Kinga Szigeti MD, PhD

Kinga Szigeti

Kinga Szigeti
MD, PhD

Associate Professor
Director of the Alzheimer‘s Disease and Memory Disorders Center

Department of Neurology

Jacobs School of Medicine & Biomedical Sciences


Specialty/Research Focus

Alzheimer Disease / Memory Disorders; Genomics and proteomics; Immunology; Ion channel kinetics and structure; Molecular genetics; Neurobiology; Neurology; Stem Cells

Contact Information
Dept. of Neurology
Jacobs School of Medicine and Biomedical Sciences
1001 Main St., 4th floor
Buffalo, New York 14203
Phone: (716) 323-0556
Fax: (716) 323-0595
szigeti@buffalo.edu


Patient Care

This faculty member is affiliated with UBMD, practicing physicians who are also professors in the Jacobs School.

View this physician on UBMD


Professional Summary:

I am a board-certified neurologist with specialty training in genetics and cognitive disorders, and I direct the Alzheimer’s Disease and Memory Disorders Center and Translational Genomics Research Laboratory, state-of-the-art facilities specializing in cognitive disorders.

Our clinical mission is to provide compassionate, state-of-the-art care for patients and families affected by Alzheimer disease (AD) and other cognitive disorders. Our multidisciplinary approach includes a team of neurologists, neuropsychologists, neuroimagers, social workers and nurses dedicated to the needs of our patients and their caregivers.

Our research mission is to employ genetic tools to identify novel risk factors and potential pathways that can be targeted with medications to prevent or modify the course of AD. Our focus is translating discoveries made in the laboratory into improved methods of disease prevention, diagnosis, and treatment.

AD is a progressive neurodegenerative disease with high prevalence imposing a substantial public health problem. The heritability of AD is estimated at 60-80 %, forecasting a potential for using genetic biomarkers for risk stratification in the future. The main risk factor of late-onset AD is the APOE4 allele with a population attributable fraction of 0.2-0.3. Several large scale genome-wide association studies (GWAS) using high frequency variants identified nine additional loci with a combined population attributable fraction of 0.31. My laboratory focuses on finding the missing heritability using copy number variation as a genetic marker map.

The research focus of my laboratory is to characterize the contribution of CNVs to the genetic architecture
of AD to develop genetic biomarkers for risk stratification.

1. We performed 3 CNV-GWAS analyses in the Texas Alzheimer Research Consortium dataset (N=600, 400 AD nd 200 normal controls) using quantitative endophenotypes and detected replicable signals (Table). For eplication, we performed locus specific analyses of the ADNI, NIA-LOAD and TGEN datasets. We detected 19 association signals in the 3 studies which survived multiple testing correction using the FDR approach. These CNV events were between 3-25 kb with an allele frequency of 0.3-1.7% and all of them have been reported in the database of Genomic Variants.
a. Shaw, C.A., Y. Li, J. Wiszniewska, S. Chasse, S.N. Zaidi, W. Jin, B. Dawson, K. Wilhelmsen, J.R. Lupski, J.W. Belmont, R.S. Doody, and K. Szigeti, Olfactory copy number association with age at onset of Alzheimer disease. Neurology, 2011. 76(15): p. 1302-9.
b. Li, Y., C.A. Shaw, I. Sheffer, N. Sule, S.Z. Powell, B. Dawson, S.N. Zaidi, K.L. Bucasas, J.R. Lupski, K.C. Wilhelmsen, R. Doody, and K. Szigeti, Integrated copy number and gene expression analysis detects a CREB1 association with Alzheimer's disease. Transl Psychiatry, 2012. 2: p. e192.
c. Szigeti, K., D. Lal, Y. Li, R.S. Doody, K. Wilhelmsen, L. Yan, S. Liu, and C. Ma, Genome-wide scan for copy number variation association with age at onset of Alzheimer's disease. J Alzheimers Dis, 2013. 33(2): p. 517-23.
d. Szigeti, K., B. Kellermayer, J.M. Lentini, B. Trummer, D. Lal, R.S. Doody, L. Yan, S. Liu, and C. Ma, Ordered subset analysis of copy number variation association with age at onset of Alzheimer's disease. J Alzheimers Dis, 2014. 41(4): p. 1063-71.

2. Functional validation of the associated CNVs occurred as a natural extension of the GWAS studies. The first signal was detected from CHRFAM7A CNV association. As CHRFAM7A is a human specific fusion gene harboring part of the a7 nicotinic acetylcholine receptor (a7 nAChR) and gets incorporated into the receptor pentamer. The a7 nAChR has been a promising target for diseases affecting cognition and higher cortical functions, however the effect observed in animal models failed to translate into human clinical trials identifying a translational gap. CHRFAM7A is human specific and, as such, the CHRFAM7A effect was not accounted for in preclinical studies. Understanding the functional impact of CHRFAM7A may offer novel approaches to explore a7 nAChR as a drug target.
a. Ihnatovych I, Lew A, Lazar E, Sheng A, Kellermayer T, Szigeti K. Timing of Wnt Inhibition Modulates Directed Differentiation of Medial Ganglionic Eminence Progenitors from Human Pluripotent Stem Cells. Stem Cells Int. 018 June; 27;2018:3983090
b. Ihnatovych I, Nayak TK, Ouf A, Sule N, Birkaya B, Chaves L, et al. iPSC model of CHRFAM7A effect on alpha7 nicotinic acetylcholine receptor function in the human context. Transl Psychiatry. 2019;9(1):59.
c. Szigeti K, Ihnatovych I, Birkaya B, Chen Z, Ouf A, Indurthi DC, Bard JE, Kann J, Adams A, Chaves L, Sule N, Reisch JS, Pavlik V, Benedict RHB, Auerbach A, Wilding G. CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease. EBioMedicine. 2020 Sep;59:102892.
d. Ihnatovych I, Birkaya B, Notari E, Szigeti K. iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer's Disease. Int J Mol Sci. 2020 Dec 18;21(24).

3. We completed a K23 translational project using olfactory deficit and olfactory genotype as biomarkers to predict conversion form aMCI to AD and differentiate it from normal aging. We found that odor identification deficit is different in aging and Alzheimer’s disease. The key observations are: i) enantiomers (mirror image of the same chemical structure) are differentially affected by aging and AD/aMCI, ii) AD associated OID reflects right mesial temporal involvement, and iii) there is a loss of OR copy number during aging.
a. Hagemeier, J., M.R. Woodward, U.A. Rafique, K. Szigeti, Odor identification deficit in mild cognitive impairment and Alzheimer's disease is associated with hippocampal and deep gray matter atrophy. Psychiatry Res, 2016. 255: p. 87-93.
b. Woodward, M.R., M.G. Dwyer, N. Bergsland, J. Hagemeier, R. Zivadinov, R.H. Benedict and K. Szigeti, Olfactory identification deficit predicts white matter tract impairment in Alzheimer's disease. Psychiatry Res Neuroimaging, 2017. 266: p. 90-95.
c. Woodward, M.R., C.V. Amrutkar, H.C. Shah, R.H. Benedict, S. Rajakrishnan, R.S. Doody, L. Yan and K. Szigeti, Validation of olfactory deficit as a biomarker of Alzheimer disease. Neurol Clin Pract, 2017. 7(1): p. 5-14.
d. Woodward, M.R., Hafeez, M.U., Qi, Q., Riaz, A., Benedict, R.H., Li, Y., and Szigeti, K., Odorant item specific olfactory identification deficit may differentiate Alzheimer’s disease from aging. Am J Geriatr Psychiatry. 2018 Aug;26(8):835-846.

Education and Training:

  • PhD, Clinical Neuroscience, University of Szeged, Hungary, Summa Cum Laude (2006)
  • Sabbatical, Medical Officer, Richter Gedeon Pharmaceutical PLC BPSE: RICHTER (2006)
  • Fellowship, Molecular and Human Genetics Fellowship, Baylor College of Medicine (2004)
  • Residency, Neurology Residency, University at Buffalo (2002)
  • Fellowship, Postdoctoral fellowship, Harvard Medical School (1998)
  • MD, Medicine, University of Pecs, Hungary, Summa Cum Laude (1994)

Employment:

  • Professor, Neurology, University at Buffalo (2020–2021)
  • Associate Professor of Neurology, Neurology, University at Buffalo Jacobs School of Medicine & Biomedical Sciences (2015–2020)
  • Assistant Professor of Neurology, Neurology, University at Buffalo Jacobs School of Medicine & Biomedical Sciences (2010–2014)
  • Assistant Professor of Neurology and Molecular and Human Genetics, Neurology, Molecular and Human Genetics, Baylor College of Medicine Baylor College of Medicine (2006–2010)
  • Texas Alzheimer Research Consortium, Genetics Subcommittee, Baylor College of Medicine (2005–2010)

Research Expertise:

  • Alzheimer’s disease and memory disorders: CHRFAM7A, a uniquely human fusion gene between CHRNA7 and FAM7A/ULK1, modifies ?7 nAChR function. While it inferred a selective advantage during evolution, it also increased disease susceptibility in an ?7 nAChR localization pattern. Mechanistic insights into CHRFAM7A function on neuroinflammation and neurodegeneration will identify novel targetable pathways with therapeutic and translational promise for AD.
  • Cholinergic anti-inflammatory system: The cholinergic anti-inflammatory response is a neuronal-immune interface, where the nervous system regulates immune function through a neurotransmitter. The very nature of the interaction between two separate biological systems historically required in vivo studies in animal models and these experiments represent the foundation of our current understanding. Evidence form animal models indicates that the cholinergic modulation is i) anti-inflammatory and ii) is mediated by the ?7 nAChR. Over the last decade extensive basic science, preclinical and human clinical research on ?7 nAChR revealed one of the most consistent translational gaps. What may be the cause of the ?7 nAChR animal to human dichotomy? CHRFAM7A is one of the duplicate genes that have emerged since the human–chimpanzee divergence thus has the potential to contribute to human-specific traits. CHRFAM7A can integrate into the ?7 nAChR pentamer and is a putative negative regulator of the receptor. CHRFAM7A alleles underwent strong positive selection and are present in 99.7% of the human population. Further complexities include that CHRFAM7A alleles are present in direct and inverted orientation and likely represent distinct mechanisms of action. Of note, direct and inverted allele frequencies predict a 75-25% human population split for CHRFAM7A direct and inverted allele related effects projecting profound translational significance.

Research Centers:

  • Clinical and Translational Research Center (CTRC)
  • Jacobs Neurological Institute

UB 2020 Strategic Strengths:

  • Health and Wellness Across the Lifespan

Grants and Sponsored Research:

  • July 2019–July 2024
    Buffalo Clinical and Translational Research Center
    NIH/NCATS
    Role: Co-Investigator
  • July 2015–July 2021
    New York State Center of Excellence for Alzheimer’s
    NYS DOH
    Role: Co-Principal Investigator
  • July 2013–July 2021
    iPSC model for the mechanism of Alzheimer’s Disease
    Edward A. and Stephanie E. Fial Fund
    Role: Principal Investigator
  • July 2019–July 2020
    D43 AdminSuppl: Alzheimer’s Disease and Related Dementias Research Training
    NIH
    Role: Co-Investigator
  • September 2010–August 2015
    Olfactory Receptor copy number variation association with age at onset of Alzheimer disease
    NIA
    Role: Principal Investigator
    $853,565
  • December 2010–November 2012
    Copy number variation genome wide association with age at onset of Alzheimer disease
    Alzheimer Association
    Role: Principal Investigator
    $88,000

Journal Articles:

See all (42 more)

Service Activities:

  • Alzheimer‘s Disease and memory Disorders Center The Alzheimer’s Disease and Memory Disorders Center at the University at Buffalo, SUNY is a state of the art center specializing in cognitive disorders. Our mission is to provide compassionate, state of the art care for patients and families affected by Alzheimer disease and other cognitive disorders. We have a multidisciplinary approach with a team of professionals caring for the patients and families. The team includes neurologists, neuropsychologists, neuroimagers, social worker and nursing to address all the needs of the patients and caregivers. The Center is headed by Kinga Szigeti, M.D., Ph.D., a board-certified neurologist with specialty training in genetics and cognitive disorders. We have a research program using genetic tools to identify novel risk factors and potential pathways that can be targeted with medications to prevent or modify the course of Alzheimer disease. Our focus is on the translation of discoveries made in the laboratory into improved methods of disease prevention, diagnosis, and treatment.; Director (2011–present)
  • Alzheimer Association;; Grant Reviewer (2008–present)

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Contact Information

Dept. of Neurology
Jacobs School of Medicine and Biomedical Sciences
1001 Main St., 4th floor
Buffalo, New York 14203
Phone: (716) 323-0556
Fax: (716) 323-0595
szigeti@buffalo.edu

This faculty member is affiliated with UBMD, practicing physicians who are also professors in the Jacobs School.

View this physician on UBMD