- Email: [email protected]
3 GENOTYPE
P1146 P4-293
Poster Presentations: Wednesday, July 27, 2016 APOE–TOMM40 ‘523 HAPLOTYPES AND THE RISK OF ALZHEIMER’S DISEASE IN OLDER CAUCASIAN AND AFRICAN AMERICANS
Lei Yu1, Michael W. Lutz2, Robert S. Wilson1, Daniel K. Burns3, Allen D. Roses4,5, Ann M. Saunders2, Philip L. De Jager6,7,8, Lisa L. Barnes1, David A. Bennett1, 1Rush Alzheimer’s Disease Center, Chicago, IL, USA; 2Duke University School of Medicine, Durham, NC, USA; 3Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; 4Duke University Medical Center, Durham, NC, USA; 5Zinfandel Pharmaceuticals, Inc., Chapel Hill, NC, USA; 6Broad Institute, Cambridge, MA, USA; 7Brigham and Women’s Hospital, Boston, MA, USA; 8Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: Pattern of allele linkage between the Apolipoprotein E (APOE) ε4 polymorphism and a poly-T polymorphism in the adjacent gene, TOMM40 ‘523, differs between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE-TOMM40‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Methods: Data came from three community
based cohort studies of diverse participants. APOE genotypes are directly determined by the polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes are defined by the length of the poly-T stretch of rs10524523 (short [‘523-S]: poly-T 19, long [‘523-L]: 20 poly-T 29, and very long [‘523-VL]: poly-T 30). The linkage between APOE and TOMM40‘523 were compared between Caucasian and African Americans. Cox proportional hazard models examined the variants effect on the risk of incident AD. Results: 1,848 Caucasian and 540 African American individuals were included. In Caucasians, 99.2% of the ε2 or ε3 carriers did not have ‘523-L, whereas 94.2% of the ε4 carriers had ‘523-L. The classification was highly concordant (k ¼0.94). ε4 doubled the risk of incident AD (HR¼1.924, p<0.0001), so did ‘523-L (HR¼1.975, p<0.0001). The dose effects were observed for both variants. In African Americans, ‘523-L was also absent from the majority of the ε2 or ε3 carriers (98.9%), but the frequency distribution of the ‘523 genotypes differed from Caucasians (p<0.0001). Further, ‘523-L was present in only 47.8% of the ε4 carriers. Thus, the concordance dropped by almost half (k ¼0.53) compared with Caucasians. In relation to incident AD, the effect of ε4 was driven by the ε4/4 homozygotes (HR¼6.317, p<0.0001). Separately, those with ‘523-L heterozygosity had increased risk of AD (HR¼2.213, p¼0.011). Conclusions: In Caucasians, almost all APOE ε4 carriers had the TOMM40 ’523-L variant and the effects of ’523-L and ε4 on incident AD were comparable, supporting a strong linkage between ε4’523-L haplotype and AD. In African Americans, less than half of the ε4 carriers had ’523-L and the effect patterns of ε4 and ’523-L on AD differed from Caucasians.
P4-294
IDENTIFICATION OF GENOME-WIDE SIGNIFICANT ASSOCIATIONS IN THE ALZHEIMER’S DISEASE SEQUENCING PROJECT DOMINICAN FAMILIES WITH VARIANTS IN UGT2B28, AXIN2, SYCE1, BCAT1, FAM13A, AND DQ594761
Antonio Parrado, Janssen Pharmaceutical, Research & Development, Spring House, PA, USA. Contact e-mail: [email protected] Background: To identify novel genetic variants contributing to increased risk or protection against developing Alzheimer’s disease
(AD) among Caribbean Hispanic and Caucasian families. Methods: We preformed family-based association tests (FBAT) to identify an over or under-transmission of alleles among affected offspring that deviate from the expected distribution, derived using Mendel’s law of segregation, using the Alzheimer’s Disease Sequencing Project (ADSP – discovery phase) whole-genome sequence (WGS) cohort consisting of 84 highly informative multiplex families. We studied the WGS data of 362 AD diagnosed patients and 68 unaffected relatives, the largest proportion (n¼67) of families self-reported from Dominican Hispanic ancestry (the first of the six consent groups from the ADSP Study). Results: We identified six variants located in the intronic or promoter region of six genes (UGT2B28, AXIN2, SYCE1, BCAT1, FAM13A and DQ594761) that achieved a genome-wide level of statistical significant association (FBAT P < 5x10-8) with Alzheimer’s disease diagnosis. Additionally, we identified six variants in or near six genes (POU6F1, NRG3, SLITRK1, SMIM15, AC092684.1, and RP11-986E7.2) with a suggestive level of statistical significant association (FBAT P < 1x10-6) with AD diagnosis. Conclusions: Interestingly, UGT2B28, SLITRK1, AXIN2, BCAT1, and NRG3 are expressed in the brain (i.e. hippocampus, glial cells, and ganglion), furthermore, NRG3 and SLITRK1 have been associated with neurological diseases (Schizophrenia and Tourette’s, respectively). Axin2 plays an important role in the Wnt/Hedgehog/Notch signaling pathway, in concert with PSEN1 and PSEN2. Neuregulin 3 (NRG3) is involved in the nuclear signaling pathway through ErbB4 with PSEN2. Noteworthy, similar to APP and PICALM, SLITRK1 (SLIT And NTRK-Like Family, Member 1) plays a role in Axonogenesis.
P4-295
TOMM40 ‘523 VARIANT AND COGNITIVE DECLINE IN COMMUNITY BASED OLDER PERSONS WITH APOE E3/3 GENOTYPE
Lei Yu1, Michael W. Lutz2, Robert S. Wilson1, Daniel K. Burns3, Allen D. Roses4,5, Ann M. Saunders2, Philip L. De Jager6,7,8, Lisa L. Barnes1, David A. Bennett1, 1Rush Alzheimer’s Disease Center, Chicago, IL, USA; 2Duke University School of Medicine, Durham, NC, USA; 3Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; 4Duke University Medical Center, Durham, NC, USA; 5Zinfandel Pharmaceuticals, Inc., Chapel Hill, NC, USA; 6Broad Institute, Cambridge, MA, USA; 7Brigham and Women’s Hospital, Boston, MA, USA; 8Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: The Apolipoprotein E (APOE) polymorphism is the
best known genetic risk factor for late-onset Alzheimer’s disease (AD). Recent data suggest that a poly-T variant (‘523) in the adjacent TOMM40 gene represents a more informative signal in predicting age of AD onset. We interrogated the ‘523 variant in older persons with homozygous APOE ε3/3 genotype for associations with longitudinal cognitive decline. Methods: Data came from two cohort studies of aging and dementia in which participants underwent annual clinical evaluations for up to 21 years. The ‘523 genotypes were determined based on the length variation of the poly-T stretch of the rs10524523 polymorphism. Linear mixed models compared the rates of decline in global cognition and five cognitive domains by the ‘523 genotypes. Results: All 1,170 APOE ε3/3 homozygotes were of European ancestry, free of dementia at baseline, and had an average age of 78.5 years. Three major genotypes at the ‘523 variant were linked to APOE ε3/3, 26.5% had 2 short poly-Ts (S/S), 48.9% had 1 short and 1 very long poly-Ts (S/VL) and 24.0%
Poster Presentations: Wednesday, July 27, 2016
had 2 very long poly-Ts (VL/VL). Longitudinal data analyses show that subjects with ‘523-S/S had faster decline in global cognition than subjects with ‘523-S/VL (p¼.002) or ‘523-VL/VL (p¼.030). The same association was observed in episodic memory (p¼.0004 for ‘523-S/VL and p¼.010 for ‘523-VL/VL) and semantic memory (p¼.002 for ‘523-S/VL and p¼.050 for ‘523-VL/VL), but not significant (all ps>.05) in working memory, processing speed or visuospatial ability. Conclusions: Our data reveal an association of the APOE ε3/3-TOMM40 ‘523 haplotypes with cognitive decline in community based older persons, such that the VL poly-T at the TOMM40 ‘523 locus is related to less decline, primarily in episodic and semantic memory.
P4-296
CEREBRAL AMYLOID-b AND GAIT SPEED IN OLDER ADULTS WITHOUT DEMENTIA: INFLUENCE OF COGNITION AND APOE-E4 GENOTYPE
Neelesh K. Nadkarni1, Subashan Perera1, Beth E. Snitz1, Julie Price1, Chester Mathis1, William E. Klunk1, Jeff Williamson2, Steven DeKosky3, Oscar L. Lopez1, 1University of Pittsburgh, Pittsburgh, PA, USA; 2Wake Forest Baptist Health, Winston Salem, NC, USA; 3University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected] Background: We studied the cross-sectional association between
global and regional amyloid-beta (Ab) deposition and gait speed in dementia-free older adults and examined the influence of cognition and APOE-ε4 genotype on this relationship. Methods: In 183 older adults without dementia (mean age: 86 years) enrolled at the Pittsburgh site of the Ginkgo Evaluation of Memory (GEM) study that included 144 cognitively normal (CN) older adults (mean age: 85 years), we obtained gait assessments concurrent with Ab-imaging. We measured Ab on Pittsburgh B (PiB) PET, gait speed over 15-feet and general cognitive abilities on the Mini-mental Status Examination (MMSE). We grouped participants into high-Ab [PiB(+)] and low-Ab [PiB(-)] on standardized global PiB cutoffs and examined group differences. We studied the influence of MMSE and APOE-ε4 on the association between gait speed and Ab in the full sample and in the sample restricted to CN individuals adjusting for covariates (age, sex, education, body weight, hypertension, coronary heart disease, stroke/TIA and, hippocampal volume and small-vessel disease burden on MRI). Results: PiB(+) were comparable to PiB(-) individuals on demographics, comorbidities, hippocampal volume and smallvessel disease but not on gait speed (0.85 vs 0.92 m/sec, p¼0.012) or proportion of APOE ε4 carriers (32% vs 6%, p<0.001). In the whole sample, the association between global PiB retention and slower gait withstood adjustment for covariates (p¼0.026) but was attenuated by MMSE (p¼0.056) and APOE ε4 status (p¼0.095). In the CN subsample, the adjusted association between global PiB retention and slow gait (p¼0.042) did not withstand further correction for MMSE or APOE-ε4 (both p>0.1). The regional associations between gait speed and PiB uptake was limited to temporal, occipital and motor cortices while those in frontal, striatal, precuneus and parietal areas were rendered statistically non-significant by APOE-ε4 in both samples. Conclusions: Cortical Ab deposition is associated with slower gait speed in older adults without dementia; however, this association is weaker when the sample is restricted to cognitively normal older adults and, tends to persist but is attenuated by cognition and APOE-ε4 genotype.
P4-297
P1147
SEX DIFFERENCES IN AMYLOID BETA COLOCALIZATION WITH TYROSINE HYDROXYLASE IN THE LOCUS COERULEUS AND WITH DOPAMINE BETA HYDROXYLASE IN THE INFRALIMBIC MEDIAL PREFRONTAL CORTEX OF MICE WITH FOREBRAIN SPECIFIC OVEREXPRESSION OF CORTICOTROPIN RELEASING FACTOR
Jennifer A. Ross1, Beverly A. S. Reyes1, Victoria Risbrough2, Rita J. Valentino3, Elisabeth J. Van Bockstaele1, 1Drexel University, College of Medicine, Philadelphia, PA, USA; 2University of California, San Diego, CA, USA; 3The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: The LC-NE system is critically involved in memory and cognitive processes, is highly responsive to stress-related stimuli, and via its global projections, facilitates large-scale changes in the brain environment. Stress is a risk factor for developing AD, and is supported by multiple clinical and preclinical studies demonstrating that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and accumulation of the amyloid beta (Ab) peptide. Stress-induced activation of the LC is mediated by corticotropin releasing factor (CRF) and CRF receptors exhibit sex-biased stress signaling. In support of this, sex differences have been described in the neurochemical, morphological and molecular regulation of LC neurons by CRF, providing a compelling basis for vulnerability of females to stress-related disorders such as AD. Methods: In the present study, we examined the cellular substrates for interactions between Ab and tyrosine hydroxylase (TH) a marker of noradrenergic somatodendritic processes in the LC, and dopamine-b-hydroxylase (DbH), a marker of noradrenergic terminals in the infralimbic medial prefrontal cortex (ILmPFC) in mice conditionally overexpressing CRF in the forebrain (CRF OE) under a Doxycycline (DOX) regulated tetO promoter. Results: Preliminary immunofluorescence data show co-localization of Ab and TH in somatodendritic processes of the LC. Using high resolution immunoelectron microscopy, semi-quantitative preliminary analysis revealed that 42.9% (51/ 119) of TH-containing somatodendritic processes also exhibited Ab-immunogold silver particles in DOX treated males, compared to 32.4% (92/284) in male transgenic littermate untreated controls and 61.6% (151/245) TH-containing somatodendritic processes also exhibited Ab-immunogold silver particles in DOX treated females compared to 34.4% (21/61) in female transgenic littermate untreated controls. Ab also co-localized with DbH in the ILmPFC of CRF OE mice, showing a trend in which Ab is preferentially localized to DbH containing terminals in females. Conclusions: The semi-quantitative preliminary results of immunoelectron microscopy experiments in male and female CRF OE mice indicate a trend towards increased Ab in TH labeled somatodendritic processes of the LC and DbH labeled terminals of the ILmPFC, and that these increases may be exaggerated in females.
P4-298
MEPRIN b IS ASSOCIATED WITH FORMATION OF PYROGLUTAMATE-MODIFIED Ab PEPTIDES
Stephan Schilling1, Dagmar Schlenzig1, Holger Cynis1, Maike HartlageR€ubsamen2, Steffen Rossner2, Hans-Ulrich Demuth1, 1Fraunhofer Institute for Cell Therapy and Immunology, Halle, Germany; 2Paul-Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. Contact e-mail: [email protected]
Poster Presentations: Wednesday, July 27, 2016 APOE–TOMM40 ‘523 HAPLOTYPES AND THE RISK OF ALZHEIMER’S DISEASE IN OLDER CAUCASIAN AND AFRICAN AMERICANS
Lei Yu1, Michael W. Lutz2, Robert S. Wilson1, Daniel K. Burns3, Allen D. Roses4,5, Ann M. Saunders2, Philip L. De Jager6,7,8, Lisa L. Barnes1, David A. Bennett1, 1Rush Alzheimer’s Disease Center, Chicago, IL, USA; 2Duke University School of Medicine, Durham, NC, USA; 3Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; 4Duke University Medical Center, Durham, NC, USA; 5Zinfandel Pharmaceuticals, Inc., Chapel Hill, NC, USA; 6Broad Institute, Cambridge, MA, USA; 7Brigham and Women’s Hospital, Boston, MA, USA; 8Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: Pattern of allele linkage between the Apolipoprotein E (APOE) ε4 polymorphism and a poly-T polymorphism in the adjacent gene, TOMM40 ‘523, differs between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE-TOMM40‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Methods: Data came from three community
based cohort studies of diverse participants. APOE genotypes are directly determined by the polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes are defined by the length of the poly-T stretch of rs10524523 (short [‘523-S]: poly-T 19, long [‘523-L]: 20 poly-T 29, and very long [‘523-VL]: poly-T 30). The linkage between APOE and TOMM40‘523 were compared between Caucasian and African Americans. Cox proportional hazard models examined the variants effect on the risk of incident AD. Results: 1,848 Caucasian and 540 African American individuals were included. In Caucasians, 99.2% of the ε2 or ε3 carriers did not have ‘523-L, whereas 94.2% of the ε4 carriers had ‘523-L. The classification was highly concordant (k ¼0.94). ε4 doubled the risk of incident AD (HR¼1.924, p<0.0001), so did ‘523-L (HR¼1.975, p<0.0001). The dose effects were observed for both variants. In African Americans, ‘523-L was also absent from the majority of the ε2 or ε3 carriers (98.9%), but the frequency distribution of the ‘523 genotypes differed from Caucasians (p<0.0001). Further, ‘523-L was present in only 47.8% of the ε4 carriers. Thus, the concordance dropped by almost half (k ¼0.53) compared with Caucasians. In relation to incident AD, the effect of ε4 was driven by the ε4/4 homozygotes (HR¼6.317, p<0.0001). Separately, those with ‘523-L heterozygosity had increased risk of AD (HR¼2.213, p¼0.011). Conclusions: In Caucasians, almost all APOE ε4 carriers had the TOMM40 ’523-L variant and the effects of ’523-L and ε4 on incident AD were comparable, supporting a strong linkage between ε4’523-L haplotype and AD. In African Americans, less than half of the ε4 carriers had ’523-L and the effect patterns of ε4 and ’523-L on AD differed from Caucasians.
P4-294
IDENTIFICATION OF GENOME-WIDE SIGNIFICANT ASSOCIATIONS IN THE ALZHEIMER’S DISEASE SEQUENCING PROJECT DOMINICAN FAMILIES WITH VARIANTS IN UGT2B28, AXIN2, SYCE1, BCAT1, FAM13A, AND DQ594761
Antonio Parrado, Janssen Pharmaceutical, Research & Development, Spring House, PA, USA. Contact e-mail: [email protected] Background: To identify novel genetic variants contributing to increased risk or protection against developing Alzheimer’s disease
(AD) among Caribbean Hispanic and Caucasian families. Methods: We preformed family-based association tests (FBAT) to identify an over or under-transmission of alleles among affected offspring that deviate from the expected distribution, derived using Mendel’s law of segregation, using the Alzheimer’s Disease Sequencing Project (ADSP – discovery phase) whole-genome sequence (WGS) cohort consisting of 84 highly informative multiplex families. We studied the WGS data of 362 AD diagnosed patients and 68 unaffected relatives, the largest proportion (n¼67) of families self-reported from Dominican Hispanic ancestry (the first of the six consent groups from the ADSP Study). Results: We identified six variants located in the intronic or promoter region of six genes (UGT2B28, AXIN2, SYCE1, BCAT1, FAM13A and DQ594761) that achieved a genome-wide level of statistical significant association (FBAT P < 5x10-8) with Alzheimer’s disease diagnosis. Additionally, we identified six variants in or near six genes (POU6F1, NRG3, SLITRK1, SMIM15, AC092684.1, and RP11-986E7.2) with a suggestive level of statistical significant association (FBAT P < 1x10-6) with AD diagnosis. Conclusions: Interestingly, UGT2B28, SLITRK1, AXIN2, BCAT1, and NRG3 are expressed in the brain (i.e. hippocampus, glial cells, and ganglion), furthermore, NRG3 and SLITRK1 have been associated with neurological diseases (Schizophrenia and Tourette’s, respectively). Axin2 plays an important role in the Wnt/Hedgehog/Notch signaling pathway, in concert with PSEN1 and PSEN2. Neuregulin 3 (NRG3) is involved in the nuclear signaling pathway through ErbB4 with PSEN2. Noteworthy, similar to APP and PICALM, SLITRK1 (SLIT And NTRK-Like Family, Member 1) plays a role in Axonogenesis.
P4-295
TOMM40 ‘523 VARIANT AND COGNITIVE DECLINE IN COMMUNITY BASED OLDER PERSONS WITH APOE E3/3 GENOTYPE
Lei Yu1, Michael W. Lutz2, Robert S. Wilson1, Daniel K. Burns3, Allen D. Roses4,5, Ann M. Saunders2, Philip L. De Jager6,7,8, Lisa L. Barnes1, David A. Bennett1, 1Rush Alzheimer’s Disease Center, Chicago, IL, USA; 2Duke University School of Medicine, Durham, NC, USA; 3Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; 4Duke University Medical Center, Durham, NC, USA; 5Zinfandel Pharmaceuticals, Inc., Chapel Hill, NC, USA; 6Broad Institute, Cambridge, MA, USA; 7Brigham and Women’s Hospital, Boston, MA, USA; 8Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: The Apolipoprotein E (APOE) polymorphism is the
best known genetic risk factor for late-onset Alzheimer’s disease (AD). Recent data suggest that a poly-T variant (‘523) in the adjacent TOMM40 gene represents a more informative signal in predicting age of AD onset. We interrogated the ‘523 variant in older persons with homozygous APOE ε3/3 genotype for associations with longitudinal cognitive decline. Methods: Data came from two cohort studies of aging and dementia in which participants underwent annual clinical evaluations for up to 21 years. The ‘523 genotypes were determined based on the length variation of the poly-T stretch of the rs10524523 polymorphism. Linear mixed models compared the rates of decline in global cognition and five cognitive domains by the ‘523 genotypes. Results: All 1,170 APOE ε3/3 homozygotes were of European ancestry, free of dementia at baseline, and had an average age of 78.5 years. Three major genotypes at the ‘523 variant were linked to APOE ε3/3, 26.5% had 2 short poly-Ts (S/S), 48.9% had 1 short and 1 very long poly-Ts (S/VL) and 24.0%
Poster Presentations: Wednesday, July 27, 2016
had 2 very long poly-Ts (VL/VL). Longitudinal data analyses show that subjects with ‘523-S/S had faster decline in global cognition than subjects with ‘523-S/VL (p¼.002) or ‘523-VL/VL (p¼.030). The same association was observed in episodic memory (p¼.0004 for ‘523-S/VL and p¼.010 for ‘523-VL/VL) and semantic memory (p¼.002 for ‘523-S/VL and p¼.050 for ‘523-VL/VL), but not significant (all ps>.05) in working memory, processing speed or visuospatial ability. Conclusions: Our data reveal an association of the APOE ε3/3-TOMM40 ‘523 haplotypes with cognitive decline in community based older persons, such that the VL poly-T at the TOMM40 ‘523 locus is related to less decline, primarily in episodic and semantic memory.
P4-296
CEREBRAL AMYLOID-b AND GAIT SPEED IN OLDER ADULTS WITHOUT DEMENTIA: INFLUENCE OF COGNITION AND APOE-E4 GENOTYPE
Neelesh K. Nadkarni1, Subashan Perera1, Beth E. Snitz1, Julie Price1, Chester Mathis1, William E. Klunk1, Jeff Williamson2, Steven DeKosky3, Oscar L. Lopez1, 1University of Pittsburgh, Pittsburgh, PA, USA; 2Wake Forest Baptist Health, Winston Salem, NC, USA; 3University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected] Background: We studied the cross-sectional association between
global and regional amyloid-beta (Ab) deposition and gait speed in dementia-free older adults and examined the influence of cognition and APOE-ε4 genotype on this relationship. Methods: In 183 older adults without dementia (mean age: 86 years) enrolled at the Pittsburgh site of the Ginkgo Evaluation of Memory (GEM) study that included 144 cognitively normal (CN) older adults (mean age: 85 years), we obtained gait assessments concurrent with Ab-imaging. We measured Ab on Pittsburgh B (PiB) PET, gait speed over 15-feet and general cognitive abilities on the Mini-mental Status Examination (MMSE). We grouped participants into high-Ab [PiB(+)] and low-Ab [PiB(-)] on standardized global PiB cutoffs and examined group differences. We studied the influence of MMSE and APOE-ε4 on the association between gait speed and Ab in the full sample and in the sample restricted to CN individuals adjusting for covariates (age, sex, education, body weight, hypertension, coronary heart disease, stroke/TIA and, hippocampal volume and small-vessel disease burden on MRI). Results: PiB(+) were comparable to PiB(-) individuals on demographics, comorbidities, hippocampal volume and smallvessel disease but not on gait speed (0.85 vs 0.92 m/sec, p¼0.012) or proportion of APOE ε4 carriers (32% vs 6%, p<0.001). In the whole sample, the association between global PiB retention and slower gait withstood adjustment for covariates (p¼0.026) but was attenuated by MMSE (p¼0.056) and APOE ε4 status (p¼0.095). In the CN subsample, the adjusted association between global PiB retention and slow gait (p¼0.042) did not withstand further correction for MMSE or APOE-ε4 (both p>0.1). The regional associations between gait speed and PiB uptake was limited to temporal, occipital and motor cortices while those in frontal, striatal, precuneus and parietal areas were rendered statistically non-significant by APOE-ε4 in both samples. Conclusions: Cortical Ab deposition is associated with slower gait speed in older adults without dementia; however, this association is weaker when the sample is restricted to cognitively normal older adults and, tends to persist but is attenuated by cognition and APOE-ε4 genotype.
P4-297
P1147
SEX DIFFERENCES IN AMYLOID BETA COLOCALIZATION WITH TYROSINE HYDROXYLASE IN THE LOCUS COERULEUS AND WITH DOPAMINE BETA HYDROXYLASE IN THE INFRALIMBIC MEDIAL PREFRONTAL CORTEX OF MICE WITH FOREBRAIN SPECIFIC OVEREXPRESSION OF CORTICOTROPIN RELEASING FACTOR
Jennifer A. Ross1, Beverly A. S. Reyes1, Victoria Risbrough2, Rita J. Valentino3, Elisabeth J. Van Bockstaele1, 1Drexel University, College of Medicine, Philadelphia, PA, USA; 2University of California, San Diego, CA, USA; 3The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: The LC-NE system is critically involved in memory and cognitive processes, is highly responsive to stress-related stimuli, and via its global projections, facilitates large-scale changes in the brain environment. Stress is a risk factor for developing AD, and is supported by multiple clinical and preclinical studies demonstrating that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and accumulation of the amyloid beta (Ab) peptide. Stress-induced activation of the LC is mediated by corticotropin releasing factor (CRF) and CRF receptors exhibit sex-biased stress signaling. In support of this, sex differences have been described in the neurochemical, morphological and molecular regulation of LC neurons by CRF, providing a compelling basis for vulnerability of females to stress-related disorders such as AD. Methods: In the present study, we examined the cellular substrates for interactions between Ab and tyrosine hydroxylase (TH) a marker of noradrenergic somatodendritic processes in the LC, and dopamine-b-hydroxylase (DbH), a marker of noradrenergic terminals in the infralimbic medial prefrontal cortex (ILmPFC) in mice conditionally overexpressing CRF in the forebrain (CRF OE) under a Doxycycline (DOX) regulated tetO promoter. Results: Preliminary immunofluorescence data show co-localization of Ab and TH in somatodendritic processes of the LC. Using high resolution immunoelectron microscopy, semi-quantitative preliminary analysis revealed that 42.9% (51/ 119) of TH-containing somatodendritic processes also exhibited Ab-immunogold silver particles in DOX treated males, compared to 32.4% (92/284) in male transgenic littermate untreated controls and 61.6% (151/245) TH-containing somatodendritic processes also exhibited Ab-immunogold silver particles in DOX treated females compared to 34.4% (21/61) in female transgenic littermate untreated controls. Ab also co-localized with DbH in the ILmPFC of CRF OE mice, showing a trend in which Ab is preferentially localized to DbH containing terminals in females. Conclusions: The semi-quantitative preliminary results of immunoelectron microscopy experiments in male and female CRF OE mice indicate a trend towards increased Ab in TH labeled somatodendritic processes of the LC and DbH labeled terminals of the ILmPFC, and that these increases may be exaggerated in females.
P4-298
MEPRIN b IS ASSOCIATED WITH FORMATION OF PYROGLUTAMATE-MODIFIED Ab PEPTIDES
Stephan Schilling1, Dagmar Schlenzig1, Holger Cynis1, Maike HartlageR€ubsamen2, Steffen Rossner2, Hans-Ulrich Demuth1, 1Fraunhofer Institute for Cell Therapy and Immunology, Halle, Germany; 2Paul-Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. Contact e-mail: [email protected]