%0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer's Disease. %A Chatterjee, Pratishtha %A Doré, Vincent %A Pedrini, Steve %A Krishnadas, Natasha %A Thota, Rohith %A Bourgeat, Pierrick %A Ikonomovic, Milos D %A Rainey-Smith, Stephanie R %A Burnham, Samantha C %A Fowler, Christopher %A Taddei, Kevin %A Mulligan, Rachel %A Ames, David %A Masters, Colin L %A Fripp, Jurgen %A Rowe, Christopher C %A Martins, Ralph N %A Villemagne, Victor L %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Astrocytes %K Biomarkers %K Brain %K Cognitive Dysfunction %K Glial Fibrillary Acidic Protein %K Humans %K Positron-Emission Tomography %K tau Proteins %X

BACKGROUND: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD.

OBJECTIVE: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers.

METHODS: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest.

RESULTS: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG.

CONCLUSION: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

%B J Alzheimers Dis %V 92 %P 615-628 %8 2023 %G eng %N 2 %R 10.3233/JAD-220908 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults. %A Gardener, Samantha L %A Weinborn, Michael %A Sohrabi, Hamid R %A Doecke, James D %A Bourgeat, Pierrick %A Rainey-Smith, Stephanie R %A Shen, Kai-Kai %A Fripp, Jurgen %A Taddei, Kevin %A Maruff, Paul %A Salvado, Olivier %A Savage, Greg %A Ames, David %A Masters, Colin L %A Rowe, Christopher C %A Martins, Ralph N %X

BACKGROUND: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable.

OBJECTIVE: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years.

METHODS: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30-44 years old, and in the unimpaired range for all other cognitive domains over the course of the study.

RESULTS: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs.

CONCLUSION: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

%B J Alzheimers Dis %V 81 %P 1039-1052 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-201243 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration. %A Moussavi Nik, Seyyed Hani %A Porter, Tenielle %A Newman, Morgan %A Bartlett, Benjamin %A Khan, Imran %A Sabale, Miheer %A Eccles, Melissa %A Woodfield, Amy %A Groth, David %A Doré, Vincent %A Villemagne, Victor L %A Masters, Colin L %A Martins, Ralph N %A Laws, Simon M %A Lardelli, Michael %A Verdile, Giuseppe %X

BACKGROUND: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined.

OBJECTIVE: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study.

METHODS: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load.

RESULTS: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= -0.269, p = 0.03).

CONCLUSION: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

%B J Alzheimers Dis %V 80 %P 1479-1489 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201133 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance. %A Pedrini, Steve %A Hone, Eugene %A Gupta, Veer B %A James, Ian %A Teimouri, Elham %A Bush, Ashley I %A Rowe, Christopher C %A Villemagne, Victor L %A Ames, David %A Masters, Colin L %A Rainey-Smith, Stephanie %A Verdile, Giuseppe %A Sohrabi, Hamid R %A Raida, Manfred R %A Wenk, Markus R %A Taddei, Kevin %A Chatterjee, Pratishtha %A Martins, Ian %A Laws, Simon M %A Martins, Ralph N %X

BACKGROUND: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL.

OBJECTIVE: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition.

METHODS: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests.

RESULTS: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels.

CONCLUSION: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.

%B J Alzheimers Dis %V 77 %P 733-744 %8 2020 Sep 15 %G eng %N 2 %R 10.3233/JAD-200291 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-β Load. %A Chatterjee, Pratishtha %A Mohammadi, Maryam %A Goozee, Kathryn %A Shah, Tejal M %A Sohrabi, Hamid R %A Dias, Cintia B %A Shen, Kaikai %A Asih, Prita R %A Dave, Preeti %A Pedrini, Steve %A Ashton, Nicholas J %A Hye, Abdul %A Taddei, Kevin %A Lovejoy, David B %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND/OBJECTIVE: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL).

METHODS: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)

RESULTS: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOEɛ4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aβ42/40 ratio (AUC = 0.829).

CONCLUSION: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

%B J Alzheimers Dis %V 76 %P 291-301 %8 2020 Jun 30 %G eng %N 1 %R 10.3233/JAD-200162 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Ultrasensitive Detection of Plasma Amyloid-β as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer's Disease. %A Chatterjee, Pratishtha %A Elmi, Mitra %A Goozee, Kathryn %A Shah, Tejal %A Sohrabi, Hamid R %A Dias, Cintia B %A Pedrini, Steve %A Shen, Kaikai %A Asih, Prita R %A Dave, Preeti %A Taddei, Kevin %A Vanderstichele, Hugo %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers.

OBJECTIVE: Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals.

METHODS: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ-, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35).

RESULTS: Plasma Aβ42/Aβ40 ratios were lower in the Aβ+ group compared to the Aβ-group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ-and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42/Aβ40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aβ+ participants being distinguished from Aβ-participants based on an area under the receiver operating characteristic curve shown to be 78%.

CONCLUSION: Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker.

%B J Alzheimers Dis %V 71 %P 775-783 %8 2019 Oct 1 %G eng %N 3 %R 10.3233/JAD-190533 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies. %A Martins, Ralph N %A Villemagne, Victor %A Sohrabi, Hamid R %A Chatterjee, Pratishtha %A Shah, Tejal M %A Verdile, Giuseppe %A Fraser, Paul %A Taddei, Kevin %A Gupta, Veer B %A Rainey-Smith, Stephanie R %A Hone, Eugene %A Pedrini, Steve %A Lim, Wei Ling %A Martins, Ian %A Frost, Shaun %A Gupta, Sunil %A O'Bryant, Sid %A Rembach, Alan %A Ames, David %A Ellis, Kathryn %A Fuller, Stephanie J %A Brown, Belinda %A Gardener, Samantha L %A Fernando, Binosha %A Bharadwaj, Prashant %A Burnham, Samantha %A Laws, Simon M %A Barron, Anna M %A Goozee, Kathryn %A Wahjoepramono, Eka J %A Asih, Prita R %A Doecke, James D %A Salvado, Olivier %A Bush, Ashley I %A Rowe, Christopher C %A Gandy, Samuel E %A Masters, Colin L %X

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

%B J Alzheimers Dis %V 62 %P 965-992 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562546?dopt=Abstract %R 10.3233/JAD-171145 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants. %A Chatterjee, Pratishtha %A Goozee, Kathryn %A Sohrabi, Hamid R %A Shen, Kaikai %A Shah, Tejal %A Asih, Prita R %A Dave, Preeti %A ManYan, Candice %A Taddei, Kevin %A Chung, Roger %A Zetterberg, Henrik %A Blennow, Kaj %A Martins, Ralph N %X

BACKGROUND: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood.

OBJECTIVE: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults.

METHODS: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire.

RESULTS: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC.

CONCLUSION: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

%B J Alzheimers Dis %V 63 %P 479-487 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29630554?dopt=Abstract %R 10.3233/JAD-180025 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations of Dietary Protein and Fiber Intake with Brain and Blood Amyloid-β. %A Fernando, W M A D Binosha %A Rainey-Smith, Stephanie R %A Gardener, Samantha L %A Villemagne, Victor L %A Burnham, Samantha C %A Macaulay, S Lance %A Brown, Belinda M %A Gupta, Veer Bala %A Sohrabi, Hamid R %A Weinborn, Michael %A Taddei, Kevin %A Laws, Simon M %A Goozee, Kathryn %A Ames, David %A Fowler, Christopher %A Maruff, Paul %A Masters, Colin L %A Salvado, Olivier %A Rowe, Christopher C %A Martins, Ralph N %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Australia %K Biomarkers %K Brain %K Cognition %K Cohort Studies %K Cross-Sectional Studies %K Dietary Fiber %K Dietary Proteins %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %X

Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer's disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of 'high' brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of 'high' Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.

%B J Alzheimers Dis %V 61 %P 1589-1598 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376865?dopt=Abstract %R 10.3233/JAD-170742 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. %A Brown, Belinda M %A Rainey-Smith, Stephanie R %A Doré, Vincent %A Peiffer, Jeremiah J %A Burnham, Samantha C %A Laws, Simon M %A Taddei, Kevin %A Ames, David %A Masters, Colin L %A Rowe, Christopher C %A Martins, Ralph N %A Villemagne, Victor L %X

Numerous animal studies have reported exercise reduces the accumulation of Alzheimer's disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: - 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA.

%B J Alzheimers Dis %V 63 %P 1299-1305 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758940?dopt=Abstract %R 10.3233/JAD-170998 %0 Journal Article %J J Alzheimers Dis %D 2017 %T APOEɛ4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults. %A Hollands, Simone %A Lim, Yen Ying %A Laws, Simon M %A Villemagne, Victor L %A Pietrzak, Robert H %A Harrington, Karra %A Porter, Tenielle %A Snyder, Peter %A Ames, David %A Fowler, Christopher %A Rainey-Smith, Stephanie R %A Martins, Ralph N %A Salvado, Olivier %A Robertson, Joanne %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ɛ4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOEɛ4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ.

OBJECTIVE: To determine the extent and nature to which APOEɛ4 increases risk for clinical disease progression in CN older adults.

METHODS: Data from the total (n = 765) and Aβ-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate ɛ4 risk for clinical disease progression over a 72-month follow-up.

RESULTS: With Aβ status unknown and risk from demographic characteristics controlled, ɛ4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ4 carriage was no longer predictive of clinical disease progression.

CONCLUSION: In CN older adults, the risk of ɛ4 for clinical disease progression occurs through the effect of ɛ4 increasing Aβ levels.

%B J Alzheimers Dis %V 57 %G eng %N 2 %& 411-422 %R 10.3233/JAD-161019 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Diabetes and Alzheimer's Disease: Can Tea Phytochemicals Play a Role in Prevention? %A Fernando, Warnakulasuriya M A D B %A Somaratne, Geeshani %A Goozee, Kathryn G %A Williams, Shehan %A Singh, Harjinder %A Martins, Ralph N %X

Dementia and diabetes mellitus are prevalent disorders in the elderly population. While recognized as two distinct diseases, diabetes has more recently recognized as a significant contributor to risk for developing dementia, and some studies make reference to type 3 diabetes, a condition resulting from insulin resistance in the brain. Alzheimer's disease, the most common form of dementia, and diabetes, interestingly, share underlying pathological processes, commonality in risk factors, and, importantly, pathways for intervention. Tea has been suggested to possess potent antioxidant properties. It is rich in phytochemicals including, flavonoids, tannins, caffeine, polyphenols, boheic acid, theophylline, theobromine, anthocyanins, gallic acid, and finally epigallocatechin-3-gallate, which is considered to be the most potent active ingredient. Flavonoid phytochemicals, known as catechins, within tea offer potential benefits for reducing the risk of diabetes and Alzheimer's disease by targeting common risk factors, including obesity, hyperlipidemia, hypertension, cardiovascular disease, and stroke. Studies also show that catechins may prevent the formation of amyloid-β plaques and enhance cognitive functions, and thus may be useful in treating patients who have Alzheimer's disease or dementia. Furthermore, other phytochemicals found within tea offer important antioxidant properties along with innate properties capable of modulating intracellular neuronal signal transduction pathways and mitochondrial function.

%B J Alzheimers Dis %V 59 %P 481-501 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582855?dopt=Abstract %R 10.3233/JAD-161200 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE Genotype on Amyloid Deposition, Brain Volume, and Memory in Cognitively Normal Older Individuals. %A Lim, Yen Ying %A Williamson, Robert %A Laws, Simon M %A Villemagne, Victor L %A Bourgeat, Pierrick %A Fowler, Christopher %A Rainey-Smith, Stephanie %A Salvado, Olivier %A Martins, Ralph N %A Rowe, Christopher C %A Masters, Colin L %A Maruff, Paul %X

BACKGROUND: The association between the apolipoprotein E (APOE) ɛ4 allele and high risk of developing Alzheimer's disease (AD) dementia before the age of 80 has been recognized for over 30 years. However, the timing and mode of action of APOE is not understood, nor has there been a detailed analysis of the effect of APOE genotype on memory, hippocampal volume, and amyloid-β (Aβ) levels in cognitively normal adults.

OBJECTIVE: Examine the effect of APOE allelic genotype on the relationship between Aβ levels, hippocampal volume, and memory in cognitively normal adults.

METHODS: This is a cross-sectional study of 989 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, all of whom underwent APOE genotyping and memory assessment. A subset of this group underwent PET neuroimaging for Aβ (n = 585) and MRI for hippocampal volume (n = 303).

RESULTS: APOEɛ4 homozygotes (ɛ4/ɛ4) showed significantly worse episodic memory and higher Aβ levels than ɛ4 heterozygotes. The relationship between increasing Aβ levels and worse episodic memory was significant for ɛ3 homozygotes (ɛ3/ɛ3), ɛ4 heterozygotes, and strongest for ɛ4 homozygotes. There were no differences in hippocampal volume between APOE groups; the relationship between smaller hippocampal volume and worse episodic memory was significant only for ɛ4 homozygotes.

CONCLUSION: APOE acts in a co-dominant fashion on Aβ levels, episodic memory, and hippocampal volume in cognitively normal older adults. APOEɛ4 is central to the events that lead to AD in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance.

%B J Alzheimers Dis %V 58 %P 1293-1302 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28550258?dopt=Abstract %R 10.3233/JAD-170072 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Carbohydrate Intake is Associated with Poorer Performance in Verbal Memory and Attention in an APOE Genotype-Dependent Manner. %A Gardener, Samantha L %A Rainey-Smith, Stephanie R %A Sohrabi, Hamid R %A Weinborn, Michael %A Verdile, Giuseppe %A Fernando, W M A D Binosha %A Lim, Yen Ying %A Harrington, Karra %A Burnham, Samantha %A Taddei, Kevin %A Masters, Colin L %A Macaulay, Stuart L %A Rowe, Christopher C %A Ames, David %A Maruff, Paul %A Martins, Ralph N %X

Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer's disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ɛ4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOEɛ4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOEɛ4 allele non-carriers, and poorer performance in attention in APOEɛ4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.

%B J Alzheimers Dis %V 58 %P 193-201 %G eng %N 1 %R 10.3233/JAD-161158 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Lipidomic Profiles in Diabetes and Dementia. %A Huynh, Kevin %A Martins, Ralph N %A Meikle, Peter J %X

Lipids are a diverse class of hydrophobic and amphiphilic molecules which make up the bulk of most biological systems and are essential for human life. The role of lipids in health and disease has been recognized for many decades, as evidenced by the early identification of cholesterol as an important risk factor of heart disease and the development and introduction of statins as a one of the most successful therapeutic interventions to date. While several studies have demonstrated an increased risk of dementia, including Alzheimer's disease (AD), in those with diabetes mellitus, the nature of this risk is not well understood. Recent developments in the field of lipidomics, driven primarily by technological advances in high pressure liquid chromatography and particularly mass spectrometry, have enabled the detailed characterization of the many hundreds of individual lipid species in mammalian systems and their association with disease states. Diabetes mellitus and AD have received particular attention due to their prominence in Western societies as a result of the ongoing obesity epidemic and the aging populations. In this review, we examine how these lipidomic studies are informing on the relationship between lipid metabolism with diabetes and AD and how this may inform on the common pathological pathways that link diabetes risk with dementia.

%B J Alzheimers Dis %V 59 %P 433-444 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28582856?dopt=Abstract %R 10.3233/JAD-161215 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer's Disease: Testosterone as a Modifier. %A Asih, Prita R %A Tegg, Michelle L %A Sohrabi, Hamid %A Carruthers, Malcolm %A Gandy, Samuel E %A Saad, Farid %A Verdile, Giuseppe %A Ittner, Lars M %A Martins, Ralph N %X

Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal aging, and although there is no significant increase in cerebral Aβ deposition in T2DM, the extent of Aβ accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk.

%B J Alzheimers Dis %V 59 %P 445-466 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28655134?dopt=Abstract %R 10.3233/JAD-161259 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Amyloid-β Peptides in Type 2 Diabetes: A Matched Case-Control Study. %A Peters, Kirsten E %A Davis, Wendy A %A Taddei, Kevin %A Martins, Ralph N %A Masters, Colin L %A Davis, Timothy M E %A Bruce, David G %X

BACKGROUND: Plasma amyloid-β (Aβ) levels have rarely been investigated in type 2 diabetes despite its known associations with Alzheimer's disease.

OBJECTIVE: To compare blood plasma Aβ concentrations (Aβ40 and Aβ42) in cognitively normal individuals with and without type 2 diabetes.

METHODS: Plasma Aβ40 and Aβ42 were measured in 194 participants with diabetes recruited from the community-based Fremantle Diabetes Study Phase II cohort (mean age 71 years, 59% males) and 194 age-, sex-, and APOEɛ4 allele-matched, control subjects without diabetes from the Australian Imaging, Biomarkers and Lifestyle Study using a multiplex microsphere-based immunoassay.

RESULTS: Plasma Aβ40 and Aβ42 were normally distributed in the controls but were bimodal in the participants with diabetes. Median Aβ40 and Aβ42 concentrations were significantly lower in those with type 2 diabetes (Aβ40 median [inter-quartile range]: 125.0 [52.6-148.3] versus 149.3 [134.0-165.6] pg/mL; Aβ42: 26.9 [14.5-38.3] versus 33.6 [28.0-38.9] pg/mL, both p < 0.001) while the ratio Aβ42:Aβ40 was significantly higher (0.26 [0.23-0.32] versus 0.22 [0.19-0.25], p < 0.001). After adjustment, participants with diabetes and plasma Aβ40 levels in the low peak of the bimodal distribution were significantly more likely to have normal to high estimated glomerular filtration rates (odds ratio (95% CI): 2.40 (1.20-4.80), p = 0.013) although the group with diabetes had lower renal function overall.

CONCLUSION: Type 2 diabetes is associated with altered plasma concentrations of Aβ peptides and is an important source of variation that needs to be taken into account when considering plasma Aβ peptides as biomarkers for Alzheimer's disease.

%B J Alzheimers Dis %V 56 %P 1127-1133 %G eng %N 3 %R 10.3233/JAD-161050 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). %A Cardoso, Bárbara R %A Hare, Dominic J %A Bush, Ashley I %A Li, Qiao-Xin %A Fowler, Christopher J %A Masters, Colin L %A Martins, Ralph N %A Ganio, Katherine %A Lothian, Amber %A Mukherjee, Soumya %A Kapp, Eugene A %A Roberts, Blaine R %X

Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.

%B J Alzheimers Dis %V 57 %P 183-193 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222503?dopt=Abstract %R 10.3233/JAD-160622 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults. %A Gardener, Samantha L %A Sohrabi, Hamid R %A Shen, Kai-Kai %A Rainey-Smith, Stephanie R %A Weinborn, Michael %A Bates, Kristyn A %A Shah, Tejal %A Foster, Jonathan K %A Lenzo, Nat %A Salvado, Olivier %A Laske, Christoph %A Laws, Simon M %A Taddei, Kevin %A Verdile, Giuseppe %A Martins, Ralph N %X

Increasing evidence suggests that Alzheimer's disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.

%B J Alzheimers Dis %V 52 %P 661-72 %8 2016 Mar 31 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031482?dopt=Abstract %R 10.3233/JAD-151084 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diet and Inflammation in Alzheimer's Disease and Related Chronic Diseases: A Review. %A Gardener, Samantha L %A Rainey-Smith, Stephanie R %A Martins, Ralph N %K Alzheimer Disease %K Cardiovascular Diseases %K Chronic Disease %K Diet %K Humans %K Inflammation %K Neurodegenerative Diseases %X

Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer's disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity.

%B J Alzheimers Dis %V 50 %P 301-34 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682690?dopt=Abstract %R 10.3233/JAD-150765 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity. %A Porter, Tenielle %A Bharadwaj, Prashant %A Groth, David %A Paxman, Adrian %A Laws, Simon M %A Martins, Ralph N %A Verdile, Giuseppe %K Amyloid beta-Peptides %K Analysis of Variance %K Antipsychotic Agents %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Drug Interactions %K Humans %K Indoles %K L-Lactate Dehydrogenase %K Microscopy, Atomic Force %K Neuroblastoma %K Peptide Fragments %K Protein Aggregates %X

Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.

%B J Alzheimers Dis %V 50 %P 895-905 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836170?dopt=Abstract %R 10.3233/JAD-150790 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study. %A Chatterjee, Pratishtha %A Lim, Wei L F %A Shui, Guanghou %A Gupta, Veer B %A James, Ian %A Fagan, Anne M %A Xiong, Chengjie %A Sohrabi, Hamid R %A Taddei, Kevin %A Brown, Belinda M %A Benzinger, Tammie %A Masters, Colin %A Snowden, Stuart G %A Wenk, Marcus R %A Bateman, Randall J %A Morris, John C %A Martins, Ralph N %K Adult %K Alzheimer Disease %K Apolipoproteins E %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Mutation %K Phospholipids %K Pilot Projects %K Presenilin-1 %K Sphingolipids %X

BACKGROUND AND OBJECTIVE: Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD).

METHODS: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient.

RESULTS: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p <  0.05).

CONCLUSION: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.

%B J Alzheimers Dis %V 50 %P 887-94 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836186?dopt=Abstract %R 10.3233/JAD-150948 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. %A Li, Qiao-Xin %A Villemagne, Victor L %A Doecke, James D %A Rembach, Alan %A Sarros, Shannon %A Varghese, Shiji %A McGlade, Amelia %A Laughton, Katrina M %A Pertile, Kelly K %A Fowler, Christopher J %A Rumble, Rebecca L %A Trounson, Brett O %A Taddei, Kevin %A Rainey-Smith, Stephanie R %A Laws, Simon M %A Robertson, Joanne S %A Evered, Lisbeth A %A Silbert, Brendan %A Ellis, Kathryn A %A Rowe, Christopher C %A Macaulay, S Lance %A Darby, David %A Martins, Ralph N %A Ames, David %A Masters, Colin L %A Collins, Steven %X

BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD).

OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands.

METHODS: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology.

RESULTS: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity.

CONCLUSIONS: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

%B J Alzheimers Dis %V 48 %P 175-87 %8 2015 Aug 28 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26401938?dopt=Abstract %R 10.3233/JAD-150247