Scholars@Duke
William Kirby Gottschalk

William Kirby Gottschalk

Assistant Professor in Neurology
Neurology, Behavioral Neurology
kirby.gottschalk@duke.edu
Box 2900 Med Ctr, DUMC Division of Neurology, Durham, NC 27710
227D Bryan Research Building, Research Drive, Durham, NC 27710
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Selected Publications

Genetic associations with longevity are on average stronger in females than in males.

Journal Article Heliyon · January 15, 2024 It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in mal ... Full text Link to item Cite

The APOE-TOMM40 Humanized Mouse Model: Characterization of Age, Sex, and PolyT Variant Effects on Gene Expression.

Journal Article J Alzheimers Dis · 2023 BACKGROUND: The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer's disease (LOAD) and other age-related conditions. OBJECTIVE: Here we developed the first humanized mouse model ... Full text Link to item Cite

Alzheimer's Disease Protein Relevance Analysis Using Human and Mouse Model Proteomics Data.

Journal Article Front Syst Biol · 2023 The principles governing genotype-phenotype relationships are still emerging(1-3), and detailed translational as well as transcriptomic information is required to understand complex phenotypes, such as the pathogenesis of Alzheimer's disease. For this reas ... Full text Link to item Cite

APOE, TOMM40, and sex interactions on neural network connectivity.

Journal Article Neurobiol Aging · January 2022 The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs ... Full text Link to item Cite

APOE, TOMM40, and Sex Interactions on Neural Network Connectivity.

Journal Article Alzheimers Dement · December 2021 BACKGROUND: The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in A ... Full text Link to item Cite

Capillary Electrophoresis-High Resolution Mass Spectrometry for Measuring In Vivo Arginine Isotope Incorporation in Alzheimer's Disease Mouse Models.

Journal Article J Am Soc Mass Spectrom · June 2, 2021 Immune-based metabolic reprogramming of arginine utilization in the brain contributes to the neuronal pathology associated with Alzheimer's disease (AD). To enable our long-term goals of differentiation of AD mouse model genotypes, ages, and sexes based on ... Full text Open Access Link to item Cite

Likelihood ratio statistics for gene set enrichment in Alzheimer's disease pathways.

Journal Article Alzheimers Dement · April 2021 INTRODUCTION: The study of Alzheimer's disease (AD) has revealed biological pathways with implications for disease neuropathology and pathophysiology. These pathway-level effects may also be mediated by individual characteristics or covariates such as age ... Full text Link to item Cite

Reassessment of Pioglitazone for Alzheimer's Disease.

Journal Article Front Neurosci · 2021 Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer's sufferers was $244B, not i ... Full text Link to item Cite

Sex Differences in Genetic Associations With Longevity.

Journal Article JAMA Netw Open · August 2018 IMPORTANCE: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. OBJECTIVE: To explore sex differences in genetic associations with longevity. DESIGN ... Full text Link to item Cite

The correlation of copy number variations with longevity in a genome-wide association study of Han Chinese.

Journal Article Aging (Albany NY) · June 5, 2018 Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individ ... Full text Link to item Cite

The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes.

Journal Article Alzheimers Dement · May 2018 The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 poly-T with the risk and age of onset of late-onset Alzhe ... Full text Link to item Cite

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease.

Journal Article Biochim Biophys Acta Mol Basis Dis · November 2017 A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very l ... Full text Link to item Cite

The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster.

Journal Article Biochim Biophys Acta Mol Basis Dis · March 2017 Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer's disease, and longevity. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear ... Full text Link to item Cite

Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages.

Journal Article Rejuvenation Res · June 2016 On the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are signific ... Full text Open Access Link to item Cite

Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease.

Journal Article Alzheimers Dement · June 2016 The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two ... Full text Link to item Cite

Novel loci and pathways significantly associated with longevity.

Journal Article Sci Rep · February 25, 2016 Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a gen ... Full text Open Access Link to item Cite

Structural variants can be more informative for disease diagnostics, prognostics and translation than current SNP mapping and exon sequencing.

Journal Article Expert Opin Drug Metab Toxicol · 2016 INTRODUCTION: In this article we discuss several human neurological diseases and their relationship to specific highly polymorphic small structural variants (SVs). Unlike genome-wide association analysis (GWAS), this methodology is not a genome screen to d ... Full text Link to item Cite

Effects of low doses of pioglitazone on resting-state functional connectivity in conscious rat brain.

Journal Article PLoS One · 2015 Pioglitazone (PIO) is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPARγ agonists may be useful for treating or delaying the onset of Alzheimer's dise ... Full text Link to item Cite

African-American TOMM40'523-APOE haplotypes are admixture of West African and Caucasian alleles.

Journal Article Alzheimers Dement · November 2014 BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of ... Full text Link to item Cite

The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes.

Journal Article Alzheimers Dement · September 2014 BACKGROUND: We investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) t ... Full text Link to item Cite

Genetic associations with longevity are on average stronger in females than in males.

Journal Article Heliyon · January 15, 2024 It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in mal ... Full text Link to item Cite

The APOE-TOMM40 Humanized Mouse Model: Characterization of Age, Sex, and PolyT Variant Effects on Gene Expression.

Journal Article J Alzheimers Dis · 2023 BACKGROUND: The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer's disease (LOAD) and other age-related conditions. OBJECTIVE: Here we developed the first humanized mouse model ... Full text Link to item Cite

Alzheimer's Disease Protein Relevance Analysis Using Human and Mouse Model Proteomics Data.

Journal Article Front Syst Biol · 2023 The principles governing genotype-phenotype relationships are still emerging(1-3), and detailed translational as well as transcriptomic information is required to understand complex phenotypes, such as the pathogenesis of Alzheimer's disease. For this reas ... Full text Link to item Cite

APOE, TOMM40, and sex interactions on neural network connectivity.

Journal Article Neurobiol Aging · January 2022 The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs ... Full text Link to item Cite

APOE, TOMM40, and Sex Interactions on Neural Network Connectivity.

Journal Article Alzheimers Dement · December 2021 BACKGROUND: The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in A ... Full text Link to item Cite

Capillary Electrophoresis-High Resolution Mass Spectrometry for Measuring In Vivo Arginine Isotope Incorporation in Alzheimer's Disease Mouse Models.

Journal Article J Am Soc Mass Spectrom · June 2, 2021 Immune-based metabolic reprogramming of arginine utilization in the brain contributes to the neuronal pathology associated with Alzheimer's disease (AD). To enable our long-term goals of differentiation of AD mouse model genotypes, ages, and sexes based on ... Full text Open Access Link to item Cite

Likelihood ratio statistics for gene set enrichment in Alzheimer's disease pathways.

Journal Article Alzheimers Dement · April 2021 INTRODUCTION: The study of Alzheimer's disease (AD) has revealed biological pathways with implications for disease neuropathology and pathophysiology. These pathway-level effects may also be mediated by individual characteristics or covariates such as age ... Full text Link to item Cite

Reassessment of Pioglitazone for Alzheimer's Disease.

Journal Article Front Neurosci · 2021 Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer's sufferers was $244B, not i ... Full text Link to item Cite

Sex Differences in Genetic Associations With Longevity.

Journal Article JAMA Netw Open · August 2018 IMPORTANCE: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. OBJECTIVE: To explore sex differences in genetic associations with longevity. DESIGN ... Full text Link to item Cite

The correlation of copy number variations with longevity in a genome-wide association study of Han Chinese.

Journal Article Aging (Albany NY) · June 5, 2018 Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individ ... Full text Link to item Cite

The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes.

Journal Article Alzheimers Dement · May 2018 The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 poly-T with the risk and age of onset of late-onset Alzhe ... Full text Link to item Cite

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease.

Journal Article Biochim Biophys Acta Mol Basis Dis · November 2017 A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very l ... Full text Link to item Cite

The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster.

Journal Article Biochim Biophys Acta Mol Basis Dis · March 2017 Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer's disease, and longevity. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear ... Full text Link to item Cite

Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages.

Journal Article Rejuvenation Res · June 2016 On the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are signific ... Full text Open Access Link to item Cite

Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease.

Journal Article Alzheimers Dement · June 2016 The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two ... Full text Link to item Cite

Novel loci and pathways significantly associated with longevity.

Journal Article Sci Rep · February 25, 2016 Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a gen ... Full text Open Access Link to item Cite

Structural variants can be more informative for disease diagnostics, prognostics and translation than current SNP mapping and exon sequencing.

Journal Article Expert Opin Drug Metab Toxicol · 2016 INTRODUCTION: In this article we discuss several human neurological diseases and their relationship to specific highly polymorphic small structural variants (SVs). Unlike genome-wide association analysis (GWAS), this methodology is not a genome screen to d ... Full text Link to item Cite

Effects of low doses of pioglitazone on resting-state functional connectivity in conscious rat brain.

Journal Article PLoS One · 2015 Pioglitazone (PIO) is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPARγ agonists may be useful for treating or delaying the onset of Alzheimer's dise ... Full text Link to item Cite

African-American TOMM40'523-APOE haplotypes are admixture of West African and Caucasian alleles.

Journal Article Alzheimers Dement · November 2014 BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of ... Full text Link to item Cite

The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes.

Journal Article Alzheimers Dement · September 2014 BACKGROUND: We investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) t ... Full text Link to item Cite

TOMM40 and APOE: Requirements for replication studies of association with age of disease onset and enrichment of a clinical trial.

Journal Article Alzheimers Dement · March 2013 A number of recent studies have not replicated the association of the translocase of the outer mitochondrial membrane pore subunit (TOMM40) rs10524523 polymorphism, which is in linkage disequilibrium with apolipoprotein E (APOE), with age of onset of Alzhe ... Full text Link to item Cite

Using genetics to enable studies on the prevention of Alzheimer's disease.

Journal Article Clin Pharmacol Ther · February 2013 Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, t ... Full text Link to item Cite

Clinical Trials of AD Delay of Onset: Enrichment by a Prognostic Genetic Biomarker

Book · January 1, 2013 Modern medicine is shifting its focus to predictive and preventive healthcare utilization. To support this change, early intervention clinical trials that delay the onset of symptomatic disease must be conducted in a safe and cost-effective manner, and wit ... Full text Cite

The human ACC2 CT-domain C-terminus is required for full functionality and has a novel twist.

Journal Article Acta Crystallogr D Biol Crystallogr · May 2009 Inhibition of acetyl-CoA carboxylase (ACC) may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly conserved amongst animals, only the yeast enzyme structure is ... Full text Link to item Cite

Preclinical developments in type 2 diabetes.

Journal Article Adv Drug Deliv Rev · November 5, 2002 Type 2 diabetes is associated with insulin resistance in peripheral tissues, such as muscle and fat, impaired glucose-stimulated insulin secretion from pancreatic beta-cells and elevated hepatic gluconeogenesis. Current pharmacotherapy does not adequately ... Full text Link to item Cite

Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues.

Journal Article Endocrinology · March 2001 Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular m ... Full text Link to item Cite

Genomewide search for type 2 diabetes susceptibility genes in four American populations.

Journal Article Am J Hum Genet · June 2000 Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. On ... Full text Link to item Cite

Insulin and glucosamine infusions increase O-linked N-acetyl-glucosamine in skeletal muscle proteins in vivo.

Journal Article Metabolism · April 1998 O-linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslational modification of serine/threonine residues of nuclear and cytoplasmic proteins. We determined whether insulin or coinfusion of glucosamine (GlcN) with insulin alters O-GlcNAc of skelet ... Full text Link to item Cite

UDP-N-acetylglucosamine transferase and glutamine: fructose 6-phosphate amidotransferase activities in insulin-sensitive tissues.

Journal Article Diabetologia · January 1997 Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc beta-N-acetylglucosaminyltransferase (O-GlcNAc transferase) catalyses final O-linked attachment of GlcNAc to serine and threonine residue ... Full text Link to item Cite

Relationship between insulin-mediated turnover of glucosamine-labeled lipids and activity of the insulin receptor tyrosine kinase.

Journal Article Arch Biochem Biophys · November 15, 1992 We studied the effects of insulin on the turnover of glucosamine-labeled lipids in embryonic RAT fibroblasts that overexpressed either normal human insulin receptors or insulin receptors with defective tyrosine kinase domains. Fractionation of organic extr ... Full text Link to item Cite

The pathway mediating insulin's effects on pyruvate dehydrogenase bypasses the insulin receptor tyrosine kinase.

Journal Article J Biol Chem · May 15, 1991 The effect of insulin on pyruvate dehydrogenase activity was examined in two different cell types that over expressed either normal or defective human insulin receptors, RAT 1 embryonic fibroblasts and Chinese hamster ovary (CHO) cells. Insulin stimulated ... Link to item Cite

The insulinomimetic effects of the polar head group of an insulin-sensitive glycophospholipid on pyruvate dehydrogenase in both subcellular and whole cell assays.

Journal Article Arch Biochem Biophys · February 15, 1988 The polar head group that was released by treating an insulin-sensitive glycophospholipid with a phosphatidylinositol-specific phospholipase C (PI-PLC) stimulated pyruvate dehydrogenase (PDH) in both subcellular and whole cell assays. Stimulation of PDH ac ... Full text Link to item Cite

Evidence that Blastocladiella emersonii zoospore maintenance factor is a sulfhydryl group-containing cyclic ribotide.

Journal Article J Biol Chem · June 10, 1985 Blastocladiella emersonii zoospore maintenance factor (ZMF), released into the medium during zoospore production, mediates a reversible developmental block to zoospore encystment (Gottschalk, W. K., and Sonneborn, D. R. (1981) Exp. Mycol. 5, 1-14 and (1982 ... Link to item Cite

Purification of a naturally produced, low molecular weight organic factor that reversibly blocks encystment of Blastocladiella emersonii zoospores.

Journal Article J Biol Chem · June 10, 1985 The water mold Blastocladiella emersonii releases zoospore maintenance factor into the medium during zoosporogenesis. Extracellular factor mediates a reversible developmental block that maintains the motile, cell wall-less zoospore phenotype. A method for ... Link to item Cite

Intracellular mediators of insulin action.

Journal Article Diabetes Metab Rev · 1985 Full text Link to item Cite

Blastocladiella emersonii zoospore maintenance factor: A quantitative bioassay used to characterize extracellular appearance and maintenance of factor and interactions between factor, zoospores, and salt

Journal Article Experimental Mycology · January 1, 1981 A quantitative bioassay for Blastocladiella emersonii zoospore maintenance factor (ZMF) is documented analyzed. The basis of the assay is an antagonistic interaction between NaCl and ZMF; the former elicits rapid encystment in zoospore populations whereas ... Full text Cite