Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
November 2020

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October 2020:

1: » Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the hippocampus

Alzheimer-Related Cerebrovascular Disease in Down Syndrome

Depression is Associated With Preserved Cortical Thickness Relative to Apathy in Frontotemporal Dementia

July 2020:

1: » Endothelial Activation of Caspase-9 Promotes Neurovascular Injury in Retinal Vein Occlusion

Proteomic Profiles for Alzheimer's Disease and Mild Cognitive Impairment Among Adults with Down Syndrome Spanning Serum and Plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) Study

Cognitive Tests aid in Clinical Differentiation of Alzheimer's Disease Versus Alzheimer's Disease with Lewy Body Disease: Evidence from a Pathological Study

June 2020:

Tau is not Necessary for Amyloid-Beta-Induced Synaptic and Memory Impairments

IL-27: An Endogenous Constitutive Repressor of Human Monocytes

Subgingival Microbiome and Clinical Periodontal Status in an Elderly Cohort: The WHICAP Ancillary Study of Oral Health

May 2020:

"Everything Hurts!" Distress in Semantic Variant Primary Progressive Aphasia

Metabolic Correlates of Prevalent Mild Cognitive Impairment and Alzheimer's Disease in Adults with Down Syndrome

Down Syndrome: Distribution of Brain Amyloid in Mild Cognitive Impairment

April 2020:

Cortical Thickness and its Associations with Age, Total Cognition and Education Across the Adult Lifespan

Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers

Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning

March 2020:

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Profilin 1 Delivery Tunes Cytoskeletal Dynamics Toward CNS Axon Regeneration

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls Across Multiple Cohorts

February 2020:

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Exceptionally Low Likelihood of Alzheimer’s Dementia in APOE2 Homozygotes from a 5,000-Person Neuropathological Study

January 2020:

Microglial Activation, but not Tau Pathology, is Independently Associated with Amyloid Positivity and Memory Impairment

CRISPR/Cas9 Editing of APP C-Terminus Attenuates β-Cleavage and Promotes α-Cleavage

December 2019:

Activity-Dependent Nucleation of Dynamic Microtubules at Presynaptic Boutons Controls Neurotransmission

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

Sleep Fragmentation, Microglial Aging, and Cognitive Impairment in Adults with and Without Alzheimer's Dementia

November 2019:

First Place: Studying Biochemical Mechanisms of Protective Gene Variants in Isogenic Stem Cell-derived Early Onset Alzheimer’s Disease Models

First Place: Glial Heterogeneity in Normal Human Cortex and Huntington Disease Interrogated Through Single Cell Nuclear RNA Sequencing

October 2019:

» Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

» Promotion of Axon Growth by the Secreted End of a Transcription Factor

September 2019:

» Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume

» Synaptic and Memory Dysfunction Induced by Tau Oligomers is Rescued by up-regulation of the Nitric Oxide Cascade

» Medicaid Contributes Substantial Costs to Dementia Care in an Ethnically Diverse Community Population

August 2019:

» Neuroinflammation in Frontotemporal Lobar Degeneration Revealed by 11C‐PBR28 PET

» Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons

July 2019:

» Alzheimer's Association International Conference (AAIC 2019)

June 2019:

» #1 CpG‐Related SNPs in the MS4A Region Have a Dose‐Dependent Effect on Risk of Late–Onset Alzheimer Disease

» #2 MFN2 Mutations in Charcot–Marie–Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics

May 2019:

» #1 Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease

» #2 Brain Biomarkers and Cognition Across Adulthood

April 2019:

» #1 Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers

» #2 Brain Arterial Dilatation and the Risk of Alzheimer's Disease

March 2019:

» #1 Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of β-Amyloid Precursor Protein

» #2 FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome

February 2019:

» #1 Effect of Aerobic Exercise on Cognition in Younger Adults: A Randomized Clinical Trial

» #2 Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimer’s Models

January 2019:

» #1 A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

» #2 Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain

December 2018:

» #1 Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimer’s Human Brains

» #2 Semantic Network Function Captured by Word Frequency in Nondemented APOE ε4 Carriers

November 2018:

» First Place: NSUN2 is Dysregulated in Alzheimer's Disease

» First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases

October 2018:

» #1 Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

» #2 An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

» #3 Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility

September 2018:

» #1 Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

» #2 Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE ε4 Haplotype Status: A Community-Based Cohort Study

August 2018:

» #1 A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research

» #2 An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

» #3 Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults

July 2018:

» #1 Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

» #2 Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease

June 2018:

» #1 Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

» #2 Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices

May 2018:

» #1 Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

» #2 Oligomeric Aβ1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons

April 2018:

» #1 Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

» #2 Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion

March 2018:

» #1 Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

» #2 White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes

February 2018:

» #1 ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

» #3 A Transcriptomic Atlas of Aged Human Microglia

January 2018:

» #1 Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

» #2 An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population

Association of APOE E2 Genotype with Alzheimer's and Non-Alzheimer's Neurodegenerative Pathologies

Dr. Terry E. Goldberg    Edward D. Huey, MD   Davangere P. Devanand, MBBS, MD
Terry E. Goldberg, PhD    Edward D. Huey, MD    Davangere P. Devanand, MBBS, MD

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer’s disease (AD), e4, and the major neuroprotective variant, e2. As recently published in Nature Communications, Drs. Terry Goldberg (Psychiatry and Anesthesiology), Ted Huey, and Davangere Devanand examined the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers, in order to examine potential neuroprotective effects.

For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. In a mediation analysis, e2 had both direct and indirect effects on tau Braak stage. The indirect effect was via amyloid neuritic plaque burden and was larger than the direct effect. Thus, e2 might modulate spread of tangles through two processes. When they separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e3/e4 carriers, not e2 carriers. Thus, in multiple analyses they found that e2/e4 was associated with greater degrees of Montine “ABC” AD pathology in contrast to e2/e3 and e3/3 genotype, and could not be distinguished from e3/e4 cases with respect to amyloid or tau pathologies. Copy number was controlled, increasing the rigor of the approach. These results indicate that the e4 isoform’s effects were neither blunted nor otherwise modified by e2 within the same brain, at least insofar as levels of the isoforms are in physiological range. This may have implications for trials in which the e2 isoform is introduced into the brains of e4 carriers in vivo.

E2 was not protective with respect to Lewy body pathology. Rather, APOE e4 increased risk for spread of Lewy bodies to limbic and neocortical regions but not for midbrain-only pathology. This result may suggest that while e4 does not increase risk for Parkinson’s disease, it may increase risk for Lewy body dementia.

Figure 1: a Association of APOE genotype and diffuse amyloid plaque distribution. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (plaque stage 5) from the e2 to e4/e4 genotype groups in stepwise fashion. Amyloid stage 0 = no pathology; stage 5 = severe. b Association of APOE genotype and Braak stage. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (Braak stages v and vi) from the e2 to e4/e4 genotype groups in stepwise fashion. Braak stage 0 = no pathology; stage vi = severe neocortical pathology. c Association of APOE genotype and neuritic amyloid plaque density level. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (plaque stages v and vi) from the e2 to e4/e4 genotype groups in stepwise fashion. Neuritic plaque stage 0 = no pathology; stage 3 = severe pathology.

E2 associations with multiple frontotemporal lobar degeneration (FTLD) pathologies and tauopathies were complex. Initially, nominally albeit marginally significant associations with e2 were found, such that e2 promoted risk for Pick bodies, PSP, and TDP-43. However, when adjustments for AD histopathology were made, these findings were no longer significant.

Last, in a follow up study now published in the Journal of Neurology, Neurosurgery & Psychiatry, Goldberg et al. examined the associations of e2 with cerebrovascular disease in this sample. They did not find that e2 was associated with protection from CAA, infarcts, microinfarcts, and microhemorrhages. It was, however, associated with increased risk of gross hemorrhage (i.e., lobar hemorrhage).

The current study had several strengths. It is perhaps the largest single study of e2 and e4 effects on multiple post-mortem human neuropathologies. Findings were independent of clinical diagnosis; thus the authors did not impose any filter or a priori bias on analyses. In terms of design the study can be considered clinically transdiagnostic, as Goldberg et al. intentionally did not examine or otherwise adjust for clinical variables. Rather, they chose to focus on gold standard neuropathological diagnoses. Finally, NACC data were collected prospectively and without regard for the specific hypotheses that were tested. Analyses were rigorous as a study wide Bonferroni correction was used and all ordinal and logistic regressions adjusted for age of death and sex so that APOE's contribution to pathology could be examined independent of these factors. However, the case series had an ascertainment bias in that all cases came from Alzheimer’s Centers and, not surprisingly, approximately 51% met pathological criteria for high AD neuropathological change scores by ABC system. In sum, Goldberg et al. found that e2 was associated with large, but circumscribed protective effects.

Terry E. Goldberg, PhD
Professor of Medical Psychology (in Psychiatry and Anesthesiology) at the Columbia University Medical Center

Edward D. Huey, MD
Associate Professor of Psychiatry and Neurology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Davangere P. Devanand, MBBS, MD
Professor of Psychiatry (in Neurology and in the Gertrude H. Sergievsky Center) at the Columbia University Medical Center

APOE Ε4 and Resting-State Functional Connectivity in Racially/Ethnically Diverse Older Adults

Indira C. Turney, PhD    Adam M. Brickman, PhD
Indira C. Turney, PhD    Adam M. Brickman, PhD

Though the APOE ε4 allele is the most well-established genetic risk factor for Alzheimer’s Disease (AD), studies show a weak association of APOE ε4 and AD risk among minority populations. Resting-state functional connectivity (rsFC), specifically within the default mode network (DMN), is vulnerable to the earliest stages of AD pathology, which accumulates years before symptom onset. Numerous neuroimaging studies demonstrated an association between APOE ε4 and rsFC of regions within the DMN, both in healthy populations and patients with AD. Nevertheless, it remains unclear whether the APOE ε4 allele differentially affects the brain’s functional network architecture across race/ethnicity.

Figure 1: Resting-state functional connectivity in DMN subsystems across race/ethnicity and APOE e4 status (95% confidence interval error bars). Abbreviations: NH, non-Hispanic; DMN, default mode network; APOE, apolipoprotein E. *P<.016 Bonferroni corrected; ˆP<.05 uncorrected

A recent study from the laboratory of Dr. Adam Brickman, including postdoctoral research scientist and first author Dr. Indira Turney, investigated the association between rsFC within the DMN and APOE ε4 across non-Hispanic whites, non-Hispanic Blacks, and Hispanics from the Washington Heights-Inwood Columbia Aging Project. As recently published in Alzheimer's and Dementia, they found that APOE ε4 carriers had lower rsFC in the temporal DMN subsystem, but only in non-Hispanic whites (Figure 1). Their findings suggest that APOE ε4 modulates rsFC in DMN subsystems differently in non-Hispanic whites compared to non-Hispanic Blacks and Hispanics. It is still critical that future studies examine how race and ethnicity modifies the risk and expression of AD to understand race-dependent biological mechanisms of AD.

Indira C. Turney, PhD
Postdoctoral Research Scientist in the Gertrude H. Sergievsky Center

Adam Brickman, PhD
Professor of Neuropsychology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center)

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults

Dr Yian Gu   
Yian Gu, MD, MS, PhD    Adam M. Brickman, PhD

Results from longitudinal epidemiological studies, including a study published by Dr. Yian Gu and colleagues last year, suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer’s disease (AD). Multiple brain structural changes, including both neurodegeneration, such as volume loss, and cerebrovascular lesions, such as white matter hyperintensities, are powerful predictors for subsequent AD development. However, data on the association between LTPA and brain magnetic resonance imaging (MRI) measures remain scarce and inconsistent.

In a study recently published in JAMA Network Open, Drs. Yian Gu, Adam Brickman, and colleagues sought to examine the association of LTPA and MRI-assessed brain measures among multiethnic participants of the community based Washington/Hamilton Heights-Inwood Columbia Aging Project study.

Figure 1: Brain measures by leisure time physical activity levels. Solid lines represent significant associations between leisure time physical activity (LTPA) and brain measures, while dotted lines indicate nonsignificant associations. TBV (total brain volume), TGMV (total gray matter volume), TWMV (total white matter volume), WMH (white matter hyperintensity).

The study found that, compared with nonactive older adults, those with the most LTPA had larger total brain volume (i.e., less brain atrophy), equivalent to approximately 3 to 4 years of healthy aging. A dose-response association was also found and even the lowest active LTPA level had benefits compared with the nonactive group (Figure 1). The association between LTPA and total brain volume was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. The results remained similar after excluding participants with mild cognitive impairment. The study provides important evidence to suggest that more physical activity is helpful in maintaining brain health in older adults.

Yian Gu, MD, MS, PhD
Assistant Professor (in the Department of Neurology, Department of Epidemiology, and Taub Institute)

Adam Brickman, PhD
Professor of Neuropsychology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center)

Alzheimer-Related Altered White Matter Microstructural Integrity in Down Syndrome: a Model for Sporadic AD?

Dr-H-Diana-Rosas    Dr. Schupf
H. Diana Rosas, PhD    Nicole Schupf, PhD

Figure 1: Violin and box plots describing the distribution of fractional anisotropy by diagnostic group. Fractional anisotropy values among mild cognitive impairment‐Down syndrome subjects were significantly lower in the forceps major, forceps minor, and left/right cingulum‐cingulate gyrus bundle compared to cognitively stable subjects

Virtually all adults with Down syndrome (DS) develop Alzheimer’s disease (AD) associated neuropathology by the age of 40 and most will develop dementia by age 60. Several recent studies in sporadic AD have suggested that decreased regional white matter (WM) integrity is correlated with cognitive dysfunction. Other studies suggest that these changes may confer a particular susceptibility to dementia in individuals with DS. The latest study from Dr. Nicole Schupf and colleagues, including lead author Dr. H. Diana Rosas (Harvard), evaluated the relationship between altered WM integrity of tracts projecting to cortical areas involved in memory function, amyloid deposition, and cognitive function.

They found that early changes in late-myelinating and relative sparing of early-myelinating pathways were associated with regional amyloid deposition and cognitive deficits. Their findings, now published in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, suggest an important pathophysiological link between WM damage, amyloid deposition and clinical status prior to onset of dementia. Further, according to Ross et al., these findings “support the use of diffusion weighted imaging as an important and clinically relevant biomarker of progression of AD in individuals with DS, and may serve as a model for sporadic AD.”

Nicole Schupf, PhD
Professor of Epidemiology (in Neurology, Psychiatry, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

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