Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspective:
September 2023





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August 2023:

Nerve Growth Factor Receptor (Ngfr) Induces Neurogenic Plasticity by Suppressing Reactive Astroglial Lcn2/Slc22a17 Signaling in Alzheimer's Disease

Multicellular Communities are Perturbed in the Aging Human Brain and Alzheimer's Disease

Simple Topological Task-based Functional Connectivity Features Predict Longitudinal Behavioral Change of Fluid Reasoning in the RANN Cohort

The Neuropathological Landscape of Hispanic and non-Hispanic White Decedents with Alzheimer Disease

July 2023:

Caspase-9 Inhibition Confers Stronger Neuronal and Vascular Protection Compared to VEGF Neutralization in a Mouse Model of Retinal Vein Occlusion

The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study Design and Methodology

Heart Failure-Induced Cognitive Dysfunction is Mediated by Intracellular Ca2+ Leak Through Ryanodine Receptor Type 2

June 2023:

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity

Dietary Flavanols Restore Hippocampal-Dependent Memory in Older Adults with Lower Diet Quality and Lower Habitual Flavanol Consumption

Survey of Neuroanatomic Sampling and Staining Procedures in Alzheimer Disease Research Center Brain Banks

May 2023:

Polygenic Risk Score Penetrance & Recurrence Risk in Familial Alzheimer Disease

Effects of Brain Maintenance and Cognitive Reserve on Age-related Decline in Three Cognitive Abilities

High School Quality is Associated with Cognition 58 Years Later

Older Adults Compensate for Switch, but not Mixing Costs, Relative to Younger Adults on an Intrinsically Cued Task Switching Experiment

April 2023:

Glucocorticoid-Driven Mitochondrial Damage Stimulates Tau Pathology

A Global View of the Genetic Basis of Alzheimer Disease

ARIA in Patients Treated with Lecanemab (BAN2401) in a Phase 2 Study in Early Alzheimer's Disease

March 2023:

CREB3L2-ATF4 Heterodimerization Defines a Transcriptional hub of Alzheimer's Disease Gene Expression Linked to Neuropathology

Healthy Lifestyle Behaviors and Biological Aging in the US National Health and Nutrition Examination Surveys 1999-2018

February 2023:

Microglia Reactivity Entails Microtubule Remodeling from Acentrosomal to Centrosomal Arrays

Genuine Selective Caspase-2 Inhibition with new Irreversible Small Peptidomimetics

Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer's Disease


January 2023:

Histopathology of the Cerebellar Cortex in Essential Rremor and Other Neurodegenerative Motor Disorders: Comparative Analysis of 320 Brains

The Caribbean-Hispanic Alzheimer's Disease Brain Transcriptome Reveals Ancestry-Specific Disease Mechanisms

Comparison of Amyloid Burden in Individuals with Down Syndrome Versus Autosomal Dominant Alzheimer's Disease: A Cross-Sectional Study

Neuronal Membrane Proteasomes Regulate Neuronal Circuit Activity in Vivo and are Required for Learning-Induced Behavioral Plasticity

December 2022:

A Systemic Cell Stress Signal Confers Neuronal Resilience Toward Oxidative Stress in a Hedgehog-Dependent Manner

RNA Methyltransferase NSun2 Deficiency Promotes Neurodegeneration through Epitranscriptomic Regulation of Tau Phosphorylation

Cell Type-Specific Changes Identified by Single-Cell Transcriptomics in Alzheimer's Disease

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample

November 2022:

First Place: CREB3L2-ATF4 Heterodimerization Defines a Transcriptional Hub of Alzheimer's Disease Gene Expression Linked to Neuropathology

First Place: Neuroproteasome Localization and Dysfunction Modulate Pathology in Alzheimer's Disease

October 2022:

Clearance of an Amyloid-Like Translational Repressor is Governed by 14-3-3 Proteins

Diet Moderates the Effect of Resting State Functional Connectivity on Cognitive Function

Longitudinal Patterns of Cortical Atrophy on MRI in Patients With Alzheimer Disease With and Without Lewy Body Pathology

September 2022:

Crosstalk Between Acetylation and the Tyrosination/Detyrosination Cycle of α-Tubulin in Alzheimer's Disease

Deep Learning of MRI Contrast Enhancement for Mapping Cerebral Blood Volume from Single-Modal Non-Contrast Scans of Aging and Alzheimer's Disease Brains

Socioeconomic Status, Biological Aging, and Memory in a Diverse National Sample of Older US Men and Women

August 2022:

Retromer Deficiency in Tauopathy Models Enhances the Truncation and Toxicity of Tau

Aβ42 Oligomers Trigger Synaptic Loss Through CAMKK2-AMPK-Dependent Effectors Coordinating Mitochondrial Fission and Mitophagy

July 2022:

GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer's Disease

Cerebral Amyloid Angiopathy Interacts with Neuritic Amyloid Plaques to Promote Tau and Cognitive Decline

Amyloid, Cerebrovascular Disease, and Neurodegeneration Biomarkers Are Associated with Cognitive Trajectories in a Racially and Ethnically Diverse, Community-Based Sample

June 2022:

Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer's Disease

May 2022:

FMNL2 Regulates Gliovascular Interactions and Is Associated with Vascular Risk Factors and Cerebrovascular Pathology in Alzheimer’s Disease

Molecular Insights into Cell Type-Specific Roles in Alzheimer's Disease: Human Induced Pluripotent Stem Cell-Based Disease Modeling

Effects of Eph/Ephrin Signalling and Human Alzheimer's Disease-Associated EphA1 on Drosophila Behaviour and Neurophysiology

April 2022:

Progranulin Mutations in Clinical and Neuropathological Alzheimer's Disease

Wolframin is a Novel Regulator of Tau Pathology and Neurodegeneration

Clinical Trajectories at the End of Life in Dementia Patients With Alzheimer Disease and Lewy Body Neuropathologic Changes

March 2022:

Homotypic Fibrillization of TMEM106B Across Diverse Neurodegenerative Diseases

Correlation of Plasma and Neuroimaging Biomarkers in Alzheimer's Disease

Probing the Proteome to Explore Potential Correlates of Increased Alzheimer's-Related Cerebrovascular Disease in Adults with Down Syndrome

February 2022:

Tubulin Tyrosination Regulates Synaptic Function and is Disrupted in Alzheimer's Disease

Pyramidal Tract Neurons Drive Amplification of Excitatory Inputs to Striatum Through Cholinergic Interneurons

Associations Between Neuropsychiatric Symptoms and Neuropathological Diagnoses of Alzheimer Disease and Related Dementias

Longitudinal Associations Between Racial Discrimination and Hippocampal and White Matter Hyperintensity Volumes Among Older Black Adults

The Penalty of Stress - Epichaperomes Negatively Reshaping the Brain in Neurodegenerative Disorders

January 2022:

The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A Resource for Genetic Discovery

Atlas of RNA Editing Events Affecting Protein Expression in Aged and Alzheimer's Disease Human Brain Tissue

The Neuronal Retromer can Regulate Both Neuronal and Microglial Phenotypes of Alzheimer's Disease

Deep Learning Improves Utility of Tau PET in the Study of Alzheimer's Disease

December 2021:

Predictors of Incident Mild Cognitive Impairment and Its Course in a Diverse Community-Based Population

Atlas of RNA Editing Events Affecting Protein Expression in Aged and Alzheimer's Disease Human Brain Tissue

Integration of GWAS and Brain Transcriptomic Analyses in a Multiethnic Sample of 35,245 Older Adults Identifies DCDC2 Gene as Predictor of Episodic Memory Maintenance

November 2021:

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer's Disease

Characterization of Mitochondrial DNA Quantity and Quality in the Human Aged and Alzheimer's Disease Brain

Self-Awareness for Financial Decision Making Abilities is Linked to Right Temporal Cortical Thickness in Older Adults

October 2021:

An Immune Response Characterizes Early Alzheimer's Disease Pathology and Subjective Cognitive Impairment in Hydrocephalus Biopsies

MEF2C Common Genetic Variation Is Associated With Different Aspects of Cognition in Non-Hispanic White and Caribbean Hispanic Non-demented Older Adults

Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults

Age of Onset of Huntington's Disease in Carriers of Reduced Penetrance Alleles

September 2021:

Traversing the Aging Research and Health Equity Divide: Toward Intersectional Frameworks of Research Justice and Participation

Epigenomic Features Related to Microglia are Associated with Attenuated Effect of APOE ε4 on Alzheimer's Disease Risk in Humans

Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease

August 2021:

Neuropsychological Predictors of Severe Functional Dependency in a Multiethnic Community Cohort of Individuals with Alzheimer's Disease

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico

Effect of Aerobic Exercise on White Matter Tract Microstructure in Young and Middle-Aged Healthy Adults

July 2021:

Quantifying Age-Related Changes in Brain and Behavior: A Longitudinal Versus Cross-Sectional Approach

The Association Between Sex and Risk of Alzheimer's Disease in Adults with Down Syndrome

June 2021:

Marked Mild Cognitive Deficits in Humanized Mouse Model of Alzheimer's-Type Tau Pathology

Rapid ATF4 Depletion Resets Synaptic Responsiveness after cLTP

Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics

Vascular-Derived SPARC and SerpinE1 Regulate Interneuron Tangential Migration and Accelerate Functional Maturation of Human Stem Cell-Derived Interneurons

May 2021:

PAC1 Receptor–Mediated Clearance of Tau in Postsynaptic Compartments Attenuates Tau Pathology in Mouse Brain

Socioeconomic and Psychosocial Mechanisms Underlying Racial/Ethnic Disparities in Cognition Among Older Adults

Recognition Memory and Divergent Cognitive Profiles in Prodromal Genetic Frontotemporal Dementia

April 2021:

Association Between Early Psychotic Symptoms and Alzheimer's Disease Prognosis in a Community-Based Cohort

Complexity and Graded Regulation of Neuronal Cell-Type-Specific Alternative Splicing Revealed by Single-Cell RNA Sequencing

The Microtubule Cytoskeleton at the Synapse & The Synaptic Life of Microtubules

Distinct Cortical Thickness Patterns Link Disparate Cerebral Cortex Regions to Select Mobility Domains

March 2021:

Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction

The AD Tau Core Spontaneously Self-Assembles and Recruits Full-Length Tau to Filaments

Olfactory Impairment is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease

Race/ethnicity and Gender Modify the Association Between Diet and Cognition in U.S. Older Adults: National Health and Nutrition Examination Survey 2011-2014

Insights Into the Role of Diet and Dietary Flavanols in Cognitive Aging: Results of a Randomized Controlled Trial

February 2021:

Plasma P-Tau181, P-Tau217, and Other Blood-Based Alzheimer's Disease Biomarkers in a Multi-Ethnic, Community Study

Pathogenic Role of Delta 2 Tubulin in Bortezomib-Induced Peripheral Neuropathy



Rie1 and Sgn1 Form an RNA-Binding Complex that Enforces the Meiotic Entry Cell Fate Decision

Alec Gaspary    Luke E. Berchowitz, PhD
Alec Gaspary, PhD    Luke E. Berchowitz, PhD

To make developmental fate decisions, the cell must sense, accurately process, and in some cases quantify multiple cues. Multicellular organisms rely on cell fate commitment to create the diverse cell types needed for proper development. The budding yeast Saccharomyces cerevisiae undergoes a few well-defined cell fate decisions during its life cycle, making it an advantageous model in which to study the mechanisms that commit a cell to a particular fate. Most cell fate decisions, including those of yeast, are understood as being triggered by the activation of master transcription factors. However, mechanisms that enforce cell fates post-transcriptionally have been more difficult to attain. In this study, led by recently minted Genetics PhD Alec Gaspary, we sought to determine whether and how post-transcriptional mechanisms act to affect commitment to meiosis in yeast. Published in the Journal of Cell Biology, the findings of our study are conceptually applicable to all organisms, including humans.

A yeast cell in G1 can remain in G1, continue vegetative growth by budding, transition to filamentous growth, enter sexual conjugation, or to commit to meiosis which occurs in the context of sporulation. The decision of whether to initiate meiosis is crucial to maintaining fitness and, if triggered in error, can be lethal. We performed a forward genetic screen to identify RNA-binding proteins that are required for meiotic initiation. Our screen revealed several candidates, the most severe being a relatively obscure protein called Rie1. We found that Rie1 binds RNA, is physically associated with translating ribosomes, and acts post-transcriptionally to enhance protein levels of the transcription factor IME1 (the master regulatory transcription factor governing entry into meiosis) in response to pro-meiotic cues. We also identified a binding partner of Rie1, Sgn1, which is another RNA-binding protein that supports Rie1 function to promote timely meiotic entry. Our results support the hypothesis that Rie1-Sgn1 is a translational activator that works by recruiting IME1 mRNA to ribosomes.

Figure 5 (A - E). Rie1 forms a functional complex with the RBP Sgn1.
Figure. Rie1 forms a functional complex with the RBP Sgn1. (A and B) Strains harboring N-terminally tagged sfGFP-IME1 and rie1∆ (B2430, red), wild type RIE1 and SGN1 (B2459, blue), sgn1∆ (B3375, orange), or rie1∆ sgn1∆ (B3378, gray) were induced to sporulate at 30°C. Protein levels of Ime1 and Pgk1 (loading) protein levels were determined by immunoblot and mRNA levels of IME1 and rRNA (loading) were determined by Northern blot. (B) Quantification of Ime1 protein levels corrected for IME1 mRNA levels are shown. Biological replicates = 3. (C) AlphaFold2 output of individual Rie1–Sgn1 structures and AlphaFold2 Multimer output of predicted Rie1–Sgn1 complex. Rie1 is shown in blue and Sgn1 is shown in orange. A ribbon diagram zoomed in on the predicted Rie1–Sgn1 interface is shown on right with key interacting residues on Rie1 highlighted. (D and E) Strains harboring SGN1-FLAG and 3V5 tagged RIE1 (B2668) or rie1 D429A, S433A, and S435A (B3551) were induced to sporulate at 30°C. RIE1-3V5 with untagged wild type SGN1 (no tag control, B3114) was also included. Rie1-3V5 was IPed from meiotic lysate using anti-V5 agarose at the indicated time points. (D) Shown are Sgn1 and Rie1 protein levels by immunoblot in lysate, unbound, and 1% IP and 99% IP samples. (E) Protein levels of Ime1 and Pgk1 (loading) were determined by immunoblot with quantifications shown below.

Because expression of Rie1 and Sgn1 is not meiosis specific, our results imply that yeast has evolved a way to control meiotic entry via RNA-binding proteins that are expressed in both mitosis and meiosis. We propose that Rie1-Sgn1 complexes are rate-limiting and act directly to promote meiotic entry as switch-like enforcers while also playing an indirect role to repress spurious meiotic entry. When IME1 transcription bursts in conjunction with Rie1 upregulation, downstream of pro-meiosis cues, the probability that an IME1 mRNA encounters a Rie1-Sgn1 complex will increase as a function of both IME1 mRNA and Rie1-Sgn1 complex abundance. Our model is conceptually similar to the “hungry spliceosome” model proposed by (Talkish et al., 2019) which rationalizes why splicing of meiotic genes containing sub-optimal introns is more efficient in starvation (Juneau et al., 2007). In this model, spliceosomes are a limiting resource predominantly recruited to optimal splicing sites on abundant transcripts that generally encode ribosomal proteins. During meiotic entry, transcription of ribosomal protein genes is downregulated, which frees spliceosomes to bind to and splice meiotic mRNAs that contain non-consensus splice sites. Like IME1, mis-translating these meiotic mRNAs could be detrimental. For this reason, the cell has evolved fail-safe mechanisms, including the Rie1-Sgn1 complex and meiotic introns, to restrict translation of meiotic mRNAs to the appropriate developmental context.

Luke E. Berchowitz, PhD
Assistant Professor of Genetics and Development (in the Taub Institute)
leb2210@cumc.columbia.edu

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Memory and Language Cognitive Data Harmonization Across the United States and Mexico

Miguel Arce Rentería, PhD
Miguel Arce Rentería, PhD

Cross-national neuropsychological research is needed to understand the social, economic, and cultural factors associated with cognitive risk and resilience across global aging populations. Memory and language have been shown to be sensitive to age-related cognitive decline and pathological cognitive aging processes and may be more sensitive to subtle cognitive decline than measures of global cognitive function. However, to accurately compare memory and language functioning cross-nationally, cultural neuropsychological expertise is needed to carefully determine whether our neuropsychological instruments are measuring the cognitive construct equivalently across linguistically and culturally diverse populations. By leveraging two cross-national studies of cognitive aging in the United States and Mexico, we applied a cultural neuropsychological approach to derive and validate harmonized cognitive domain scores for memory and language.

Figure1

Figure 1. The top halves of the plots represent the reliability of factor scores, and the bottom halves are histograms of factor scores for memory (left panel) and language (right panel) domains by study. The goal of this figure is to illustrate the change in the reliability of estimated factor scores as a function of corresponding levels on the latent trait. HRS-HCAP, Health and Retirement Study Harmonized Cognitive Assessment Protocol; MexCog, Mexican Health and Aging Study Ancillary Study on Cognitive Aging.

As recently reported in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, data came from the Health and Retirement Study (HRS) Harmonized Cognitive Assessment Protocol (HCAP) and the Mexican Health and Aging Study (MHAS) Ancillary Study on Cognitive Aging (Mex-Cog). We used confirmatory factor analysis methodology to create statistically co-calibrated cognitive domains of memory and language. We performed differential item functioning (DIF) analysis to evaluate measurement differences across studies, using a cultural neuropsychological approach to identify comparable items across studies (i.e., cross-study anchors). Briefly, in collaboration with the other neuropsychologist on the team (Dr. Emily Briceño from University of Michigan), we reviewed all memory and language items for cross-study comparability in conjunction with study team members with competence in the languages and cultures represented in the two cohorts. Comparability was evaluated across 1) administration and scoring procedures, 2) coding procedures, and 3) linguistic and cultural equivalence. After review for comparability, potential linking items were classified as either “confident” (i.e., no known features violating item comparability) or as “tentative” (i.e., possible features that may violate item comparability) linking items. Items determined to be non-comparable across cohorts were treated as unique items. We then used an item banking approach with confirmatory factor analysis to develop our harmonized cognitive domains and subsequently evaluate for DIF by cohort. Lastly, we then evaluated harmonized scores by examining their relationship to age and education in each study.

Figure 2
Figure 2. A, Associations between memory factor scores and age, and associations between language factor scores and age by study. B, Associations between memory factor scores and years of education, and the associations between language factor scores and years of education by study. HRS-HCAP, Health and Retirement Study Harmonized Cognitive Assessment Protocol; Mex-Cog, Mexican Health and Aging Study Ancillary Study on Cognitive Aging.

After identifying the comparable items to derive our harmonized cognitive scores using our cultural neuropsychological approach, we observed minor measurement differences in the harmonized memory and language scores which impacted few participants in the HRS-HCAP and Mex-Cog, suggesting that cognitive performance is measured comparably in each study by the HCAP (Figure 1). Our results also showed that memory demonstrated strong measurement precision across all levels of the latent ability for both studies. However, the language domain demonstrated lower measurement precision, particularly at higher levels of the latent trait. Initial validation of these harmonized scores demonstrated similar and expected associations with age and education across studies (Figure 2). In conclusion, a cultural neuropsychology approach to statistical harmonization facilitates the generation of harmonized measures of cognitive functioning in cross-national studies. Future work can utilize these harmonized cognitive scores to investigate determinants of late-life cognitive decline and dementia in the US and Mexico.

Miguel Arce Rentería, PhD
Assistant Professor of Neuropsychology (in Neurology)
ma3347@cumc.columbia.edu

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Stephanie Cosentino, PhD
Stephanie Cosentino, PhD

Education as a Moderator of Help Seeking Behavior in Subjective Cognitive Decline

Early help-seeking is an important factor contributing to accurate diagnosis and treatment of Alzheimer's disease (AD). There are vast and far-reaching disparities in dementia-related help seeking. The decision to seek help for memory difficulties is likely to be multifactorial; it is influenced by a range of factors including knowledge of dementia, family history of dementia, social support, financial resources, perceptions of the healthcare system, and more. These disparities in help seeking will become more critical over time as individuals from marginalized backgrounds including those with fewer years of formal education, a risk factor for dementia, are expected to suffer additional burden with increasing dementia prevalence.

Figure 1. Association between SCD and help seeking behavior
as a function of education. SCD indicates subjective cognitive
decline.

Figure 1. Association between SCD and help seeking behavior as a function of education.

Subjective Cognitive Decline (SCD), the self-perception of cognitive decline in the absence of clinical impairment on formal testing, may be one of the earliest clinical indications of AD. We examined the extent to which education, a factor known to influence help seeking across a range of medical conditions, affected the degree to which older adults seek help for subjective cognitive decline. We studied 167 cognitively intact older adults (of which 6% were Hispanic and 22% were Black), with an average age of 73 and median education of 16 years. As recently reported in Alzheimer’s Disease & Associated Disorders, we found that higher levels of SCD and higher levels of education were both associated with greater help seeking for perceived memory changes. Moreover, education interacted with SCD such that in the context of higher SCD, those with higher education were more likely to address memory concerns with a healthcare professional. These findings can be used to inform proactive psychoeducation efforts regarding the importance of memory screenings, memory loss, and addressing memory concerns with healthcare providers.

Stephanie Cosentino, PhD
Professor of Neuropsychology (in Neurology, the Gertrude H. Sergievsky Center, and the Taub Institute)
sc2460@cumc.columbia.edu

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