Director of the Alzheimer‘s Disease and Memory Disorders Center
Alzheimer Disease / Memory Disorders; Genomics and proteomics; Immunology; Ion channel kinetics and structure; Molecular genetics; Neurobiology; Neurology; Stem Cells
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.