SD = 7.27; age range 55‐90 years, 34.6% male, mean education = 16.7 years; SD = 2.2) free of dementia, clinical stroke, and major neurological or psychiatric disorder, were recruited from the community and underwent brain MRI and clinical interview. Pseudo‐continuous arterial spin‐labeling MRI and capnography was used to quantify whole brain cerebral perfusion during CVR to hypercapnia induced by visually guided, 15sec breath‐hold exercises. Sex differences in whole brain CVR to hypercapnia were studied.

Result

An independent samples t‐test revealed women (M = 6.52, SD = 5.40) to have significantly higher CVR to hypercapnia than men (M = 4.24, SD = 4.20), t(125) = 2.63, p = 0.01, which remained significant in an ANCOVA model after correcting for age F(125) = 4.407, p = 0.038.

Conclusion

Older men exhibited lower cerebral vasodilatory responses to hypercapnia relative to women, independent of the effects of aging. These results are consistent with prior findings suggesting that women have higher cerebral blood flow relative to age‐matched men. Findings could suggest older women are at increased risk of vascular brain injury and resulting cognitive decline, and inform future studies of CVR as a marker of risk in this population.