- Email: [email protected]
VEGFA IS ASSOCIATED WITH CEREBRAL BLOOD FLOW AND WHITE MATTER HYPERINTENSITY IN MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER'S DISEASE
P300
Poster Presentations: Sunday, July 16, 2017
clauses can clarify that data will continue to be shared and used after a loss of capacity. Where individuals are unable to consent, we clarify processes and principles governing proxy decision making. A proxy is legally and ethically bound to respect the incapable adult’s best interests, including his or her previously expressed wishes; values and beliefs; and well-being. Conclusions: By removing consent barriers to sharing, we hope to show that international collaboration in dementia research is not only possible, it is imperative.
P1-150
INVESTIGATION OF THE ASSOCIATION BETWEEN GENETIC VARIATION IN IL1RAP AND ALZHEIMER’S-RELATED CSF-BIOMARKERS
Anna Zettergren1, Silke Kern1, Ingmar Skoog1, Oskar Hansson2,3, Henrik Zetterberg4,5, Kaj Blennow6, Kina H€oglund7, 1Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of ane Gothenburg, M€ olndal, Sweden; 2Lund University, Malm€o, Sweden; 3Sk University Hospital, Malm€ o, Sweden; 4Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 5University College London, London, United Kingdom; 6Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; 7Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€ olndal, Sweden. Contact e-mail: anna.zettergren@neuro. gu.se Background: The gene IL1RAP (Interleukin-1 receptor associated protein) encodes a necessary component of the IL-1 pro-inflammatory signaling pathway. A possible involvement of this gene in the pathogenesis of Alzheimer’s disease has been suggested in GWASs of cerebrospinal fluid (CSF) tau-levels and longitudinal change in brain amyloid burden. The aim of our study was to analyse genetic variation in and near IL1RAPin relation to CSF-biomarkers of amyloid- and tangle pathology and neurodegeneration in a population consisting of cognitively normal and demented individuals. Methods: A total of 1402 individuals (cognitively normal¼749, AD-diagnosis¼653) were included in the study. Genotyping of single nucleotide polymorphisms (SNPs) in or near IL1RAP (rs3773976, rs12053868, rs3773970, rs4687151 and rs9877502) was performed using the KASPar PCR SNP genotyping system (LGC Genomics, Hoddesdon, Herts, UK), and the selection of SNPs was based on the results of previous GWASs. The relations between CSF-levels of betaamyloid (Ab42), total-tau and phospho-tau and IL1RAP-SNPs were analysed in the total sample, as well as in cognitively healthy individuals and individuals with an AD-diagnosis separately. Results: Associations between the levels of total-tau and phospho-tau and the SNP rs9877502 were found in analyses of the total sample, as well as in sub-group analyses of cognitively healthy individuals and individuals with AD, respectively. The strongest association between the SNP and tau-levels (p¼0.0004 for phospho-tau) was found in the sub-group of cognitively normal individuals. Further, nominal associations between the SNP rs4687151 and tau-levels were found in analyses of the AD sub-group. Conclusions: In this study we found associations between genetic variation in IL1RAP and CSF tau (total-tau and phospho-tau). The results support previous studies suggesting that IL1RAP may be involved in the pathogenesis of Alzheimer’s disease, although the associations found in our
study did not reach the low p-value levels described in the previous GWASs.
P1-151
VEGFA IS ASSOCIATED WITH CEREBRAL BLOOD FLOW AND WHITE MATTER HYPERINTENSITY IN MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER’S DISEASE
Emrin Horgusluoglu1,2, Kwangsik Nho1,2, Shannon L. Risacher1,2, Andrew J. Saykin1,2,3, 1Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3Indiana University Network Science Institute, Bloomington, IN, USA. Contact e-mail: [email protected] Background: Vascular endothelial growth factor (VEGF) plays a
crucial role in neuronal development, angiogenesis, homeostasis of adult vasculature as well as neurogenesis. VEGF induction increases capillary density and blood flow throughout the brain. Cerebral blood flow (CBF) is strongly related with angiogenesis. White matter hyperintensity (WMH) accumulation is one of the most important markers of cerebral small vessel disease and is correlated with amyloid burden, a known pathological hallmark of Alzheimer’s disease (AD). We investigated whether variation in the VEGFA gene, a vascular regulator that contributes to AD pathology, is specifically related to CBF and WMH on MRI. Methods: Non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort with arterial spin labeling (ASL) perfusion imaging (N¼203) and MRI-derived WMH burden (N¼788) as well as genotype data were included. A gene-based association analysis was performed by using setbased test in Plink v 1.07. Whole brain and subcortical cerebral blood flow (ml/100mg/min) extracted from ASL perfusion brain imaging were used as phenotypes. Factors known to influence CBF and WMH such as age and sex were used as covariates. An empirical p value was reported to take into account the number of significant SNPs in VEGFA. Results: VEGFA was significantly associated with whole brain cerebral blood flow (p¼0.0178, corrected) and subcortical blood flow (p¼0.018, corrected) (Table1). For the most significant SNP (rs3025035) in VEGFA, increased blood flow was associated with the dosage of the minor allele (T) (Figure 1a). In addition, individuals carrying at least one minor allele (T) of rs3002535 have lower WMH than those without the T allele (Figure 1b). Conclusions: Genetic variation in VEGFA is associated with neuroimaging markers of vascular integrity and may provide novel insights into vascular contributions to AD pathophysiology.
Figure 1. (a) Mean cerebral blood flow of each genotype group (minor allele: T) of rs3025035 in VEGFA, (b) White matter hyperintensity of each group (minor allele: T) of rs3025035 in VEGFA.
Poster Presentations: Sunday, July 16, 2017 Table 1 Gene-based association results (p-values) of VEGFA for whole brain and subcortical cerebral blood flows, where empirical p values were calculated using 20,000 permutations in PLINK
VEGFA
p-value before adjusting for DX
p-value after adjusting for DX
Whole Brain no cerebellum Subcortical no cerebellum
0.0178 0.018
0.025 0.028
P1-152
A NOVEL APP (V669L) MUTATION IN A KOREAN AD PATIENT
Eva Bagyinszky1, Vo Van Giau2,3, Kyu Hwan Shim4, Young Ho Park5, Minjung Wang5,6, Seong Soo An3,4, SangYun Kim5,7,8,9, 1Gachon University, Seongnam, Republic of South Korea; 2Department of Bionano Technology, Gachon University, Sungnam, Republic of South Korea; 3Gachon University, Seongnam, Republic of South Korea; 4Department of Bionano Technology, Gachon University, Seongnam, Republic of South Korea; 5Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam, Republic of South Korea; 6Roa Neurology Clinic, Seoungnam, Republic of South Korea; 7Seoul National University Bundang Hospital, Seoungnam, Republic of South Korea; 8Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seoungnam, Republic of South Korea; 9Seoul National University Bundang Hospital, Seongnam, Republic of South Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease is the most common form of de-
mentia two types, early onset AD (EOAD) and late onset AD (LOAD). Three main genes in EOAD are APP, PSEN1 and PSEN2, however, mutations in these genes are relatively rare. Methods: We performed standard Sanger sequencing of APP, PSEN1 and PSEN2 genes for the AD patient. 3D modeling and bioinformatics studies (SIFT, PolyPhen2) were also performed for the mutation. Results: In this study, a novel mutation in APP gene, V669L, was found in a 67 years old Korean female AD patient. Two of her family members were also carried this mutation. APP V669L was predicted as non-damaging variant by PolyPhen and SIFT tools. Conclusions: In Korea, APP mutations may be rare, since only one mutation was found in APP, V715M (V715M). APP V669L is located nearby the beta secretase cleavage site, right next to the Swedish APP (KM670/671NL) mutation. Currently, cell studies are performed on this mutation for the functional implication. We will also measure the amyloid beta 42/40 ratio.
P1-153
THE INFLUENCE OF APOE GENOTYPE ON PATTERN SEPARATION IN HUMAN DENTATE GYRUS
Hwee Ling Lee1, Verena Heise2, Daniel Brenner1, Ruediger Stirnberg1, Tony Stoecker1, Christian Montag3,4, Sonja Jung4, Nikolai Axmacher1,5, 1German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 2 University of Oxford, Oxford, United Kingdom; 3School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China; 4Institute of Psychology and Education, Ulm University, Ulm, Germany; 5Institute of
P301
Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany. Contact e-mail: [email protected] Background: The Apolipoprotein (APOE)-e4 allele is associated with an increased risk of developing Alzheimer’s disease (AD). Although the entorhinal cortex is one of the first brain areas to show AD pathology, other parts of the medial temporal lobe such as the hippocampus are relatively early affected as well [1]. The hippocampal dentate gyrus (DG), which has been linked to pattern separation, may be particularly vulnerable [2, 3]. However, it is unknown if young APOE-e4 carriers show subtle pattern separation deficits and activity alternations in the hippocampal subfields. Methods: A preliminary study of 26 healthy volunteers (13 heterozygous APOE-e4 carriers, and 13 APOE-e3 homozygotes) performed a pattern separation paradigm using repeated, similar lures and novel foil items while being scanned in a 7T Siemens MRI scanner. We manipulated 4 levels of difficulty for similar lures (lures 1-4). For each subject, t-statistics were extracted in the hippocampal subfields using SPM12. We tested for group differences (APOE-e4 carriers vs. non-carriers) in novelty and pattern separation effects. Using representational similarity analysis (RSA), we investigated the correlation between first and second presentation of trials in each condition. We hypothesized that lower correlations reflect more distinct items representations, i.e. pattern separation. Results: Behaviourally, we found that APOEe4 carriers as compared to non-carriers were less accurate in pattern separation of the most difficult lure1 items and were more likely to incorrectly label those lures as repeated items (Fig. 1A). In the fMRI data, we found a stronger novelty effect (first > repeat) in right DG of the APOE-e4 carriers as compared to non-carriers (Fig. 1Bi). We did not find any group differences for brain activity related to pattern separation (lure1 > repeat) (Fig. 1Bii). No significant differences in RSA patterns were found, due to the small sample size (Fig. 1C). Conclusions: Our analyses with a small group of participants reveal possible differences between APOE-e4 carriers and non-carriers in pattern separation in the DG and in other hippocampal subfields. References: 1. Yassa, M.A., et al., Neuroimage, 2010. 51(3): p. 1242-52. 2. Baker, S., et al., Curr Biol, 2016. 26(19): p. 2629-2634. 3. Berron, D., et al., J Neurosci, 2016. 36(29): p. 7569-79.
P1-154
APOE ε4 IS ASSOCIATED WITH HIGHER TDP-43 PROTEINOPATHY BURDEN IN ALZHEIMER’S DISEASE
Hyun-Sik Yang1,2,3, Lei Yu4,5, Charles C. White1,3, Reisa A. Sperling1,2,6,7, Philip L. De Jager1,3,8, David A. Bennett4,5, Julie A. Schneider4,5, 1Brigham and Women’s Hospital, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA; 3Broad Institute, Cambridge, MA, USA; 4Rush Alzheimer’s Disease Center, Chicago, IL, USA; 5Rush University Medical Center, Chicago, IL, USA; 6Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA; 7Massachusetts General Hospital, Boston, MA, USA; 8Columbia University Medical Center, New York, NY, USA. Contact e-mail: hyang18@ partners.org Background: TDP-43 (transactive response DNA-binding protein
43kDa) inclusion proteinopathy frequently coexists with Alzheimer’s disease (AD) pathology, and contributes to cognitive impairment in AD patients. Nonetheless, the pathophysiologic link between TDP-43 proteinopathy and AD is not well understood.
Poster Presentations: Sunday, July 16, 2017
clauses can clarify that data will continue to be shared and used after a loss of capacity. Where individuals are unable to consent, we clarify processes and principles governing proxy decision making. A proxy is legally and ethically bound to respect the incapable adult’s best interests, including his or her previously expressed wishes; values and beliefs; and well-being. Conclusions: By removing consent barriers to sharing, we hope to show that international collaboration in dementia research is not only possible, it is imperative.
P1-150
INVESTIGATION OF THE ASSOCIATION BETWEEN GENETIC VARIATION IN IL1RAP AND ALZHEIMER’S-RELATED CSF-BIOMARKERS
Anna Zettergren1, Silke Kern1, Ingmar Skoog1, Oskar Hansson2,3, Henrik Zetterberg4,5, Kaj Blennow6, Kina H€oglund7, 1Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of ane Gothenburg, M€ olndal, Sweden; 2Lund University, Malm€o, Sweden; 3Sk University Hospital, Malm€ o, Sweden; 4Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 5University College London, London, United Kingdom; 6Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; 7Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€ olndal, Sweden. Contact e-mail: anna.zettergren@neuro. gu.se Background: The gene IL1RAP (Interleukin-1 receptor associated protein) encodes a necessary component of the IL-1 pro-inflammatory signaling pathway. A possible involvement of this gene in the pathogenesis of Alzheimer’s disease has been suggested in GWASs of cerebrospinal fluid (CSF) tau-levels and longitudinal change in brain amyloid burden. The aim of our study was to analyse genetic variation in and near IL1RAPin relation to CSF-biomarkers of amyloid- and tangle pathology and neurodegeneration in a population consisting of cognitively normal and demented individuals. Methods: A total of 1402 individuals (cognitively normal¼749, AD-diagnosis¼653) were included in the study. Genotyping of single nucleotide polymorphisms (SNPs) in or near IL1RAP (rs3773976, rs12053868, rs3773970, rs4687151 and rs9877502) was performed using the KASPar PCR SNP genotyping system (LGC Genomics, Hoddesdon, Herts, UK), and the selection of SNPs was based on the results of previous GWASs. The relations between CSF-levels of betaamyloid (Ab42), total-tau and phospho-tau and IL1RAP-SNPs were analysed in the total sample, as well as in cognitively healthy individuals and individuals with an AD-diagnosis separately. Results: Associations between the levels of total-tau and phospho-tau and the SNP rs9877502 were found in analyses of the total sample, as well as in sub-group analyses of cognitively healthy individuals and individuals with AD, respectively. The strongest association between the SNP and tau-levels (p¼0.0004 for phospho-tau) was found in the sub-group of cognitively normal individuals. Further, nominal associations between the SNP rs4687151 and tau-levels were found in analyses of the AD sub-group. Conclusions: In this study we found associations between genetic variation in IL1RAP and CSF tau (total-tau and phospho-tau). The results support previous studies suggesting that IL1RAP may be involved in the pathogenesis of Alzheimer’s disease, although the associations found in our
study did not reach the low p-value levels described in the previous GWASs.
P1-151
VEGFA IS ASSOCIATED WITH CEREBRAL BLOOD FLOW AND WHITE MATTER HYPERINTENSITY IN MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER’S DISEASE
Emrin Horgusluoglu1,2, Kwangsik Nho1,2, Shannon L. Risacher1,2, Andrew J. Saykin1,2,3, 1Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3Indiana University Network Science Institute, Bloomington, IN, USA. Contact e-mail: [email protected] Background: Vascular endothelial growth factor (VEGF) plays a
crucial role in neuronal development, angiogenesis, homeostasis of adult vasculature as well as neurogenesis. VEGF induction increases capillary density and blood flow throughout the brain. Cerebral blood flow (CBF) is strongly related with angiogenesis. White matter hyperintensity (WMH) accumulation is one of the most important markers of cerebral small vessel disease and is correlated with amyloid burden, a known pathological hallmark of Alzheimer’s disease (AD). We investigated whether variation in the VEGFA gene, a vascular regulator that contributes to AD pathology, is specifically related to CBF and WMH on MRI. Methods: Non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort with arterial spin labeling (ASL) perfusion imaging (N¼203) and MRI-derived WMH burden (N¼788) as well as genotype data were included. A gene-based association analysis was performed by using setbased test in Plink v 1.07. Whole brain and subcortical cerebral blood flow (ml/100mg/min) extracted from ASL perfusion brain imaging were used as phenotypes. Factors known to influence CBF and WMH such as age and sex were used as covariates. An empirical p value was reported to take into account the number of significant SNPs in VEGFA. Results: VEGFA was significantly associated with whole brain cerebral blood flow (p¼0.0178, corrected) and subcortical blood flow (p¼0.018, corrected) (Table1). For the most significant SNP (rs3025035) in VEGFA, increased blood flow was associated with the dosage of the minor allele (T) (Figure 1a). In addition, individuals carrying at least one minor allele (T) of rs3002535 have lower WMH than those without the T allele (Figure 1b). Conclusions: Genetic variation in VEGFA is associated with neuroimaging markers of vascular integrity and may provide novel insights into vascular contributions to AD pathophysiology.
Figure 1. (a) Mean cerebral blood flow of each genotype group (minor allele: T) of rs3025035 in VEGFA, (b) White matter hyperintensity of each group (minor allele: T) of rs3025035 in VEGFA.
Poster Presentations: Sunday, July 16, 2017 Table 1 Gene-based association results (p-values) of VEGFA for whole brain and subcortical cerebral blood flows, where empirical p values were calculated using 20,000 permutations in PLINK
VEGFA
p-value before adjusting for DX
p-value after adjusting for DX
Whole Brain no cerebellum Subcortical no cerebellum
0.0178 0.018
0.025 0.028
P1-152
A NOVEL APP (V669L) MUTATION IN A KOREAN AD PATIENT
Eva Bagyinszky1, Vo Van Giau2,3, Kyu Hwan Shim4, Young Ho Park5, Minjung Wang5,6, Seong Soo An3,4, SangYun Kim5,7,8,9, 1Gachon University, Seongnam, Republic of South Korea; 2Department of Bionano Technology, Gachon University, Sungnam, Republic of South Korea; 3Gachon University, Seongnam, Republic of South Korea; 4Department of Bionano Technology, Gachon University, Seongnam, Republic of South Korea; 5Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam, Republic of South Korea; 6Roa Neurology Clinic, Seoungnam, Republic of South Korea; 7Seoul National University Bundang Hospital, Seoungnam, Republic of South Korea; 8Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seoungnam, Republic of South Korea; 9Seoul National University Bundang Hospital, Seongnam, Republic of South Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease is the most common form of de-
mentia two types, early onset AD (EOAD) and late onset AD (LOAD). Three main genes in EOAD are APP, PSEN1 and PSEN2, however, mutations in these genes are relatively rare. Methods: We performed standard Sanger sequencing of APP, PSEN1 and PSEN2 genes for the AD patient. 3D modeling and bioinformatics studies (SIFT, PolyPhen2) were also performed for the mutation. Results: In this study, a novel mutation in APP gene, V669L, was found in a 67 years old Korean female AD patient. Two of her family members were also carried this mutation. APP V669L was predicted as non-damaging variant by PolyPhen and SIFT tools. Conclusions: In Korea, APP mutations may be rare, since only one mutation was found in APP, V715M (V715M). APP V669L is located nearby the beta secretase cleavage site, right next to the Swedish APP (KM670/671NL) mutation. Currently, cell studies are performed on this mutation for the functional implication. We will also measure the amyloid beta 42/40 ratio.
P1-153
THE INFLUENCE OF APOE GENOTYPE ON PATTERN SEPARATION IN HUMAN DENTATE GYRUS
Hwee Ling Lee1, Verena Heise2, Daniel Brenner1, Ruediger Stirnberg1, Tony Stoecker1, Christian Montag3,4, Sonja Jung4, Nikolai Axmacher1,5, 1German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 2 University of Oxford, Oxford, United Kingdom; 3School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China; 4Institute of Psychology and Education, Ulm University, Ulm, Germany; 5Institute of
P301
Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany. Contact e-mail: [email protected] Background: The Apolipoprotein (APOE)-e4 allele is associated with an increased risk of developing Alzheimer’s disease (AD). Although the entorhinal cortex is one of the first brain areas to show AD pathology, other parts of the medial temporal lobe such as the hippocampus are relatively early affected as well [1]. The hippocampal dentate gyrus (DG), which has been linked to pattern separation, may be particularly vulnerable [2, 3]. However, it is unknown if young APOE-e4 carriers show subtle pattern separation deficits and activity alternations in the hippocampal subfields. Methods: A preliminary study of 26 healthy volunteers (13 heterozygous APOE-e4 carriers, and 13 APOE-e3 homozygotes) performed a pattern separation paradigm using repeated, similar lures and novel foil items while being scanned in a 7T Siemens MRI scanner. We manipulated 4 levels of difficulty for similar lures (lures 1-4). For each subject, t-statistics were extracted in the hippocampal subfields using SPM12. We tested for group differences (APOE-e4 carriers vs. non-carriers) in novelty and pattern separation effects. Using representational similarity analysis (RSA), we investigated the correlation between first and second presentation of trials in each condition. We hypothesized that lower correlations reflect more distinct items representations, i.e. pattern separation. Results: Behaviourally, we found that APOEe4 carriers as compared to non-carriers were less accurate in pattern separation of the most difficult lure1 items and were more likely to incorrectly label those lures as repeated items (Fig. 1A). In the fMRI data, we found a stronger novelty effect (first > repeat) in right DG of the APOE-e4 carriers as compared to non-carriers (Fig. 1Bi). We did not find any group differences for brain activity related to pattern separation (lure1 > repeat) (Fig. 1Bii). No significant differences in RSA patterns were found, due to the small sample size (Fig. 1C). Conclusions: Our analyses with a small group of participants reveal possible differences between APOE-e4 carriers and non-carriers in pattern separation in the DG and in other hippocampal subfields. References: 1. Yassa, M.A., et al., Neuroimage, 2010. 51(3): p. 1242-52. 2. Baker, S., et al., Curr Biol, 2016. 26(19): p. 2629-2634. 3. Berron, D., et al., J Neurosci, 2016. 36(29): p. 7569-79.
P1-154
APOE ε4 IS ASSOCIATED WITH HIGHER TDP-43 PROTEINOPATHY BURDEN IN ALZHEIMER’S DISEASE
Hyun-Sik Yang1,2,3, Lei Yu4,5, Charles C. White1,3, Reisa A. Sperling1,2,6,7, Philip L. De Jager1,3,8, David A. Bennett4,5, Julie A. Schneider4,5, 1Brigham and Women’s Hospital, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA; 3Broad Institute, Cambridge, MA, USA; 4Rush Alzheimer’s Disease Center, Chicago, IL, USA; 5Rush University Medical Center, Chicago, IL, USA; 6Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA; 7Massachusetts General Hospital, Boston, MA, USA; 8Columbia University Medical Center, New York, NY, USA. Contact e-mail: hyang18@ partners.org Background: TDP-43 (transactive response DNA-binding protein
43kDa) inclusion proteinopathy frequently coexists with Alzheimer’s disease (AD) pathology, and contributes to cognitive impairment in AD patients. Nonetheless, the pathophysiologic link between TDP-43 proteinopathy and AD is not well understood.