- Email: [email protected]
WHICH NEUROPATHOLOGICAL MARKER CORRELATES BEST WITH ANTE-MORTEM COGNITIVE SYMPTOMS?
P956 P3-300
Poster Presentations: Tuesday, July 26, 2016 PHOSPHORYLATED TAU AND ALPHASYNUCLEIN ACCUMULATION IN FAMILIAL GRANULIN MUTATION CASES
Masato Hosokawa1, Tetsuaki Arai1,2, Hiromi Kondo1, Geidy E. Serrano3, Thomas G. Beach3, Masato Hasegawa1, Haruhiko Akiyama1, 1Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; 2University of Tsukuba, Tsukuba, Japan; 3Banner Sun Health Research Institute, Sun City, AZ, USA. Contact e-mail: [email protected] Background: Granulin (GRN) mutations were identified in patients with familial frontotemporal lobar degeneration (FTLD) with ubiquitin pathology in 2006 studies. GRN transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. GRN mutations were first found in tau-negative FTLD patients, however, recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, PGRN reduction in tau transgenic mice is associated with increasing tau phosphorylation and accumulation. Methods: To investigate the influence of a decline in PGRN protein on other forms of neurodegenerativerelated protein accumulation, human GRN mutation cases were investigated by histochemical and biochemical analyses. Results: The results showed neuronal and glial tau accumulation in all cases analyzed. Massive neuronal tau staining revealed pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated alpha-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau protein was present in the sarkosyl-insoluble fraction, which was composed of threeand four-repeat tau isoforms, resembling Alzheimer’s disease. Conclusions: Our data suggest that PGRN reduction might be the cause of neuronoglial multiple proteinopathies, including TDP-43 proteinopathy, tauopathy and alpha-synucleinopathy, due to the accelerating accumulation of abnormal proteins.
P3-301
WHICH NEUROPATHOLOGICAL MARKER CORRELATES BEST WITH ANTE-MORTEM COGNITIVE SYMPTOMS?
Arnaud Francois1, Cyntia Tremblay2, Charlotte Delay3, Milene Vandal1,4, David A. Bennett5, Frederic Calon2,6, 1CHU de Quebec, Quebec City, QC, Canada; 2CHU de Quebec, Quebec, QC, Canada; 3INSERM U1167, Lilles, France; 4Pharmacy, LAVAL University, Quebec City, QC, Canada; 5Rush Alzheimer’s Disease Center, Chicago, IL, USA; 6Faculty of Pharmacy, Universite Laval, Quebec, QC, Canada. Contact e-mail: frederic.calon@ crchul.ulaval.ca Background: In the present study, we investigated the relationship
between ante mortem global cognitive scores and a series of key AD neuropathological markers assessed post mortem in the same brain cortex region from the same 36 volunteers (12 NCI, 12 MCI and 12 AD) from the Religious Order Study. Methods: Homogenates from the anterior parietal cortex were subjected to differential centrifugation procedures to generate soluble, detergentsoluble, formic acid soluble and sarkosyl insoluble fractions. Biochemical approaches (Western immunoblots and ELISA) were performed to determine the relative levels of tau, Ab, synaptic proteins and other AD-relevant markers in each fraction. Semiquantitative assessments of Ab plaques, tau-laden tangles and TDP-43 inclusions were also analyzed. Results: Overall, the strongest correlation coefficients with global cognitive scores were obtained for insoluble phosphorylated tau (r2 ¼ -0.484), insoluble Ab42 (r2 ¼ -0.389) and neurofibrillary tangles counts (r2 ¼ -0.494). Robust associations were also established for TDP-43-positive cytoplasmic inclusion (r2 ¼ -0.476), total insoluble tau (r2 ¼ -0.385) and Ab plaque counts (r2 ¼ -0.426). Sarkosyl or formic acid-extracted tau led to similar data. Synaptophysin (r2 ¼ +0.335), pS403/404 TDP43 (r2 ¼ +0.265) and Septin-3 (r2¼ +0.257) were also associated with cognitive scores. No correlation was detected with Ab42 or tau in soluble fractions. Conclusions: The most prominent molecular correlates of cognitive decline
Summary of linear correlations between neuropathological markers and ante mortem global cognitive scores. Linear relationship Adjusted(1) Neuropathological Markers(2)
Extraction Method
r2
P
r2
P
Tangle counts S396/404 pTau (AD2) Cytoplasmic S403/404 pTDP43 Inclusion T231 pTau (AT180) Plaque Counts S396/404 pTau (PHF1) iAb42 (pg/mg tissue) Total Tau (tau-13) Synaptophysin Soluble S396/404 pTau (PHF1) Total Tau (HT7) Soluble S403/404 pTDP43 Septin Soluble GSTP1 Xll Soluble PAK123 SIRT1
Bielschowsky silver staining Formic acid extracts Immunofluorescence Formic acid extracts Bielschowsky silver staining Formic acid extracts Formic acid extracts Formic acid extracts Detergent-soluble TBS-soluble Formic acid extracts TBS-soluble Detergent-soluble Detergent-soluble Detergent-soluble TBS-soluble Detergent-soluble
-0,307 -0,385 -0,295 -0,268 -0,279 -0,294 -0,308 -0,265 0,233 -0,211 -0,163 0,174 0,152 -0,105 0,096 0,148 0,116
0.0006 <0.0001 0.0028 0.0017 0.0011 0.0008 0.0005 0.0016 0.0038 0.0063 0.016 0.0127 0.0226 ns ns 0.0270 0.0491
-0,494 -0,484 -0,476 -0,463 -0,426 -0,394 -0,389 -0,385 0,335 -0,314 -0,310 0,265 0,257 -0,254 0,241 0,239 0,179
<0.0001 0.0001 0.0015 0.0003 0.0006 0.0014 0.0017 0.0019 0.0427 0.0066 0.0113 0.0316 0.0254 0.0407 ns ns ns
Notes: (1) Linear regressions were adjusted by age of death, educational level, gender and APOE genotype; (2) Tau antibodies are given in parentheses.
Poster Presentations: Tuesday, July 26, 2016
P957
MCI patients positive to amyloid-PET is overall worse than in negative ones, but significantly greater deterioration over 12 months emerged in only a minority of tests. Longer time or more specific episodic memory tests may be useful for more sensitive monitoring of performance. Differences with previous studies may be due to different selection of tests or to our shorter follow-up. These data contribute information to define the proper time window for repeated testing for neuropsychology used as a biomarker for AD. P3-303 Figure. Cognitive decline in MCI patients over a 12-month follow-up. Horizontal parentheses indicate significant effect of the factor ‘time’, vertical parenthese indicate significant effect of the factor ‘FBP-PET result’, and ‘*’ indicates significant interaction of these factors.
were insoluble phosphorylated tau, followed by TDP43, Ab42 and synaptic proteins. This substantiates the relevance of investigating these markers, discriminated by solubility or phosphorylated epitopes when applicable, to understand the pathogenesis of AD and develop therapeutic tools.
P3-302
BRAIN AMYLOIDOSIS AND COGNITIVE DECLINE IN MCI: 12-MONTH FOLLOW-UP
Daniele Altomare1,2, Cristina Festari1,2, Cristina Muscio1,3, Alessandro Padovani2,4, Giovanni B. Frisoni1,5, Marina Boccardi1, INDIAFBP Working Group, 1IRCCS Fatebenefratelli, Brescia, Italy; 2University of Brescia, Brescia, Italy; 3Fondazione IRCCS Istituto Neurologico, Milano, Italy; 4Spedali Civili di Brescia, Brescia, Italy; 5Universite de Geneve, Geneve, Switzerland. Contact e-mail: [email protected] Background: Two previous studies demonstrated greater cognitive
decline in MCI patients with positive amyloid-PET compared to negative MCI, as assessed by several neuropsychological tests, over 18 (Doraiswamy et al., 2012) and 36 months (Doraiswamy et al., 2014) follow-up. Our aim is to evaluate whether positive amyloid-PET scans are predictive of greater cognitive decline than negative scans over a shorter 12 months period. Methods: A naturalistic series of seventy-six MCI patients underwent amyloid-PET with 18F-Florbetapir (FBP-PET), and homogeneous clinical and neuropsychological multi-domain assessment before FBP-PET and after 12 months (12-FU). For each neuropsychological test we constructed a linear mixed model with scores as the dependent variable, and ‘FBP-PET result’ (positive or negative) and ‘time’ (baseline or 12-FU) as main factors. ‘Age’ and ‘education’ were included as covariates. Effect size indices (partial Eta-squared, hp2) were also computed (0.02, 0.13 and 0.26 referring respectively to small, medium and large Eta-squared). Results: Patients with positive scan had overall worse performance on tests of global functioning (MMSE, p¼0.005, hp2¼0.11; ADAS-COG, p¼0.007, hp2¼0.10) and on tests involving memory (Story recall, p¼0.002, hp2¼0.13; Rey AVLT – Delayed recall, p¼0.005, hp2¼0.11; ReyOsterrieth complex figure – Recall, p ¼ 0.001, hp2¼0.15). A significant worsening over 12 months was observed in ADAS-COG (p¼0.003, hp2¼0.12), Rey-Osterrieth complex figure – Copy (p<0.001, hp2¼0.19), Raven’s CPM (p¼0.039, hp2¼0.06), Letter (p¼0.044, hp2¼0.06) and Category fluency (p¼0.021, hp2¼0.08). Finally, positive patients showed a significantly greater cognitive decline over the time in the Story recall test (p¼0.026, hp2¼0.07) and the Rey-Osterrieth complex figure – Copy (p¼0.018, hp2¼0.08) (Figure). Conclusions: The cognitive performance of
EFFECTS OF AB AND BDNF VAL66MET ON EPISODIC MEMORY, HIPPOCAMPAL VOLUME AND SERUM BDNF IN PRECLINICAL ALZHEIMER’S DISEASE
Yen Ying Lim1, Stephanie R. Rainey-Smith2,3, Simon M. Laws3,4, Veer Gupta5, Tenielle Porter3, Pierrick Bourgeat6, David Ames7, Christopher Fowler8, Olivier Salvado6, Victor L. Villemagne8,9, Christopher C. Rowe10, Colin L. Masters8, Ralph N. Martins2,3, Paul Maruff11,12, AIBL Research Group, 1The Florey Institute, The University of Melbourne, Parkville, Australia; 2Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Australia; 3Edith Cowan University, Perth, Australia; 4Cooperative Research Centre for Mental Health, Melbourne, Australia; 5Edith Cowan University, Joondalup, Australia; 6CSIRO, Brisbane, Australia; 7National Ageing Research Institute, Melbourne, Australia; 8The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 9Department of Molecular Imaging and Therapy, Centre for PET, Austin Health, Heidelberg, Australia; 10Austin Health, Melbourne, Australia; 11Cogstate Ltd., Melbourne, Australia; 12The Florey Institutes of Neurosciences and Mental Health, Melbourne, Australia. Contact e-mail: [email protected]. au Background: In non-demented older adults carriage of the brainderived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Ab) related decline in episodic memory (EM) and hippocampal volume (HV) loss over 36 months. The extent to which Ab+ and BDNF Val66Met is related to circulating markers of BDNF (e.g., serum) is unknown. The aim of this study was to determine the effect of Ab+ and the BDNF Val66Met polymorphism on levels of serum mature BDNF (mBDNF), EM and HV volume at baseline and over 18-months in non-demented older adults. Methods: Non-demented older adults (n¼446) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent Ab neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18-months later. Fasted blood samples were obtained from each participant at baseline and at 18month follow-up. Ab PET neuroimaging was used to classify participants as Ab- or Ab+. Results: At baseline, compared to the Abgroup, the Ab+ group showed significantly worse EM impairment and lower levels of serum mBDNF. Groups did not differ on HV at baseline. BDNF Val66Met polymorphism did not significantly affect serum mBDNF levels, EM performance or HV at baseline. When considered over 18-months, compared to Ab- Val homozygotes, Ab+ Val homozygotes showed significant moderate decline in EM (d¼0.28) and HV (d¼0.42) but not serum mBDNF levels (d¼0.02). Similarly, compared to Ab+ Val homozygotes, Ab+ Met carriers showed significant and moderate decline in EM (d¼0.32) and HV (d¼0.56) over 18-months but showed no change in serum mBDNF levels (d¼0.02). Conclusions: In Ab+ Met carriers, there is substantial EM decline and HV loss over relatively short time intervals. However, there was no relationship between BDNF Val66Met polymorphism and serum mBDNF levels at baseline or over 18-months. Thus, while allelic variation in BDNF Val66Met may influence Ab+ related neurodegeneration and
Poster Presentations: Tuesday, July 26, 2016 PHOSPHORYLATED TAU AND ALPHASYNUCLEIN ACCUMULATION IN FAMILIAL GRANULIN MUTATION CASES
Masato Hosokawa1, Tetsuaki Arai1,2, Hiromi Kondo1, Geidy E. Serrano3, Thomas G. Beach3, Masato Hasegawa1, Haruhiko Akiyama1, 1Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; 2University of Tsukuba, Tsukuba, Japan; 3Banner Sun Health Research Institute, Sun City, AZ, USA. Contact e-mail: [email protected] Background: Granulin (GRN) mutations were identified in patients with familial frontotemporal lobar degeneration (FTLD) with ubiquitin pathology in 2006 studies. GRN transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. GRN mutations were first found in tau-negative FTLD patients, however, recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, PGRN reduction in tau transgenic mice is associated with increasing tau phosphorylation and accumulation. Methods: To investigate the influence of a decline in PGRN protein on other forms of neurodegenerativerelated protein accumulation, human GRN mutation cases were investigated by histochemical and biochemical analyses. Results: The results showed neuronal and glial tau accumulation in all cases analyzed. Massive neuronal tau staining revealed pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated alpha-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau protein was present in the sarkosyl-insoluble fraction, which was composed of threeand four-repeat tau isoforms, resembling Alzheimer’s disease. Conclusions: Our data suggest that PGRN reduction might be the cause of neuronoglial multiple proteinopathies, including TDP-43 proteinopathy, tauopathy and alpha-synucleinopathy, due to the accelerating accumulation of abnormal proteins.
P3-301
WHICH NEUROPATHOLOGICAL MARKER CORRELATES BEST WITH ANTE-MORTEM COGNITIVE SYMPTOMS?
Arnaud Francois1, Cyntia Tremblay2, Charlotte Delay3, Milene Vandal1,4, David A. Bennett5, Frederic Calon2,6, 1CHU de Quebec, Quebec City, QC, Canada; 2CHU de Quebec, Quebec, QC, Canada; 3INSERM U1167, Lilles, France; 4Pharmacy, LAVAL University, Quebec City, QC, Canada; 5Rush Alzheimer’s Disease Center, Chicago, IL, USA; 6Faculty of Pharmacy, Universite Laval, Quebec, QC, Canada. Contact e-mail: frederic.calon@ crchul.ulaval.ca Background: In the present study, we investigated the relationship
between ante mortem global cognitive scores and a series of key AD neuropathological markers assessed post mortem in the same brain cortex region from the same 36 volunteers (12 NCI, 12 MCI and 12 AD) from the Religious Order Study. Methods: Homogenates from the anterior parietal cortex were subjected to differential centrifugation procedures to generate soluble, detergentsoluble, formic acid soluble and sarkosyl insoluble fractions. Biochemical approaches (Western immunoblots and ELISA) were performed to determine the relative levels of tau, Ab, synaptic proteins and other AD-relevant markers in each fraction. Semiquantitative assessments of Ab plaques, tau-laden tangles and TDP-43 inclusions were also analyzed. Results: Overall, the strongest correlation coefficients with global cognitive scores were obtained for insoluble phosphorylated tau (r2 ¼ -0.484), insoluble Ab42 (r2 ¼ -0.389) and neurofibrillary tangles counts (r2 ¼ -0.494). Robust associations were also established for TDP-43-positive cytoplasmic inclusion (r2 ¼ -0.476), total insoluble tau (r2 ¼ -0.385) and Ab plaque counts (r2 ¼ -0.426). Sarkosyl or formic acid-extracted tau led to similar data. Synaptophysin (r2 ¼ +0.335), pS403/404 TDP43 (r2 ¼ +0.265) and Septin-3 (r2¼ +0.257) were also associated with cognitive scores. No correlation was detected with Ab42 or tau in soluble fractions. Conclusions: The most prominent molecular correlates of cognitive decline
Summary of linear correlations between neuropathological markers and ante mortem global cognitive scores. Linear relationship Adjusted(1) Neuropathological Markers(2)
Extraction Method
r2
P
r2
P
Tangle counts S396/404 pTau (AD2) Cytoplasmic S403/404 pTDP43 Inclusion T231 pTau (AT180) Plaque Counts S396/404 pTau (PHF1) iAb42 (pg/mg tissue) Total Tau (tau-13) Synaptophysin Soluble S396/404 pTau (PHF1) Total Tau (HT7) Soluble S403/404 pTDP43 Septin Soluble GSTP1 Xll Soluble PAK123 SIRT1
Bielschowsky silver staining Formic acid extracts Immunofluorescence Formic acid extracts Bielschowsky silver staining Formic acid extracts Formic acid extracts Formic acid extracts Detergent-soluble TBS-soluble Formic acid extracts TBS-soluble Detergent-soluble Detergent-soluble Detergent-soluble TBS-soluble Detergent-soluble
-0,307 -0,385 -0,295 -0,268 -0,279 -0,294 -0,308 -0,265 0,233 -0,211 -0,163 0,174 0,152 -0,105 0,096 0,148 0,116
0.0006 <0.0001 0.0028 0.0017 0.0011 0.0008 0.0005 0.0016 0.0038 0.0063 0.016 0.0127 0.0226 ns ns 0.0270 0.0491
-0,494 -0,484 -0,476 -0,463 -0,426 -0,394 -0,389 -0,385 0,335 -0,314 -0,310 0,265 0,257 -0,254 0,241 0,239 0,179
<0.0001 0.0001 0.0015 0.0003 0.0006 0.0014 0.0017 0.0019 0.0427 0.0066 0.0113 0.0316 0.0254 0.0407 ns ns ns
Notes: (1) Linear regressions were adjusted by age of death, educational level, gender and APOE genotype; (2) Tau antibodies are given in parentheses.
Poster Presentations: Tuesday, July 26, 2016
P957
MCI patients positive to amyloid-PET is overall worse than in negative ones, but significantly greater deterioration over 12 months emerged in only a minority of tests. Longer time or more specific episodic memory tests may be useful for more sensitive monitoring of performance. Differences with previous studies may be due to different selection of tests or to our shorter follow-up. These data contribute information to define the proper time window for repeated testing for neuropsychology used as a biomarker for AD. P3-303 Figure. Cognitive decline in MCI patients over a 12-month follow-up. Horizontal parentheses indicate significant effect of the factor ‘time’, vertical parenthese indicate significant effect of the factor ‘FBP-PET result’, and ‘*’ indicates significant interaction of these factors.
were insoluble phosphorylated tau, followed by TDP43, Ab42 and synaptic proteins. This substantiates the relevance of investigating these markers, discriminated by solubility or phosphorylated epitopes when applicable, to understand the pathogenesis of AD and develop therapeutic tools.
P3-302
BRAIN AMYLOIDOSIS AND COGNITIVE DECLINE IN MCI: 12-MONTH FOLLOW-UP
Daniele Altomare1,2, Cristina Festari1,2, Cristina Muscio1,3, Alessandro Padovani2,4, Giovanni B. Frisoni1,5, Marina Boccardi1, INDIAFBP Working Group, 1IRCCS Fatebenefratelli, Brescia, Italy; 2University of Brescia, Brescia, Italy; 3Fondazione IRCCS Istituto Neurologico, Milano, Italy; 4Spedali Civili di Brescia, Brescia, Italy; 5Universite de Geneve, Geneve, Switzerland. Contact e-mail: [email protected] Background: Two previous studies demonstrated greater cognitive
decline in MCI patients with positive amyloid-PET compared to negative MCI, as assessed by several neuropsychological tests, over 18 (Doraiswamy et al., 2012) and 36 months (Doraiswamy et al., 2014) follow-up. Our aim is to evaluate whether positive amyloid-PET scans are predictive of greater cognitive decline than negative scans over a shorter 12 months period. Methods: A naturalistic series of seventy-six MCI patients underwent amyloid-PET with 18F-Florbetapir (FBP-PET), and homogeneous clinical and neuropsychological multi-domain assessment before FBP-PET and after 12 months (12-FU). For each neuropsychological test we constructed a linear mixed model with scores as the dependent variable, and ‘FBP-PET result’ (positive or negative) and ‘time’ (baseline or 12-FU) as main factors. ‘Age’ and ‘education’ were included as covariates. Effect size indices (partial Eta-squared, hp2) were also computed (0.02, 0.13 and 0.26 referring respectively to small, medium and large Eta-squared). Results: Patients with positive scan had overall worse performance on tests of global functioning (MMSE, p¼0.005, hp2¼0.11; ADAS-COG, p¼0.007, hp2¼0.10) and on tests involving memory (Story recall, p¼0.002, hp2¼0.13; Rey AVLT – Delayed recall, p¼0.005, hp2¼0.11; ReyOsterrieth complex figure – Recall, p ¼ 0.001, hp2¼0.15). A significant worsening over 12 months was observed in ADAS-COG (p¼0.003, hp2¼0.12), Rey-Osterrieth complex figure – Copy (p<0.001, hp2¼0.19), Raven’s CPM (p¼0.039, hp2¼0.06), Letter (p¼0.044, hp2¼0.06) and Category fluency (p¼0.021, hp2¼0.08). Finally, positive patients showed a significantly greater cognitive decline over the time in the Story recall test (p¼0.026, hp2¼0.07) and the Rey-Osterrieth complex figure – Copy (p¼0.018, hp2¼0.08) (Figure). Conclusions: The cognitive performance of
EFFECTS OF AB AND BDNF VAL66MET ON EPISODIC MEMORY, HIPPOCAMPAL VOLUME AND SERUM BDNF IN PRECLINICAL ALZHEIMER’S DISEASE
Yen Ying Lim1, Stephanie R. Rainey-Smith2,3, Simon M. Laws3,4, Veer Gupta5, Tenielle Porter3, Pierrick Bourgeat6, David Ames7, Christopher Fowler8, Olivier Salvado6, Victor L. Villemagne8,9, Christopher C. Rowe10, Colin L. Masters8, Ralph N. Martins2,3, Paul Maruff11,12, AIBL Research Group, 1The Florey Institute, The University of Melbourne, Parkville, Australia; 2Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Australia; 3Edith Cowan University, Perth, Australia; 4Cooperative Research Centre for Mental Health, Melbourne, Australia; 5Edith Cowan University, Joondalup, Australia; 6CSIRO, Brisbane, Australia; 7National Ageing Research Institute, Melbourne, Australia; 8The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 9Department of Molecular Imaging and Therapy, Centre for PET, Austin Health, Heidelberg, Australia; 10Austin Health, Melbourne, Australia; 11Cogstate Ltd., Melbourne, Australia; 12The Florey Institutes of Neurosciences and Mental Health, Melbourne, Australia. Contact e-mail: [email protected]. au Background: In non-demented older adults carriage of the brainderived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Ab) related decline in episodic memory (EM) and hippocampal volume (HV) loss over 36 months. The extent to which Ab+ and BDNF Val66Met is related to circulating markers of BDNF (e.g., serum) is unknown. The aim of this study was to determine the effect of Ab+ and the BDNF Val66Met polymorphism on levels of serum mature BDNF (mBDNF), EM and HV volume at baseline and over 18-months in non-demented older adults. Methods: Non-demented older adults (n¼446) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent Ab neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18-months later. Fasted blood samples were obtained from each participant at baseline and at 18month follow-up. Ab PET neuroimaging was used to classify participants as Ab- or Ab+. Results: At baseline, compared to the Abgroup, the Ab+ group showed significantly worse EM impairment and lower levels of serum mBDNF. Groups did not differ on HV at baseline. BDNF Val66Met polymorphism did not significantly affect serum mBDNF levels, EM performance or HV at baseline. When considered over 18-months, compared to Ab- Val homozygotes, Ab+ Val homozygotes showed significant moderate decline in EM (d¼0.28) and HV (d¼0.42) but not serum mBDNF levels (d¼0.02). Similarly, compared to Ab+ Val homozygotes, Ab+ Met carriers showed significant and moderate decline in EM (d¼0.32) and HV (d¼0.56) over 18-months but showed no change in serum mBDNF levels (d¼0.02). Conclusions: In Ab+ Met carriers, there is substantial EM decline and HV loss over relatively short time intervals. However, there was no relationship between BDNF Val66Met polymorphism and serum mBDNF levels at baseline or over 18-months. Thus, while allelic variation in BDNF Val66Met may influence Ab+ related neurodegeneration and