- Email: [email protected]
PLASMA FREE AMINO ACID (PFAA) PROFILE IS A POTENTIAL BLOOD-BASED BIOMARKER FOR ALZHEIMER'S DISEASE
P886
Poster Presentations: P4
EEG (delta, theta, alfa-1, alfa-2 and beta) giving five 64x64 association matrixes for each group. Once the synchronization was measured, graphs were built to obtain differences in the brain network measures between the groups. To build the graphs different thresholds were used trying to maintain the same connectivity density between groups. A total of eleven densities were evaluated in the range between [0.25, 0.5]. To obtain statistical confidence interval for the measures 1000 random networks were obtained and used as surrogates. Results: We found significant differences (p < 0.001) in all the EEG bands for different densities in the clustering coefficient, the path length and the Lambda coefficient. For the alfa-2 and beta bands the differences existed for almost all (8 of the 11) of the densities evaluated. In both bands the clustering coefficient, the characteristic path length and Lambda, were bigger in the control than the carriers group. To avoid the possibility that the differences in the characteristic path length were given by nodes without any connection we also used the global efficiency which was bigger also in the carriers group. Conclusions: In this study carriers were characterized by differences in the network topology, evidenced in the path length and clustering coefficients. These findings constitute new evidences of neurophysiological changes in the brain dynamics in preclinical forms of familial Alzheimer disease.
P4-278
IDENTIFICATION OF NOVEL DIAGNOSTIC CSF PROTEIN BIOMARKERS FOR FTD WITH HIGH DISCRIMINATORY POWER
Charlotte Teunissen1, Marleen Koel-Simmelink1, Naura Elias1, Sisi Durieux-Lu1, Thang Pham1, John van Swieten2, Connie Jimenez3, Yolande Pijnenburg3, 1VU University Medical Center Amsterdam, Amsterdam, Netherlands; 2Erasmus University Medical Center, Rotterdam, Netherlands; 3VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: Frontotemporal dementia (FTD) is the second commonest cause of early-onset dementia. Its underlying pathological spectrum, frontotemporal lobar degeneration (FTLD), can be divided in 2 main subtypes characterized by either tau or TDP-43 accumulations. Thus far, reliable biomarkers enabling the identification of FTD or distinguishing between its pathological subtypes are lacking. In the light of upcoming treatment options, such markers are highly needed. The aim of this study was to identify cerebrospinal fluid (CSF) biomarkers for accurate diagnosis of the two main pathological subtypes of FTD using unbiased in-depth mass-spectrometry based proteomics. Methods: FTD patients with TDP-43 (FTD-TDP-43, FTLD-TDP, n¼12) or tau pathology (FTLD-tau, n¼8), and asymptomatic controls with subjective memory complaints (SMC, n¼10) were included. We analysed the CSF proteome after abundant protein depletion by 1D gel-nano-liquid chromatography coupled to tandem mass spectrometry. For validation, we carefully selected commercial ELISAs and tested their robustness before validation of these biomarkers in CSF of FTD patients in a partly overlapping larger cohort (FTLD-TDP, n¼21, FTLD-tau,
Figure 1. CSF FABP in different patient groups as validated by ELISA
Figure 2. CSF YKL-40in different patient groups as validated by ELISA
n¼10, SMC, n¼23) and of patients with other dementias (Alzheimer’s disease (AD), n¼20, dementia with Lewy bodies (DLB), n¼20 and vascular dementia (VaD, n¼18)). Results: Out of a total dataset of 1914 CSF proteins, we identified 57 proteins that were differentially regulated (fold change>1.2, p<0.05) between the different patient groups: either between the two pathological subtypes (24 proteins), or between at least one of these FTD subtypes and controls (53 proteins). We confirmed the differential expression of 2 out of 4 candidate proteins for which commercial ELISA and Western blot were available, namely YKL-40 and FABP4, which are both known to be expressed in microglia. Further validation in a larger cohort showed that level of YKL-40 was 2-fold increased in both FTD pathological subtypes compared to controls, and that the levels in FTLD-tau were significantly higher compared to AD, DLB, and VaD patients. The CSF levels of FABP4 were significantly increased in FTLD-tau compared to controls, AD and DLB. Conclusions: We performed high resolution CSF proteomics and identified 57 CSF biomarkers that appear very promising for both FTD diagnosis as well as subtyping of pathologies. The positively validated subset of biomarkers have a high potential for differential diagnosis, targeted treatment development and evaluation of FTD pathology-specific treatments.
P4-279
PLASMA FREE AMINO ACID (PFAA) PROFILE IS A POTENTIAL BLOOD-BASED BIOMARKER FOR ALZHEIMER’S DISEASE
Nobuhiro Kawai1, Takahiko Muramatsu2, Maiko Mori2, Yasushi Noguchi2, Minoru Yamakado3, Toshiyuki Tezuka4, Mayumi Sakuma4, Kou Tanaka5, Akinori Miyashita6, Naoto Endo4, Ryozo Kuwano7, Takeshi Ikeuchi7, 1Ajinomoto Co., Inc, Kawasaki-shi, Kanagawa, Japan; 2Ajinomoto Co., Inc., Kawasaki-shi, Kanagawa, Japan; 3 Mitsui Memorial Hospital, Tokyo, Japan; 4Niigata University, Niigata-shi, Japan; 5Mishima Hospital, Nagaoka-shi, Niigata, Japan; 6Brain Research Institute, Niigata University, Niigata, Japan; 7Niigata University, Niigata, Japan. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is by far the most common form of dementia in adults. Blood-based biomarker which is minimally invasive and less costly compared with CSF marker has significant potential applications as a diagnostic tool for AD; however, such blood-based biomarkers have not been established to date. In this study, we performed plasma analyses of patients with AD using our state-of-the-art technology of analyzing PFAA to assess PFAA as a possible biomarker for AD. Methods: Plasma sample of patients with AD (n¼36) and cognitively normal subjects (CNC, n¼34) were collected under fasting condition from 9:00AM to 12:00AM. The mini-mental state examination (MMSE) was performed to assess the cognitive function. The APOE genotypes
Poster Presentations: P4 were determined using a Taq-Man assay. A total of 35 PFAA profiles were measured by liquid chromatography-mass spectrometry (LCMS). The PFAA profiles were also compared with age- and gender-matched healthy control subjects (HC, n ¼ 36) who had undergone a comprehensive health screening. Results: Several PFAAs have shown significant changes between patients with AD and cognitively normal subjects as well as age- and gender- matched healthy subjects. Neither age at onset, MMSE score, nor APOE genotype affects the PFAA profiles significantly in patients with AD. The area under the curve (AUC) of receiver operating characteristic (ROC) curve by a certain PFAA was found to be 0.86, suggesting a high discriminating power of PFAA to make a diagnosis of AD. Conclusions: Our results suggest that PFAA profile could be a potential blood-based biomarker for AD. We will discuss the implications of our findings for the development of screening tool and companion diagnostic test for patients with AD.
P4-280
FIRST STEPS IN THE DEVELOPMENT AND PRODUCTION OF CLINICAL REFERENCE MATERIAL FOR AMYLOID-B1-42 IN HUMAN CEREBROSPINAL FLUID
Julia Kuhlmann1, Ingrid Zegers2, Erik Portelius3, Ulf Andreasson4, Amalia Mu~ noz2, Heinz Schimmel2, Kaj Blennow5, Henrik Zetterberg5, 1 European Commission, Joint Research Centre, Institute for Reference Materials and Measurements, Geel, Belgium; 2European Commission, Joint Research Centre, Institute for Reference Materials and Measurements, Geel, Belgium; 3Sahlgrenska University Hospital, M€olndal, Sweden; 4 Clinical Neurochemistry Laboratory, M€olndal, Sweden; 5Sahlgrenska Academy, University of Gothenburg, M€olndal, Sweden. Contact e-mail: [email protected] Background: Early diagnosis and treatment of Alzheimer’s disease (AD) remain challenging. The use of biomarkers could contribute to early diagnosis, but there are still large variances between results from different diagnostic assays for AD biomarkers. This is partly due to lack of standardization of those assays and highlights the need for a common reference material for each AD biomarker.The JRC-IRMM has a long-standing experience in developing clinical reference materials (RMs) to support the implementation of the EU Directive on In Vitro Diagnostics Medical Devices (Directive 98/79/EC), which requires traceability of calibrants and control materials to reference measurement procedures and/or reference materials of higher order. Recently, JRC-IRMM decided to support the development of a certified reference material (RM) based on human cerebrospinal fluid (hCSF) that can be used by assay manufacturers to calibrate their diagnostic assays for Amyloid-b1-42 (Ab1-42). The RM is developed in collaboration with the Working Group for Cerebrospinal Fluid Proteins of the International Federation of Clinical Chemistry and Laboratory Medicine. Methods: The development of a reference system for Ab1-42 requires that the measured biomarker is clearly defined, and that a valid traceability chain is set up. Therefore, feasibility studies are needed for different reference material formats and the reference method development. The calibrant used for the value assignment of a RM property needs to be carefully characterized, as it forms the link between the certified RM value and the reference, the International System of Units (SI). A calibrant batch was produced and characterized using liquid chromatography, electrophoresis and mass spectrometry. Results: Procedures for preparing an Ab1-42 peptide calibrant solution have been developed. The resulting calibrant preparation has been characterized regarding purity by using orthogonal methods and the peptide concentration was determined by amino acid analysis. The homogeneity and stability of the calibrant solution have been verified. The purity of the preparation was found to be sufficiently high, so that values can be assigned to the calibrant solution with a suitable uncertainty. Conclusions: The first steps in developing a reference system for measurements of Ab142 in hCSF have been made by producing a characterized pure peptide calibrant.
P4-281
P887 RELATION OF PLASMALOGEN BIOSYNTHESIS TO COGNITION AND AD IN OLDER PERSONS
Dayan Goodenowe1, Vijitha Senanayake2, Bassirou Chitou2, Asuka Mochizuki2, Dushmanthi Jayasinghe2, Raj C. Shah3, David Bennett4, 1 Phenomenome Discoveries Inc., Saskatoon, Saskatchewan, Canada; 2 Phenomenome Discoveries Inc., Saskatoon, Saskatchewan, Canada; 3Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States; 4Rush University Medical Center, Chicago, Illinois, United States. Contact e-mail: [email protected] Background: Serum plasmalogen levels have been implicated in AD. Plasmalogen biosynthesis involves two peroxisome-dependent steps: 1), the sn1 fatty alcohol is synthesized from acetyl-CoA derived exclusively from intra-peroxisomal b-oxidation of very long chain fatty acids; and 2), this alcohol is used to synthesize 1-alkylglycerolphosphate which subsequently enters phospholipid-independent and plasmalogen-specific metabolic pathways outside the peroxisome. Peroxisomal b-oxidation and plasmalogen biosynthesis was investigated in participants in the Religious Orders Study and Rush Memory and Aging Project as potential biomarkers for AD. Methods: Stable isotope mass spectrometry was used to comprehensively measure phosphatidylcholine, phosphatidylethanolamine, plasmalogens, and lyso-phosphatidylcholine species in the serum in 1255 older persons. All subjects were without known dementia at enrollment and underwent comprehensive clinical evaluation on an annual basis. Analyses were based on the cognitive assessment from the most recent clinical evaluation proximate to the blood draw. Peroxisomal b-oxidation status was measured by calculating the ratio of a peroxisomal b-oxidation product 20:5 (eicosapentaenoic acid) to a peroxisomal b-oxidation precursor 22:4 (adrenic acid). Plasmalogen biosynthesis status was determined by measuring individual phospholipid species. All models were adjusted for age, sex, education, and APOE status. Results: In cross-sectional analyses, higher peroxisomal b-oxidation levels, and higher plasmalogen levels were associated with better cognition (r¼0.59 and r¼0.34, p’s<0.001), and a reduced Odds Ratio (OR) of AD (OR¼0.08 and OR¼0.22, p<0.001 and p¼0.03); APOE ε4 was associated with lower cognition (r¼-0.35, p<0.001) and an increased OR of AD (OR¼2.8, p<0.001). In stratified analyses the relation of both peroxisomal b-oxidation levels and plasmalogen levels on the odds of AD differed by APOE genotype (Figure 1, p’s<0.001). In APOE ε3/3 persons AD OR¼0.08 and OR¼0.08 and in ε3/4 persons AD OR¼0.09 and OR¼0.11 for higher peroxisomal b-oxidation levels and higher plasmalogen levels, respectively (p’s<0.01). By contrast, no effect was observed in APOE ε2/3 persons. Conclusions: Impaired plasmalogen biosynthesis was associated with lower cognition and ahigher odds of AD. Further, these associations appear to be modified by APOE allele status.
P4-282
PLD3 ASSOCIATES TO PROLINE A PROPOSED BIOMARKER IN MAPSTONE ET AL
Sven J. van der Lee1, Ayse Demirkan1, M. Arfan Ikram1, Ko Willems van Dijk2, Gerd Schmitz3, Thomas Hankemeier4, Najaf Amin1, Cornelia M. van duijn1, 1Erasmus University Medical Center, Rotterdam, Netherlands; 2 Leiden University Medical Center, Leiden, Netherlands; 3University Hospital Regensburg, Regensburg, Germany; 4Leiden Academic Centre for
Poster Presentations: P4
EEG (delta, theta, alfa-1, alfa-2 and beta) giving five 64x64 association matrixes for each group. Once the synchronization was measured, graphs were built to obtain differences in the brain network measures between the groups. To build the graphs different thresholds were used trying to maintain the same connectivity density between groups. A total of eleven densities were evaluated in the range between [0.25, 0.5]. To obtain statistical confidence interval for the measures 1000 random networks were obtained and used as surrogates. Results: We found significant differences (p < 0.001) in all the EEG bands for different densities in the clustering coefficient, the path length and the Lambda coefficient. For the alfa-2 and beta bands the differences existed for almost all (8 of the 11) of the densities evaluated. In both bands the clustering coefficient, the characteristic path length and Lambda, were bigger in the control than the carriers group. To avoid the possibility that the differences in the characteristic path length were given by nodes without any connection we also used the global efficiency which was bigger also in the carriers group. Conclusions: In this study carriers were characterized by differences in the network topology, evidenced in the path length and clustering coefficients. These findings constitute new evidences of neurophysiological changes in the brain dynamics in preclinical forms of familial Alzheimer disease.
P4-278
IDENTIFICATION OF NOVEL DIAGNOSTIC CSF PROTEIN BIOMARKERS FOR FTD WITH HIGH DISCRIMINATORY POWER
Charlotte Teunissen1, Marleen Koel-Simmelink1, Naura Elias1, Sisi Durieux-Lu1, Thang Pham1, John van Swieten2, Connie Jimenez3, Yolande Pijnenburg3, 1VU University Medical Center Amsterdam, Amsterdam, Netherlands; 2Erasmus University Medical Center, Rotterdam, Netherlands; 3VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: Frontotemporal dementia (FTD) is the second commonest cause of early-onset dementia. Its underlying pathological spectrum, frontotemporal lobar degeneration (FTLD), can be divided in 2 main subtypes characterized by either tau or TDP-43 accumulations. Thus far, reliable biomarkers enabling the identification of FTD or distinguishing between its pathological subtypes are lacking. In the light of upcoming treatment options, such markers are highly needed. The aim of this study was to identify cerebrospinal fluid (CSF) biomarkers for accurate diagnosis of the two main pathological subtypes of FTD using unbiased in-depth mass-spectrometry based proteomics. Methods: FTD patients with TDP-43 (FTD-TDP-43, FTLD-TDP, n¼12) or tau pathology (FTLD-tau, n¼8), and asymptomatic controls with subjective memory complaints (SMC, n¼10) were included. We analysed the CSF proteome after abundant protein depletion by 1D gel-nano-liquid chromatography coupled to tandem mass spectrometry. For validation, we carefully selected commercial ELISAs and tested their robustness before validation of these biomarkers in CSF of FTD patients in a partly overlapping larger cohort (FTLD-TDP, n¼21, FTLD-tau,
Figure 1. CSF FABP in different patient groups as validated by ELISA
Figure 2. CSF YKL-40in different patient groups as validated by ELISA
n¼10, SMC, n¼23) and of patients with other dementias (Alzheimer’s disease (AD), n¼20, dementia with Lewy bodies (DLB), n¼20 and vascular dementia (VaD, n¼18)). Results: Out of a total dataset of 1914 CSF proteins, we identified 57 proteins that were differentially regulated (fold change>1.2, p<0.05) between the different patient groups: either between the two pathological subtypes (24 proteins), or between at least one of these FTD subtypes and controls (53 proteins). We confirmed the differential expression of 2 out of 4 candidate proteins for which commercial ELISA and Western blot were available, namely YKL-40 and FABP4, which are both known to be expressed in microglia. Further validation in a larger cohort showed that level of YKL-40 was 2-fold increased in both FTD pathological subtypes compared to controls, and that the levels in FTLD-tau were significantly higher compared to AD, DLB, and VaD patients. The CSF levels of FABP4 were significantly increased in FTLD-tau compared to controls, AD and DLB. Conclusions: We performed high resolution CSF proteomics and identified 57 CSF biomarkers that appear very promising for both FTD diagnosis as well as subtyping of pathologies. The positively validated subset of biomarkers have a high potential for differential diagnosis, targeted treatment development and evaluation of FTD pathology-specific treatments.
P4-279
PLASMA FREE AMINO ACID (PFAA) PROFILE IS A POTENTIAL BLOOD-BASED BIOMARKER FOR ALZHEIMER’S DISEASE
Nobuhiro Kawai1, Takahiko Muramatsu2, Maiko Mori2, Yasushi Noguchi2, Minoru Yamakado3, Toshiyuki Tezuka4, Mayumi Sakuma4, Kou Tanaka5, Akinori Miyashita6, Naoto Endo4, Ryozo Kuwano7, Takeshi Ikeuchi7, 1Ajinomoto Co., Inc, Kawasaki-shi, Kanagawa, Japan; 2Ajinomoto Co., Inc., Kawasaki-shi, Kanagawa, Japan; 3 Mitsui Memorial Hospital, Tokyo, Japan; 4Niigata University, Niigata-shi, Japan; 5Mishima Hospital, Nagaoka-shi, Niigata, Japan; 6Brain Research Institute, Niigata University, Niigata, Japan; 7Niigata University, Niigata, Japan. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is by far the most common form of dementia in adults. Blood-based biomarker which is minimally invasive and less costly compared with CSF marker has significant potential applications as a diagnostic tool for AD; however, such blood-based biomarkers have not been established to date. In this study, we performed plasma analyses of patients with AD using our state-of-the-art technology of analyzing PFAA to assess PFAA as a possible biomarker for AD. Methods: Plasma sample of patients with AD (n¼36) and cognitively normal subjects (CNC, n¼34) were collected under fasting condition from 9:00AM to 12:00AM. The mini-mental state examination (MMSE) was performed to assess the cognitive function. The APOE genotypes
Poster Presentations: P4 were determined using a Taq-Man assay. A total of 35 PFAA profiles were measured by liquid chromatography-mass spectrometry (LCMS). The PFAA profiles were also compared with age- and gender-matched healthy control subjects (HC, n ¼ 36) who had undergone a comprehensive health screening. Results: Several PFAAs have shown significant changes between patients with AD and cognitively normal subjects as well as age- and gender- matched healthy subjects. Neither age at onset, MMSE score, nor APOE genotype affects the PFAA profiles significantly in patients with AD. The area under the curve (AUC) of receiver operating characteristic (ROC) curve by a certain PFAA was found to be 0.86, suggesting a high discriminating power of PFAA to make a diagnosis of AD. Conclusions: Our results suggest that PFAA profile could be a potential blood-based biomarker for AD. We will discuss the implications of our findings for the development of screening tool and companion diagnostic test for patients with AD.
P4-280
FIRST STEPS IN THE DEVELOPMENT AND PRODUCTION OF CLINICAL REFERENCE MATERIAL FOR AMYLOID-B1-42 IN HUMAN CEREBROSPINAL FLUID
Julia Kuhlmann1, Ingrid Zegers2, Erik Portelius3, Ulf Andreasson4, Amalia Mu~ noz2, Heinz Schimmel2, Kaj Blennow5, Henrik Zetterberg5, 1 European Commission, Joint Research Centre, Institute for Reference Materials and Measurements, Geel, Belgium; 2European Commission, Joint Research Centre, Institute for Reference Materials and Measurements, Geel, Belgium; 3Sahlgrenska University Hospital, M€olndal, Sweden; 4 Clinical Neurochemistry Laboratory, M€olndal, Sweden; 5Sahlgrenska Academy, University of Gothenburg, M€olndal, Sweden. Contact e-mail: [email protected] Background: Early diagnosis and treatment of Alzheimer’s disease (AD) remain challenging. The use of biomarkers could contribute to early diagnosis, but there are still large variances between results from different diagnostic assays for AD biomarkers. This is partly due to lack of standardization of those assays and highlights the need for a common reference material for each AD biomarker.The JRC-IRMM has a long-standing experience in developing clinical reference materials (RMs) to support the implementation of the EU Directive on In Vitro Diagnostics Medical Devices (Directive 98/79/EC), which requires traceability of calibrants and control materials to reference measurement procedures and/or reference materials of higher order. Recently, JRC-IRMM decided to support the development of a certified reference material (RM) based on human cerebrospinal fluid (hCSF) that can be used by assay manufacturers to calibrate their diagnostic assays for Amyloid-b1-42 (Ab1-42). The RM is developed in collaboration with the Working Group for Cerebrospinal Fluid Proteins of the International Federation of Clinical Chemistry and Laboratory Medicine. Methods: The development of a reference system for Ab1-42 requires that the measured biomarker is clearly defined, and that a valid traceability chain is set up. Therefore, feasibility studies are needed for different reference material formats and the reference method development. The calibrant used for the value assignment of a RM property needs to be carefully characterized, as it forms the link between the certified RM value and the reference, the International System of Units (SI). A calibrant batch was produced and characterized using liquid chromatography, electrophoresis and mass spectrometry. Results: Procedures for preparing an Ab1-42 peptide calibrant solution have been developed. The resulting calibrant preparation has been characterized regarding purity by using orthogonal methods and the peptide concentration was determined by amino acid analysis. The homogeneity and stability of the calibrant solution have been verified. The purity of the preparation was found to be sufficiently high, so that values can be assigned to the calibrant solution with a suitable uncertainty. Conclusions: The first steps in developing a reference system for measurements of Ab142 in hCSF have been made by producing a characterized pure peptide calibrant.
P4-281
P887 RELATION OF PLASMALOGEN BIOSYNTHESIS TO COGNITION AND AD IN OLDER PERSONS
Dayan Goodenowe1, Vijitha Senanayake2, Bassirou Chitou2, Asuka Mochizuki2, Dushmanthi Jayasinghe2, Raj C. Shah3, David Bennett4, 1 Phenomenome Discoveries Inc., Saskatoon, Saskatchewan, Canada; 2 Phenomenome Discoveries Inc., Saskatoon, Saskatchewan, Canada; 3Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States; 4Rush University Medical Center, Chicago, Illinois, United States. Contact e-mail: [email protected] Background: Serum plasmalogen levels have been implicated in AD. Plasmalogen biosynthesis involves two peroxisome-dependent steps: 1), the sn1 fatty alcohol is synthesized from acetyl-CoA derived exclusively from intra-peroxisomal b-oxidation of very long chain fatty acids; and 2), this alcohol is used to synthesize 1-alkylglycerolphosphate which subsequently enters phospholipid-independent and plasmalogen-specific metabolic pathways outside the peroxisome. Peroxisomal b-oxidation and plasmalogen biosynthesis was investigated in participants in the Religious Orders Study and Rush Memory and Aging Project as potential biomarkers for AD. Methods: Stable isotope mass spectrometry was used to comprehensively measure phosphatidylcholine, phosphatidylethanolamine, plasmalogens, and lyso-phosphatidylcholine species in the serum in 1255 older persons. All subjects were without known dementia at enrollment and underwent comprehensive clinical evaluation on an annual basis. Analyses were based on the cognitive assessment from the most recent clinical evaluation proximate to the blood draw. Peroxisomal b-oxidation status was measured by calculating the ratio of a peroxisomal b-oxidation product 20:5 (eicosapentaenoic acid) to a peroxisomal b-oxidation precursor 22:4 (adrenic acid). Plasmalogen biosynthesis status was determined by measuring individual phospholipid species. All models were adjusted for age, sex, education, and APOE status. Results: In cross-sectional analyses, higher peroxisomal b-oxidation levels, and higher plasmalogen levels were associated with better cognition (r¼0.59 and r¼0.34, p’s<0.001), and a reduced Odds Ratio (OR) of AD (OR¼0.08 and OR¼0.22, p<0.001 and p¼0.03); APOE ε4 was associated with lower cognition (r¼-0.35, p<0.001) and an increased OR of AD (OR¼2.8, p<0.001). In stratified analyses the relation of both peroxisomal b-oxidation levels and plasmalogen levels on the odds of AD differed by APOE genotype (Figure 1, p’s<0.001). In APOE ε3/3 persons AD OR¼0.08 and OR¼0.08 and in ε3/4 persons AD OR¼0.09 and OR¼0.11 for higher peroxisomal b-oxidation levels and higher plasmalogen levels, respectively (p’s<0.01). By contrast, no effect was observed in APOE ε2/3 persons. Conclusions: Impaired plasmalogen biosynthesis was associated with lower cognition and ahigher odds of AD. Further, these associations appear to be modified by APOE allele status.
P4-282
PLD3 ASSOCIATES TO PROLINE A PROPOSED BIOMARKER IN MAPSTONE ET AL
Sven J. van der Lee1, Ayse Demirkan1, M. Arfan Ikram1, Ko Willems van Dijk2, Gerd Schmitz3, Thomas Hankemeier4, Najaf Amin1, Cornelia M. van duijn1, 1Erasmus University Medical Center, Rotterdam, Netherlands; 2 Leiden University Medical Center, Leiden, Netherlands; 3University Hospital Regensburg, Regensburg, Germany; 4Leiden Academic Centre for