Medical Genetics Commons^™

Genetic Drivers Of Progression In Alzheimer’S Disease Are Distinct From Disease Risk, Celeste E. Cohen, Shane Fernandez, Umran Yaman, Ahmad R. Ehyaei, Eleftheria Kodosaki, Aydan Askarova, Tenielle Porter, Eleanor O’Brien, Paul Maruff, Alexi Nott, John A. Hardy, Simon M. Laws, Dervis A. Salih, Maryam Shoai

Research outputs 2022 to 2026

Background: Recent trials in Alzheimer’s disease (AD) demonstrate encouraging outcomes. These trials target risk mechanisms identified through genetic analysis whilst directly aiming to reduce progression rates. Evidence from other neurodegenerative diseases suggests the genetics of progression is distinct from risk of disease. To expand these initial successes and improve clinical outcomes further we need to understand genetics of progression of disease. These can be deduced through rigorous analysis of meticulously phenotyped longitudinal cohorts. In this study we first looked at known genetic drivers of risk, namely polygenic risk scores for AD and APOE‑ε4, to assess their role in progression. This …

A Genomic Approach For Accurate Identification Of Closely Related Species With Next-Generation Sequencing Samples, Nour Al Dain Marzouka, Amira Al-Aamri, Fatima Alshamsi, Mariam Khalili, Sarah El Hajj Chehadeh, Meera S. Mohamed, Yassir Mohammed Eltahir, Rafeek Koliyan, Mohamed Moustafa Abdelhalim, Assem Attia, Mira Mousa, Guan Tay, Habiba Alsafar

Research outputs 2022 to 2026

Accurate species identification from Whole Genome Sequencing (WGS) data remains challenging, particularly for closely related species such as sheep (Ovis aries) and goats (Capra hircus). Through analysis of mapping quality metrics and Kraken2 taxonomic classification of 40 WGS sheep and goat samples, we demonstrate that conventional approaches yield ambiguous results, with overlapping alignment rates and inconclusive taxonomic assignments. We present a robust comparative genomic approach that uses species-specific genomic regions to distinguish these species in WGS samples. We define species-specific regions as those exhibiting distinctive coverage patterns: average coverage when samples are aligned to their matching reference genome but absent/low …

Mtorc2-Nav1.2 Signaling Drives Early Hyperexcitability In Alzheimer’S Disease Mouse Model, Nolan M Dvorak, Jeffrey L Noebels

Faculty, Staff and Students Publications

Hyperexcitability is a biomarker of early-stage Alzheimer’s Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced …

In-Hospital Mortality Patterns And Readmissions In Patients With Chronic Obstructive Pulmonary Disease: An Analysis Of The Role Of Pulmonary Hypertension, Saad Afzal Khan, Trishna Parikh, Adishwar Rao, Akriti Agrawal, Aarohi Parikh, Farah Kazzaz, Sarah Shin, Harry Karmouty-Quintana, Maulin Patel, Kha Dinh, Bela Patel, Bindu Akkanti

Faculty, Staff and Student Publications

Chronic obstructive pulmonary disease (COPD) may be complicated by pulmonary hypertension (PH). We aimed to understand the impact of PH on in-hospital mortality and quantify the 30-day readmission rate among patients with COPD. For this cross-sectional study, we used the Nationwide Readmissions Database from 2017-2020 to identify adults ≥18 years with COPD. Patients were stratified according to PH diagnosis. Baseline characteristics between groups were compared using the Pearson chi-square test and two-sample t-test. Predictors of in-hospital mortality were determined using multivariate logistic regression analysis adjusted for demographics and confounders. The 30-day readmission rate and prevalence of PH subgroups by baseline …

Arriving At A Diagnosis: Effective Strategies Used By The Undiagnosed Diseases Network, Somin Hwang, Rachel M Brown, Dustin Baldridge, Erin E Baldwin, Alan H Beggs, Jonathan A Bernstein, Elizabeth Blue, Nicholas A Borja, Lorenzo D Botto, Lauren C Briere, Thomas Cassini, Cecilia Esteves, Elizabeth L Fieg, Gail P Jarvik, Shilpa Nadimpalli Kobren, Mia P Levanto, Julian A Martínez-Agosto, Shruti Marwaha, Stanley F Nelson, Jill A Rosenfeld, Tim Schedl, Tina K Truong, Jennifer A Wambach, Matthew T Wheeler, Shinya Yamamoto, Undiagnosed Diseases Network, Vandana Shashi, Alexa T Mccray, David R Adams, Kimberly Leblanc

Duncan NRI Faculty and Staff Publications

Purpose: Despite the increasing use of exome sequencing (ES) and genome sequencing (GS) in clinical settings, many individuals remain undiagnosed. This study examined the Undiagnosed Diseases Network (UDN)'s approach to establishing diagnoses for participants.

Methods: As a continuation of the first UDN cohort (9/16/2015-5/23/2017), this study reviewed diagnostic strategies and outcomes in the second UDN cohort (5/24/2017-6/30/2023).

Results: Over the study period, the proportion of UDN participants with prior ES/GS increased from 40.2% to 75.0%. The diagnostic rate for the UDN was 22.1% (379/1,713). Reanalysis/reinterpretation of sequencing data (prior ES: 21.4%, prior GS: 2.6%, UDN ES: 4.8%, UDN GS: 17.3%) …

Charge Modulation Of Peptide/Nucleic Acid Complexes: An Anionic Additive Enhances Gene Silencing And Crispr/Cas9 Editing By Promoting Intracellular Nucleic Acid Release, Abdulelah Alhazza, Sorour Khayyatnejad Shoushtari, Hasan Uludag, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Introduction: Small interfering RNA (siRNA) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated Protein 9 (Cas9) complexes are effective approaches to temporarily downregulate protein expression via post-transcription RNA interference or permanently altering protein expression via editing genomic DNA, respectively. However, the efficient delivery of these mediators to targeted cells has been challenging, largely due to their anionic and hydrophilic nature, which hinders their interaction with the cell membrane and cellular internalization. Cell-penetrating peptides (CPPs) exhibit dual characteristics as a carrier for nucleic acid delivery, where positively charged components bind to the negatively charged nucleic acid, and the hydrophobic components …

Variation In Meningioma Recurrence Risk Estimates Across Observational Cohorts: The Influence Of Calendar Time, Who Classifications, Geographical Settings, And Healthcare Systems, Christian Mirian, Lasse Rehné Jensen, Adam Gorm Hoffmann, Tareq A Juratli, Anders Broechner, Sverre H Torp, Helen A Shih, Ramin A Morshed, Jacob S Young, Stephen T Magill, Luca Bertero, Walter Stummer, Dorothee Cäcilia Spille, Benjamin Brokinkel, Soichi Oya, Satoru Miyawaki, Nobuhito Saito, Martin Proescholdt, Yasuhiro Kuroi, Konstantinos Gousias, Matthias Simon, Jennifer Moliterno, Ricardo Prat-Acin, Stéphane Goutagny, Vikram C Prabhu, John T Tsiang, Johannes Wach, Erdem Güresir, Junkoh Yamamoto, Young Zoon Kim, Joo Ho Lee, Daniel W Kim, Matthew Koshy, Karthikeyan Perumal, Mustafa K Baskaya, Donald M Cannon, Dennis C Shrieve, Chang-Ok Suh, Jong Hee Chang, Maria Kamenova, Sven Straumann, Jehuda Soleman, Ilker Y Eyüpoglu, Tony Catalan, Austin Lui, Philip V Theodosopoulos, Michael W Mcdermott, Fang Wang, Pedro Góes, Manoel Antonio De Paiva Neto, Ricardo Komotar, Michael E Ivan, Aria Jamshidi, Evan Luther, Luis Souhami, Marie-Christine Guiot, Tamás Csonka, Toshiki Endo, Olivia Claire Barrett, Randy Jensen, Tejpal Gupta, Akash J Patel, Tiemo J Klisch, Jun Won Kim, Francesco Maiuri, Valeria Barresi, María Dolores Tabernero, Simon Skyrman, Ian Law, Bjarne Winther Kristensen, Tina Nørgaard Munch, Torstein Meling, Kåre Fugleholm, Paul Blanche, Tiit Mathiesen, Andrea Daniela Maier

Duncan NRI Faculty and Staff Publications

Purpose: Recurrence risk estimates underpin meningioma research, including molecular classification and clinical trial benchmarking, yet are often based on retrospective or historical data. The aim of this study was to assess the variation of recurrence risk estimates across calendar periods, WHO classification editions, geographical settings, and healthcare systems.thetermine METHODS: We analyzed 4,111 patients with primary WHO-1/-2 meningiomas from 31 centers in 15 countries (1990-2019). Recurrence was defined according to local radiological assessment. The 5- and 10-year recurrence risks were estimated using regression standardization with inverse probability of censoring weights, adjusting for key clinical, surgical, and histopathological variables.

Results: Recurrence risk …

Selective Loss Of Primary Cilia And Neurotrophic Signaling In G51d Α-Synuclein Mice Highlights A Common Pathway To Parkinson’S Disease, Yu-En Lin, Ebsy Jaimon, Youngdoo Kim, Annabeth Loftman, Aaran Vijayakumaran, Benjamin D W Belfort, Claire Y Chiang, Benjamin R Arenkiel, Huda Y Zoghbi, Suzanne R Pfeffer

Duncan NRI Faculty and Staff Publications

Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform …

Lineage Tracing Reveals A Shared Cellular Origin For Supraclavicular Brown And Inguinal Beige Adipocytes, Yali Ran, Kai Zhang, Yi-Ting Shen, Qianxing Mo, Ziyi Wang, Hari Krishna Yalamanchili, Sharon John, Mari Kogiso, Xia Gao, Chunmei Wang, Tanvi Sinha, Brian L Black, Miao-Hsueh Chen

Duncan NRI Faculty and Staff Publications

The metabolic importance of brown adipose tissue (BAT) has been recognized, but its origins, particularly supraclavicular BAT (scBAT), remain unclear. Here, we traced scBAT to Mef2c-anterior heart field (AHF)-marked cells. Mef2c-AHF-marked cells isolated from scBAT can spontaneously differentiate into brown adipocytes, express mesenchymal stem cell markers, and can be isolated from the stromal-vascular fraction (SVF) of wild-type scBAT as [CD31

Digital Markers For Passive Remote Monitoring Of Bipolar Disorder: Systematic Review, Thomas P Kutcher, Isha Chakraborty, Kristin Kostick-Quenet, Akane Sano, Nidal Moukaddam, Jeffrey A Herron, Wayne K Goodman, Sameer A Sheth, Ashutosh Sabharwal, Nicole R Provenza

Duncan NRI Faculty and Staff Publications

Background: Bipolar disorder (BD) features episodic shifts among mania, hypomania, depression, mixed states, and euthymia. Timely detection of mood transitions is difficult due to infrequent clinical touchpoints. Digital health technologies, including wearables and smartphones, offer a unique opportunity to passively and continuously monitor behavior and physiology that could reflect underlying mood dynamics in real-world settings.

Objective: This study aimed to systematically review passively collected digital markers for BD mood states, characterize devices/modalities and analytic approaches, appraise risk of bias, and identify design gaps and priorities for clinical translation.

Methods: Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) …

Translational Reading Frame Predicts The Pathogenicity Of C-Terminal Frameshift Deletions In Mecp2, Jacky Guy, Elena Hein, Beatrice Alexander-Howden, Timur Von Bock Und Polach, Tricia Mathieson, Benjamin P Kleinstiver, Huda Y Zoghbi, Adrian Bird

Duncan NRI Faculty and Staff Publications

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline …

Shared Neural Geometries For Bilingual Semantic Representations In Human Hippocampal Neurons, Xinyuan Yan, Ana G Chavez, Melissa Franch, Kalman A Katlowitz, Ivy Gautam, Brian Kim, Aaditya Krishna, Aadit Shrivastava, Katie Van Arsdel, James Belanger, Assia Chericoni, Taha Ismail, Elizabeth A Mickiewicz, Danika Paulo, Hanlin Zhu, Alica M Goldman, Vaishnav Krishnan, Atul Maheshwari, Eleonora Bartoli, Nicole R Provenza, Seng Bum Michael Yoo, Benjamin Y Hayden, Sameer A Sheth

Duncan NRI Faculty and Staff Publications

The human brain has the remarkable ability to comprehend and express similar concepts in multiple languages. To understand how it does so, we examined responses of hippocampal neurons during passive listening, directed speaking, and spontaneous conversation in both English and Spanish in a small group of balanced bilinguals. We found a small number of putative "cross-language neurons," whose responses to equivalent words (e.g., "tierra" and "earth") are correlated. However, neurons' semantic tunings differed substantially by language, suggesting language-specific neural implementations. Instead, the crucial driver of translation was a preserved geometric organization of neural responses between the two languages, one that …

De Novo Complex Genomic Rearrangement Spanning 2q31.1 In A Proband With Congenital Malformations: Genotype-Phenotype Correlation And Development Of A Cgr Detection Pipeline, Katherine Helle, Jesse D Bengtsson, Mira Gandhi, Christopher M Grochowski, Ming Yin Lun, Neha Sudhir, Shalini N Jhangiani, Fritz J Sedlazeck, Seema R Lalani, Neil A Hanchard, Claudia M B Carvalho

Faculty, Staff and Students Publications

The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house …

In Vivo Model Of Neurotropic Human Metapneumovirus Infection In Mice Brain, Joanna Yuen, Gage Greening, Eric S. Geanes, Dharitri Betha, Rebecca Mclennan Phd, Todd Bradley

Posters

No abstract provided.

The Association Between Apoe Genotype, Race, And Dementia: An Analysis Of 7 Population-Based Cohort Studies, Natalia Lakomski, Katherine Giorgio, John Stephen, Maxwell Mansolf, Aïcha Soumaré, Alden L Gross, Allison E Aiello, Archana Singh-Manoux, M Arfan Ikram, Catherine Helmer, Claudia L Satizabal, Deborah A Levine, Donald M Lloyd-Jones, Emily M Briceño, Farzaneh A Sorond, Frank J Wolters, Jayandra J Himali, Lenore J Launer, Djass Mbangdadji, David Li, Lihui Zhao, Oscar L Lopez, Stéphanie Debette, Sudha Seshadri, Suzanne E Judd, Timothy M Hughes, Vilmundur Guðnason, Michael Griswold, Paul S De Vries, Alison Fohner, Pamela L Lutsey, Rachel Zmora, Elizabeth A Peterson, Denise Scholtens, Norrina B Allen, Sanaz Sedaghat

Faculty, Staff and Student Publications

Background and objectives: The apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 allele serves as a protective factor for dementia. However, data on the effects of the homozygous APOE ε2/ε2 genotype are limited, likely due to the rarity of the APOE ε2/ε2 genotype. Furthermore, the association between APOE genotypes and dementia may differ across self-reported race. We aim to investigate the association between APOE genotypes and dementia overall and across self-reported race, with a focus on the potential protective …

Extending Genome-Wide Association Studies To Admixed Cohorts With High Degrees Of Relatedness, Taotao Tan, Alejandra Vergara-Lope, José Jaime Martínez-Magaña, Nirav N Shah, Yi-Sian Lin, Kai Yuan, Jaime Berumen, Jesus Alegre-Díaz, Pablo Kuri-Morales, Roberto Tapia-Conyer, Joel Gelenter, Janitza L Montalvo-Ortiz, Wei Zhou, Jason M Torres, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

Admixed populations comprise a large portion of the human population worldwide, but are often excluded from genome-wide association studies (GWASs) due to analytic challenges. Our group developed Tractor, a local-ancestry-informed GWAS tool designed for admixed samples that produces accurate ancestry-specific effect sizes and boosts the discovery power to identify ancestry-enriched loci. However, Tractor operates under an assumption of unrelated samples. Here, to address this gap, we propose Tractor-Mix, which allows for well-calibrated association studies in datasets containing admixed samples with relatedness. Extensive simulations show that this method is competitive with other state-of-the-art approaches that do not produce ancestry-specific results. Empirical …

A Blended Genome And Exome Sequencing Method Captures Genetic Variation In An Unbiased And Cost-Effective Manner, Toni A Boltz, Benjamin B Chu, Matthew Defelice, Calwing Liao, Julia M Sealock, Robert Ye, Jacqueline I Goldstein, Lerato Majara, Jack M Fu, Susan K Service, Lingyu Zhan, Sarah E Medland, Sinéad B Chapman, Simone Rubinacci, Jonna L Grimsby, Tamrat Abebe, Melkam Alemayehu, Fred K Ashaba, Elizabeth G Atkinson, Tim B Bigdeli, Amanda B Bradway, Harrison Brand, Lori B Chibnik, Samuel Deluca, Ana M Diaz-Zuluaga, Abebaw Fekadu, Michael Gatzen, Bizu Gelaye, Stella Gichuru, Marissa L Gildea, Toni C Hill, Hailiang Huang, Kalyn M Hubbard, Wilfred E Injera, Roxanne James, Moses Joloba, Christopher Kachulis, Phillip R Kalmbach, Rogers Kamulegeya, Gabriel Kigen, Soyeon Kim, Nastassja Koen, Edith K Kwobah, Joseph Kyebuzibwa, Seungmo Lee, Niall J Lennon, Penelope A Lind, Esteban A Lopera-Maya, Johnstone Makale, Serghei Mangul, Justin Mcmahon, Pierre Mowlem, Henry Musinguzi, Rehema M Mwema, Noeline Nakasujja, Carter P Newman, Lethukuthula L Nkambule, Conor R O'Neil, Ana Maria Olivares, Catherine M Olsen, Linnet Ongeri, Sophie J Parsa, Adele Pretorius, Shengying Qin, Raj Ramesar, Faye L Reagan, Chiara Sabatti, Jacquelyn A Schneider, Welelta Shiferaw, Christine Stevens, Anne Stevenson, Erik Stricker, Rocky E Stroud, Jessie Tang, Megan Townsend, David Whiteman, Mary T Yohannes, Mingrui Yu, Kai Yuan, Dickens Akena, Lukoye Atwoli, Symon M Kariuki, Karestan C Koenen, Charles R J C Newton, Dan J Stein, Solomon Teferra, Zukiswa Zingela, Carlos N Pato, Michele T Pato, Carlos Lopez-Jaramillo, Nelson B Freimer, Roel A Ophoff, Loes M Olde Loohuis, Michael E Talkowski, Benjamin M Neale, Daniel P Howrigan, Alicia R Martin

Duncan NRI Faculty and Staff Publications

Here we developed and deployed the blended genome exome (BGE) method, a DNA library approach that generates low-pass whole-genome (1–4× mean depth) and deep whole-exome (30–40× mean depth) data in a single sequencing run. BGE is cost-effective, empowers most genomic discoveries possible with deep whole-genome sequencing and captures global common single-nucleotide polymorphism diversity. We applied BGE to sequence >53,000 samples from the PUMAS Project (Populations Underrepresented in Mental Illness Associations Studies), including African, African American and Latin American populations. Imputed genotypes showed high concordance with Illumina Global Screening Array calls (R2 ≥ 95% for minor allele frequency ≥1%; …

Hippo Signaling Regulates Cuticle Pigmentation And Dopamine Metabolism In Drosophila, Shelley B Gibson, Samantha L Deal, Ye-Jin Park, Bo Sun, Yanyan Qi, Jung-Wan Mok, Hyung-Lok Chung, Hongjie Li, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Pigmentation plays multiple important roles in development, physiology and evolution. Melanization of the insect cuticle requires dopamine as a precursor of melanin and involves key enzymes in dopamine biosynthesis including Tyrosine hydroxylase (TH) and Dopa decarboxylase (Ddc). Some studies have hinted that disruption of the evolutionarily conserved Hippo signaling pathway, which has been primarily studied in the context of tissue growth, may lead to changes in cuticle pigmentation in the fruit fly Drosophila melanogaster. However, to our knowledge, there have not been any systematic investigations into their potential mechanistic links. In this study, we identified that all genes that comprise …

Intermembrane Coupling Between Bcl-Xl And The Ip3 Receptor Supports Local Ca2+ Transfer At Er-Mitochondrial Contacts, Arijita Ghosh, David Weaver, Chi Li, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP₃ receptor Ca²⁺ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca²⁺ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca²⁺ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca²⁺ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy …

Tau Pathology In Epilepsy: Emerging Mechanisms And Translational Opportunities, Arjune Sen, Xin You Tai, Aristea Galanopoulou, Maria Thom, Eleonora Aronica, Lucy Vivash, Martin Hardmeier, Action Amos, Stephan Rueegg, Matthias Koepp, Yaroslav Winter, Christoph Helmstaedter, Jeffrey L Noebels, Hilal A Lashuel, Terence J O'Brien

Faculty, Staff and Students Publications

The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental …