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1. Author Correction: Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease (Nature Communications, (2021), 12, 1, (721), 10.1038/s41467-021-21057-y)

Author

Roe, JM, Vidal-Piñeiro, D, Sørensen, Ø, Brandmaier, AM, Düzel, S, Gonzalez, HA, Kievit, RA, Knights, E, Kühn, S, Lindenberger, U, Mowinckel, AM, Nyberg, L, Park, DC, Pudas, S, Rundle, MM, Walhovd, KB, Fjell, AM, Westerhausen, R, Masters, CL, Bush, AI, Fowler, C, Darby, D, Pertile, K, Restrepo, C, Roberts, B, Robertson, J, Rumble, R, Ryan, T, Collins, S, Thai, C, Trounson, B, Lennon, K, Li, QX, Ugarte, FY, Volitakis, I, Vovos, M, Williams, R, Baker, J, Russell, A, Peretti, M, Milicic, L, Lim, L, Rodrigues, M, Taddei, K, Taddei, T, Hone, E, Lim, F, Fernandez, S, Rainey-Smith, S, Pedrini, S, Martins, R, Doecke, J, Bourgeat, P, Fripp, J, Gibson, S, Leroux, H, Hanson, D, Dore, V, Zhang, P, Burnham, S, Rowe, CC, Villemagne, VL, Yates, P, Pejoska, SB, Jones, G, Ames, D, Cyarto, E, Lautenschlager, N, Barnham, K, Cheng, L, Hill, A, Killeen, N, Maruff, P, Silbert, B, Brown, B, Sohrabi, H, Savage, G, Vacher, M, Roe, JM, Vidal-Piñeiro, D, Sørensen, Ø, Brandmaier, AM, Düzel, S, Gonzalez, HA, Kievit, RA, Knights, E, Kühn, S, Lindenberger, U, Mowinckel, AM, Nyberg, L, Park, DC, Pudas, S, Rundle, MM, Walhovd, KB, Fjell, AM, Westerhausen, R, Masters, CL, Bush, AI, Fowler, C, Darby, D, Pertile, K, Restrepo, C, Roberts, B, Robertson, J, Rumble, R, Ryan, T, Collins, S, Thai, C, Trounson, B, Lennon, K, Li, QX, Ugarte, FY, Volitakis, I, Vovos, M, Williams, R, Baker, J, Russell, A, Peretti, M, Milicic, L, Lim, L, Rodrigues, M, Taddei, K, Taddei, T, Hone, E, Lim, F, Fernandez, S, Rainey-Smith, S, Pedrini, S, Martins, R, Doecke, J, Bourgeat, P, Fripp, J, Gibson, S, Leroux, H, Hanson, D, Dore, V, Zhang, P, Burnham, S, Rowe, CC, Villemagne, VL, Yates, P, Pejoska, SB, Jones, G, Ames, D, Cyarto, E, Lautenschlager, N, Barnham, K, Cheng, L, Hill, A, Killeen, N, Maruff, P, Silbert, B, Brown, B, Sohrabi, H, Savage, G, and Vacher, M

Abstract

In this article the affiliation details for Ulman Lindenberger were incorrectly given as ‘Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany’ but should have been ‘Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany’, ‘Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany’. The original article has been corrected.

Published
2022

2. Fifteen years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and observations from 2,359 older adults spanning the spectrum from cognitive normality to Alzheimer’s Disease

Author

Fowler, C., Rainey-Smith, S.R., Bird, S., Bomke, J., Bourgeat, P., Brown, B.M., Burnham, S.C., Bush, A.I., Chadunow, C., Collins, S., Doecke, J., Doré, V., Ellis, K.A., Evered, L., Fazlollahi, A., Fripp, J., Gardener, S.L., Gibson, S., Grenfell, R., Harrison, E., Head, R., Jin, L., Kamer, A., Lamb, F., Lautenschlager, N.T., Laws, S.M., Li, Q-X, Lim, L., Lim, Y.Y., Louey, A., Macaulay, S.L., Mackintosh, L., Martins, R.N., Maruff, P., Masters, C.L., McBride, S., Milicic, L., Peretti, M., Pertile, K., Porter, T., Radler, M., Rembach, A., Robertson, J., Rodrigues, M., Rowe, C.C., Rumble, R., Salvado, O., Savage, G., Silbert, B., Soh, M., Sohrabi, H.R., Taddei, K., Taddei, T., Thai, C., Trounson, B., Tyrrell, R., Vacher, M., Varghese, S., Villemagne, V.L., Weinborn, M., Woodward, M., Xia, Y., Ames, D., Fowler, C., Rainey-Smith, S.R., Bird, S., Bomke, J., Bourgeat, P., Brown, B.M., Burnham, S.C., Bush, A.I., Chadunow, C., Collins, S., Doecke, J., Doré, V., Ellis, K.A., Evered, L., Fazlollahi, A., Fripp, J., Gardener, S.L., Gibson, S., Grenfell, R., Harrison, E., Head, R., Jin, L., Kamer, A., Lamb, F., Lautenschlager, N.T., Laws, S.M., Li, Q-X, Lim, L., Lim, Y.Y., Louey, A., Macaulay, S.L., Mackintosh, L., Martins, R.N., Maruff, P., Masters, C.L., McBride, S., Milicic, L., Peretti, M., Pertile, K., Porter, T., Radler, M., Rembach, A., Robertson, J., Rodrigues, M., Rowe, C.C., Rumble, R., Salvado, O., Savage, G., Silbert, B., Soh, M., Sohrabi, H.R., Taddei, K., Taddei, T., Thai, C., Trounson, B., Tyrrell, R., Vacher, M., Varghese, S., Villemagne, V.L., Weinborn, M., Woodward, M., Xia, Y., and Ames, D.

Abstract

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

Published
2021

3. SPON1 Is associated with Amyloid-β and APOE ε4-Related cognitive decline in cognitively normal adults

Author

Fernandez, S., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Peretti, M., Sohrabi, H.R., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Porter, T., Laws, S.M., Fernandez, S., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Peretti, M., Sohrabi, H.R., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Porter, T., and Laws, S.M.

Abstract

Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease. Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults. Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study. Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020). Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.

Published
2021

4. Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition

Author

Tan, S., Porter, T., Bucks, R.S., Weinborn, M., Milicic, L., Brown, A., Rainey-Smith, S.R., Taddei, K., Ames, D., Masters, C.L., Maruff, P., Savage, G., Rowe, C.C., Villemagne, V.L., Brown, B., Sohrabi, H.R., Laws, S.M., Martins, R.N., Tan, S., Porter, T., Bucks, R.S., Weinborn, M., Milicic, L., Brown, A., Rainey-Smith, S.R., Taddei, K., Ames, D., Masters, C.L., Maruff, P., Savage, G., Rowe, C.C., Villemagne, V.L., Brown, B., Sohrabi, H.R., Laws, S.M., and Martins, R.N.

Abstract

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.

Published
2021

5. Alzheimer’s Disease-related Gene Expression Is Reduced Following Six Months Of High-intensity Exercise

Author

Brown, B.M., Milicic, L., Porter, T., Rainey-Smith, S.R., Peretti, M., Vacher, M., Sohrabi, H.R., Martins, R.N., Peiffer, J.J., Laws, S.M., Brown, B.M., Milicic, L., Porter, T., Rainey-Smith, S.R., Peretti, M., Vacher, M., Sohrabi, H.R., Martins, R.N., Peiffer, J.J., and Laws, S.M.

Abstract

Extensive research supports the use of exercise to protect against Alzheimer’s disease (AD). Nevertheless, there is limited evidence from human studies regarding the mechanisms underlying the positive effects of exercise on the brain. Gene expression determines the extent to which a gene is ‘turned on or off’ and can be used to understand mechanistic pathways. Animal research has demonstrated that exercise influences the expression of genes related to various AD biological pathways; however, the impact of exercise on AD-related gene expression has not yet been studied in humans. PURPOSE: To examine changes in AD-related gene expression following a six-month high-intensity exercise intervention. METHODS: Cognitively normal men and women (60-80y) were randomised to either six-months of work-matched high-intensity exercise (n=33), moderate-intensity exercise (n=34) or an inactive control group (n=32). Blood samples were collected pre- and post-intervention and expression levels from a panel of genes implicated in AD were measured. Analysis of covariance (covaried for age and gender), with adjustment for multiple comparisons, was conducted to determine group differences. RESULTS: Decreases in AD-related gene expression following six months of exercise, compared with the control group. More specifically, gene expression associated with cholesterol metabolism (ABCA1; p < 0.001), amyloid precursor protein processing (ADAM17, BACE1; p < 0.05) and synaptic plasticity (UCHL1; p < 0.001) was favourably altered in the high-intensity exercise intervention, compared with the moderate-intensity intervention and control groups. CONCLUSIONS: Investigation of AD-related gene expression has the potential to play an important role in understanding the biological pathways by which exercise reduces AD risk and contributes to enhanced cognitive health. The current work indicates a dose-dependent effect of exercise intensity on the expression of genes associated with AD, revealing mechanis

Published
2020

6. Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture

Author

Zhang, Q, Sidorenko, J, Couvy-Duchesne, B, Marioni, RE, Wright, MJ, Goate, AM, Marcora, E, Huang, KL, Porter, T, Laws, SM, Masters, CL, Bush, AI, Fowler, C, Darby, D, Pertile, K, Restrepo, C, Roberts, B, Robertson, J, Rumble, R, Ryan, T, Collins, S, Thai, C, Trounson, B, Lennon, K, Li, QX, Ugarte, FY, Volitakis, I, Vovos, M, Williams, R, Baker, J, Russell, A, Peretti, M, Milicic, L, Lim, L, Rodrigues, M, Taddei, K, Taddei, T, Hone, E, Lim, F, Fernandez, S, Rainey-Smith, S, Pedrini, S, Martins, R, Doecke, J, Bourgeat, P, Fripp, J, Gibson, S, Leroux, H, Hanson, D, Dore, V, Zhang, P, Burnham, S, Rowe, CC, Villemagne, VL, Yates, P, Pejoska, SB, Jones, G, Ames, D, Cyarto, E, Lautenschlager, N, Barnham, K, Cheng, L, Hill, A, Killeen, N, Maruff, P, Silbert, B, Brown, B, Sohrabi, H, Savage, G, Vacher, M, Sachdev, PS, Mather, KA, Armstrong, NJ, Thalamuthu, A, Brodaty, H, Yengo, L, Yang, J, Wray, NR, McRae, AF, Visscher, PM, Zhang, Q, Sidorenko, J, Couvy-Duchesne, B, Marioni, RE, Wright, MJ, Goate, AM, Marcora, E, Huang, KL, Porter, T, Laws, SM, Masters, CL, Bush, AI, Fowler, C, Darby, D, Pertile, K, Restrepo, C, Roberts, B, Robertson, J, Rumble, R, Ryan, T, Collins, S, Thai, C, Trounson, B, Lennon, K, Li, QX, Ugarte, FY, Volitakis, I, Vovos, M, Williams, R, Baker, J, Russell, A, Peretti, M, Milicic, L, Lim, L, Rodrigues, M, Taddei, K, Taddei, T, Hone, E, Lim, F, Fernandez, S, Rainey-Smith, S, Pedrini, S, Martins, R, Doecke, J, Bourgeat, P, Fripp, J, Gibson, S, Leroux, H, Hanson, D, Dore, V, Zhang, P, Burnham, S, Rowe, CC, Villemagne, VL, Yates, P, Pejoska, SB, Jones, G, Ames, D, Cyarto, E, Lautenschlager, N, Barnham, K, Cheng, L, Hill, A, Killeen, N, Maruff, P, Silbert, B, Brown, B, Sohrabi, H, Savage, G, Vacher, M, Sachdev, PS, Mather, KA, Armstrong, NJ, Thalamuthu, A, Brodaty, H, Yengo, L, Yang, J, Wray, NR, McRae, AF, and Visscher, PM

Abstract

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer’s disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.

Published
2020

7. P4-485: SPON1 is associated with Aβ-Amyloid and APOE ε4 related cognitive decline in cognitively normal adults

Author

Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Peretti, M., Sohrabi, H.R., Ying Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S.R., Rowe, C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Peretti, M., Sohrabi, H.R., Ying Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S.R., Rowe, C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.

Abstract

Poster presentation

Published
2019

8. COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

Author

Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Sohrabi, H.R., Peretti, M., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Sohrabi, H.R., Peretti, M., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.

Abstract

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol-O-methyltransferase (COMT) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E (APOE) ε4 allele on cognition in preclinical Alzheimer’s disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults.

Published
2019

9. Klotho allele status is not associated with Aβ and APOE ε4–related cognitive decline in preclinical Alzheimer's disease

Author

Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.

Abstract

The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4–driven cognitive decline in preclinical AD.

Published
2019

10. Validation of a priori candidate Alzheimer’s disease SNPs with brain amyloid-beta deposition

Author

Vacher, M., Porter, T., Villemagne, V.L., Milicic, L., Peretti, M., Fowler, C., Martins, R., Rainey-Smith, S., Ames, D., Masters, C.L., Rowe, C.C., Doecke, J.D., Laws, S.M., Vacher, M., Porter, T., Villemagne, V.L., Milicic, L., Peretti, M., Fowler, C., Martins, R., Rainey-Smith, S., Ames, D., Masters, C.L., Rowe, C.C., Doecke, J.D., and Laws, S.M.

Abstract

The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer’s disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ−) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts.

Published
2019

11. Klotho allele status is not associated with Aß and APOE e4–related cognitive decline in preclinical Alzheimer's disease

Author

Porter, T., Burnham, S., Milicic, L., Savage, G., Maruff, P., Lim, Y., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Groth, David, Verdile, Giuseppe, Villemagne, V., Laws, S., Porter, T., Burnham, S., Milicic, L., Savage, G., Maruff, P., Lim, Y., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Groth, David, Verdile, Giuseppe, Villemagne, V., and Laws, S.

Abstract

© 2019 Elsevier Inc. The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-ß (Aß) burden, and carriage of the apolipoprotein E (APOE) e4 allele on cognitive decline. This study involved 581 Aß-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aß burden and APOE e4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aß burden and APOE e4–driven cognitive decline in preclinical AD.

Published
2019

12. A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease

Author

Porter, T., Burnham, S., Savage, G., Lim, Y., Maruff, P., Milicic, L., Peretti, M., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Taddei, K., Groth, David, Verdile, Giuseppe, Villemagne, V., Laws, Simon, Porter, T., Burnham, S., Savage, G., Lim, Y., Maruff, P., Milicic, L., Peretti, M., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Taddei, K., Groth, David, Verdile, Giuseppe, Villemagne, V., and Laws, Simon

Abstract

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of

Published
2018

13. Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden

Author

Rainey-Smith, S.R., Mazzucchelli, G.N., Villemagne, V.L., Brown, B.M., Porter, T., Weinborn, M., Bucks, R.S., Milicic, L., Sohrabi, H.R., Taddei, K., Ames, D., Maruff, P., Masters, C.L., Rowe, C.C., Salvado, O., Martins, R.N., Laws, S.M., Rainey-Smith, S.R., Mazzucchelli, G.N., Villemagne, V.L., Brown, B.M., Porter, T., Weinborn, M., Bucks, R.S., Milicic, L., Sohrabi, H.R., Taddei, K., Ames, D., Maruff, P., Masters, C.L., Rowe, C.C., Salvado, O., Martins, R.N., and Laws, S.M.

Abstract

The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.

Published
2018

14. Cognitive gene risk profile for the prediction of cognitive decline in presymptomatic Alzheimer’s disease

Author

Porter, T., Villemagne, V.L., Savage, G., Milicic, L., Ying Lim, Y.Y., Maruff, P., Masters, C.L., Ames, D., Bush, A.I., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Taddei, K., Groth, D., Verdile, G., Burnham, S.C., Laws, S.M., Porter, T., Villemagne, V.L., Savage, G., Milicic, L., Ying Lim, Y.Y., Maruff, P., Masters, C.L., Ames, D., Bush, A.I., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Taddei, K., Groth, D., Verdile, G., Burnham, S.C., and Laws, S.M.

Abstract

Introduction In cognitively normal (CN) older adults, high levels of Aβ-amyloid are associated with significant decline in cognition, especially episodic memory. Several genes have previously been associated with cognition, including APOE, KIBRA, KLOTHO, BDNF, COMT, SPON1 and CSMD1. While some of this variation has been attributed to some of these genes individually, the combined effects of these genes on rates of cognitive decline, particularly in preclinical Alzheimer’s Disease remain largely unknown. Methods To elucidate if risk alleles within these genes can be suitably combined to predict cognitive decline 127 CN older adults with elevated PET-ascertained Aβ-amyloid were included in a decision tree analysis to define a “Cognitive Gene Risk Profile” for decline in a verbal episodic memory composite. Results The episodic memory-derived Cognitive Gene Risk Profile defined four groups: APOE ε4+ Risk, ε4+ Resilient, ε4− Risk, ε4− Resilient, with the ε4+ Risk group declining significantly faster than all other groups (ε4+ Resilient, p = 0.0008; ε4− Risk, p = 0.025; ε4− Resilient, p = 0.0006). The ε4+ Risk group also declined significantly faster than all other groups on Global, Clinical Progression and Pre-Alzheimer’s cognitive composites. Discussion The defined Cognitive Gene Risk Profile has potential utility in participant selection/stratification for preclinical AD trials that incorporate Aβ-amyloid and where decline in cognition is essential to determine therapeutic effectiveness.

Published
2018

15. KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ε4-positive cognitively normal adults with high Aβ-amyloid burden

Author

Porter, T., Burnham, S.C., Doré, V., Savage, G., Bourgeat, P., Begemann, K., Milicic, L., Ames, D., Bush, A.I., Maruff, P., Masters, C.L., Rowe, C.C., Rainey-Smith, S., Martins, R.N., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Doré, V., Savage, G., Bourgeat, P., Begemann, K., Milicic, L., Ames, D., Bush, A.I., Maruff, P., Masters, C.L., Rowe, C.C., Rainey-Smith, S., Martins, R.N., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.

Abstract

A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer’s disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.

Published
2018

16. Utility of an Alzheimer’s disease risk-weighted polygenic risk score for predicting rates of cognitive decline in preclinical Alzheimer’s disease: A prospective longitudinal study

Author

Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Li, Q-X, Ames, D., Masters, C.L., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Li, Q-X, Ames, D., Masters, C.L., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.

Abstract

Background:With the exception of APOE, genetic variants associated with increased Alzheimer’s disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. Objective:To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. Methods:The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer’s Cognitive Composite (PACC). Results:PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. Conclusions:An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Published
2018

17. Plasma cortisol, brain Amyloid-β, and cognitive decline in preclinical Alzheimer’s disease: A 6-Year prospective cohort study

Author

Pietrzak, R.H., Laws, S.M., Lim, Y.Y., Bender, S. J., Porter, T., Doecke, J., Ames, D., Fowler, C., Masters, C.L., Milicic, L., Rainey-Smith, S., Villemagne, V.L., Rowe, C.C., Martins, R.N., Maruff, P., Pietrzak, R.H., Laws, S.M., Lim, Y.Y., Bender, S. J., Porter, T., Doecke, J., Ames, D., Fowler, C., Masters, C.L., Milicic, L., Rainey-Smith, S., Villemagne, V.L., Rowe, C.C., Martins, R.N., and Maruff, P.

Abstract

Background Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer’s disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Methods Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults. Results Results revealed that Aβ+ older adults experienced faster decline than Aβ− older adults in all cognitive domains (Cohen’s d at 6-year assessment = 0.37–0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type. Conclusions In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.

Published
2017

18. O4-06-01: Genetic variation in aquaporins moderates the relationship between sleep and brain Aβ-Amyloid burden

Author

Rainey-Smith, S.R., Mazzucchelli, G.N., Villemagne, V.L., Brown, B.M., Porter, T., Weinborn, M., Bucks, R.S., Milicic, L., Sohrabi, H.R., Taddei, K., Ames, D., Maruff, P., Masters, C.L., Rowe, C.C., Salvado, O., Martins, R.N., Laws, S.M., Rainey-Smith, S.R., Mazzucchelli, G.N., Villemagne, V.L., Brown, B.M., Porter, T., Weinborn, M., Bucks, R.S., Milicic, L., Sohrabi, H.R., Taddei, K., Ames, D., Maruff, P., Masters, C.L., Rowe, C.C., Salvado, O., Martins, R.N., and Laws, S.M.

Abstract

Oral presentation

Published
2006

19. Exploration of Alzheimer's disease-related gene expression following high-intensity and moderate-intensity exercise interventions.

Author

Marston KJ, de Frutos-Lucas J, Porter T, Milicic L, Vacher M, Sewell KR, Peiffer JJ, Laws SM, and Brown BM

Subjects
Humans, Male, Aged, Female, Pilot Projects, Gene Expression, Exercise Therapy methods, Middle Aged, Cognition, Alzheimer Disease genetics, Alzheimer Disease therapy, Exercise physiology
Abstract

Objectives: There are currently 29 genome regions that demonstrate associations with Alzheimer's disease (AD) risk. Regular physical exercise can promote systemic change in gene expression and may modify the risk of cognitive decline and AD. This study is a secondary analysis of a randomised controlled trial and examines the effect of a six-month exercise intervention versus control on AD-related gene expression., Design: Single-site parallel pilot randomised controlled trial., Methods: 91 cognitively unimpaired older adults were enrolled in the Intense Physical Activity and Cognition (IPAC) study. Participants were randomised into one of three groups: high-intensity exercise, moderate-intensity exercise, or inactive control for six months. Blood samples were collected prior to, and within two weeks of intervention completion, for later expression analysis of 96 genes. To explore the relationship between changes in gene expression and the intervention groups, an interaction term ("time point × intervention group") was subsequently used., Results: There were no significant differences in gene expression between the three intervention groups at baseline, nor after the intervention. Within groups, five genes were upregulated, seven were downregulated and the remainder remained unchanged. None of the examined genes showed significant change from pre- to post-intervention in the exercise groups compared to the control., Conclusions: Exercise does not change AD-related gene expression in cognitively unimpaired older adults. Several gene expression targets have been identified for further study., Competing Interests: Declaration of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Belinda M. Brown reports that financial support was provided by National Health and Medical Research Council. Belinda M. Brown reports that financial support was provided by Brain Foundation. Simon M. Laws reports a relationship with Cytox Group Limited that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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20. Utility of DNA Methylation as a Biomarker in Aging and Alzheimer's Disease.

Author

Milicic L, Porter T, Vacher M, and Laws SM

Abstract

Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual's biological age based on an algorithmically defined set of CpGs. A number of studies have found associations between disease and/or disease risk with increased biological age, adding weight to the theory of increased biological age being linked with disease processes. Hence, this review takes a closer look at the utility of DNA methylation as a biomarker in aging and disease, with a particular focus on Alzheimer's disease., Competing Interests: The authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

Published
2023
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21. Sixteen-Year Longitudinal Evaluation of Blood-Based DNA Methylation Biomarkers for Early Prediction of Alzheimer's Disease.

Author

Schäfer Hackenhaar F, Josefsson M, Nordin Adolfsson A, Landfors M, Kauppi K, Porter T, Milicic L, Laws SM, Hultdin M, Adolfsson R, Degerman S, and Pudas S

Subjects
Female, Humans, Male, Biomarkers, Epigenesis, Genetic, Prospective Studies, Alzheimer Disease diagnosis, Alzheimer Disease genetics, DNA Methylation
Abstract

Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction., Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers., Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points., Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEɛ4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.

Published
2023
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22. Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume.

Author

Milicic L, Vacher M, Porter T, Doré V, Burnham SC, Bourgeat P, Shishegar R, Doecke J, Armstrong NJ, Tankard R, Maruff P, Masters CL, Rowe CC, Villemagne VL, and Laws SM

Subjects
Aging genetics, Amyloid beta-Peptides, Australia, Cross-Sectional Studies, Epigenesis, Genetic, Hippocampus diagnostic imaging, Humans, Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics
Abstract

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes., (© 2022. The Author(s).)

Published
2022
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23. Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer's disease.

Author

Vacher M, Doré V, Porter T, Milicic L, Villemagne VL, Bourgeat P, Burnham SC, Cox T, Masters CL, Rowe CC, Fripp J, Doecke JD, and Laws SM

Subjects
Atrophy, Australia, Cross-Sectional Studies, Humans, Multifactorial Inheritance, Alzheimer Disease genetics
Abstract

Background: With a growing number of loci associated with late-onset (sporadic) Alzheimer's disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility., Results: Using genotype and imaging data from 780 individuals enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aβ-amyloid (Aβ) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aβ burden, faster regional brain atrophy and an earlier age of onset., Conclusion: Overall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone., (© 2022. The Author(s).)

Published
2022
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24. A Targeted Association Study of Blood-Brain Barrier Gene SNPs and Brain Atrophy.

Author

Vacher M, Porter T, Milicic L, Bourgeat P, Dore V, Villemagne VL, Laws SM, and Doecke JD

Subjects
Atrophy pathology, Blood-Brain Barrier pathology, Brain diagnostic imaging, Brain pathology, Endothelial Cells, Humans, Polymorphism, Single Nucleotide genetics, Hypertension genetics, Hypertension pathology, Neurodegenerative Diseases pathology
Abstract

Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens., Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP)., Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change., Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOEɛ4 allele and were significant post correction for multiple comparisons., Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation.

Published
2022
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25. Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

Author

Fowler C, Rainey-Smith SR, Bird S, Bomke J, Bourgeat P, Brown BM, Burnham SC, Bush AI, Chadunow C, Collins S, Doecke J, Doré V, Ellis KA, Evered L, Fazlollahi A, Fripp J, Gardener SL, Gibson S, Grenfell R, Harrison E, Head R, Jin L, Kamer A, Lamb F, Lautenschlager NT, Laws SM, Li QX, Lim L, Lim YY, Louey A, Macaulay SL, Mackintosh L, Martins RN, Maruff P, Masters CL, McBride S, Milicic L, Peretti M, Pertile K, Porter T, Radler M, Rembach A, Robertson J, Rodrigues M, Rowe CC, Rumble R, Salvado O, Savage G, Silbert B, Soh M, Sohrabi HR, Taddei K, Taddei T, Thai C, Trounson B, Tyrrell R, Vacher M, Varghese S, Villemagne VL, Weinborn M, Woodward M, Xia Y, and Ames D

Abstract

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer's disease dementia (AD)) as an 'Inception cohort' who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an 'Enrichment cohort' (as of 10 April 2019)., Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation., Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations., Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression., Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims., Competing Interests: The following authors have no CoI to declare: CF, SRRS, SB, JB, PB, BMB, SCB, CC, JD, VD, KAE, LE, AF, JF, SLG, SG, RG, EH, RH, LJ, AK, FL, NTL, QXL, LL, YYL, AL, SLM, LMa, SM, LMi, MP, KP, TP, MRa, AR, JR, MRo, RR, OS, GS, BS, MS, HRS, KT, TT, CT, BT, RT, MV, MWe, MWo, YX. AIB is a shareholder in Alterity Therapeutics Ltd, Cogstate Ltd, Mesoblast Ltd, and is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd. SC has received payments from Biogen for advice in relation to CSF biomarkers of Alzheimer’s disease. SML has previously been a paid consultant to Alzhyme. RNM is founder of, and owns stock in, Alzhyme, and is a co-founder of the KaRa Institute of Neurological Diseases. PM is a full-time employee of Cogstate Ltd. CLM is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. CCR has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca, has received speaker honoraria from Bayer Pharma and GE Healthcare, and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. VLV has served as a consultant for Bayer Pharma and received research support from a NEDO grant from Japan. DA has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc., (© 2021 – The authors. Published by IOS Press.)

Published
2021
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26. Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition.

Author

Tan S, Porter T, Bucks RS, Weinborn M, Milicic L, Brown A, Rainey-Smith SR, Taddei K, Ames D, Masters CL, Maruff P, Savage G, Rowe CC, Villemagne VL, Brown B, Sohrabi HR, Laws SM, and Martins RN

Subjects
Aged, Australia, Cognition, Humans, Male, Testosterone, Receptors, Androgen genetics, Trinucleotide Repeats genetics
Abstract

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Published
2021
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27. SPON1 Is Associated with Amyloid-β and APOE ε4-Related Cognitive Decline in Cognitively Normal Adults.

Author

Fernandez S, Burnham SC, Milicic L, Savage G, Maruff P, Peretti M, Sohrabi HR, Lim YY, Weinborn M, Ames D, Masters CL, Martins RN, Rainey-Smith S, Rowe CC, Salvado O, Groth D, Verdile G, Villemagne VL, Porter T, and Laws SM

Abstract

., Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease., Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults., Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study., Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ 4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ 4/rs11023139-A carriers declined significantly faster than APOE ɛ 4/rs11023139-G&#95;G carriers in measures of global cognition ( p  = 0.011) and verbal episodic memory ( p  = 0.020)., Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ 4 cognitively normal older adults with a high neocortical amyloid-β burden., Competing Interests: CLM is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. PM is a full-time employee of Cogstate Ltd. DA has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc. RNM is a consultant to Alzhyme. HRS has received/is receiving remuneration from activities with Pfizer and Takeda pharmaceuticals. CCR has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca; has received speaker honoraria from Bayer Pharma and GE Healthcare; and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. VLV served as a consultant for Bayer Pharma; and received research support from a NEDO grant from Japan. SML serves on the scientific advisory board of Cytox Ltd. All other authors have no conflicts of interest to report., (© 2021 – The authors. Published by IOS Press.)

Published
2021
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28. Validation of a priori candidate Alzheimer's disease SNPs with brain amyloid-beta deposition.

Author

Vacher M, Porter T, Villemagne VL, Milicic L, Peretti M, Fowler C, Martins R, Rainey-Smith S, Ames D, Masters CL, Rowe CC, Doecke JD, and Laws SM

Subjects
Aged, Apolipoproteins E genetics, Australia, Biomarkers analysis, Brain pathology, Female, Genetic Association Studies, Humans, Male, Membrane Transport Proteins genetics, Mitochondrial Precursor Protein Import Complex Proteins, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides analysis, Polymorphism, Single Nucleotide genetics
Abstract

The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer's disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ-) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts.

Published
2019
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29. COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults.

Author

Porter T, Burnham SC, Milicic L, Savage G, Maruff P, Sohrabi HR, Peretti M, Lim YY, Weinborn M, Ames D, Masters CL, Martins RN, Rainey-Smith S, Rowe CC, Salvado O, Groth D, Verdile G, Villemagne VL, and Laws SM

Abstract

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol- O -methyltransferase ( COMT ) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E ( APOE) ε4 allele on cognition in preclinical Alzheimer's disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults.

Published
2019
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30. Klotho allele status is not associated with Aβ and APOE ε4-related cognitive decline in preclinical Alzheimer's disease.

Author

Porter T, Burnham SC, Milicic L, Savage G, Maruff P, Lim YY, Ames D, Masters CL, Martins RN, Rainey-Smith S, Rowe CC, Salvado O, Groth D, Verdile G, Villemagne VL, and Laws SM

Subjects
Aged, Amyloid beta-Peptides metabolism, Female, Genotype, Humans, Klotho Proteins, Male, Middle Aged, Alleles, Alzheimer Disease genetics, Alzheimer Disease psychology, Amyloid beta-Peptides genetics, Apolipoprotein E4 genetics, Cognition, Cognitive Dysfunction genetics, Genetic Association Studies, Glucuronidase genetics
Abstract

The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4-driven cognitive decline in preclinical AD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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31. A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease.

Author

Porter T, Burnham SC, Savage G, Lim YY, Maruff P, Milicic L, Peretti M, Ames D, Masters CL, Martins RN, Rainey-Smith S, Rowe CC, Salvado O, Taddei K, Groth D, Verdile G, Villemagne VL, and Laws SM

Abstract

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS ( em PRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample ( n = 151). These were then summed to generate a em PRS either including APOE ( em PRS c̅ APOE ) or excluding APOE ( em PRS s̅ APOE ). Resultant em PRS were then evaluated, in a test sample ( n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of em PRSs were observed with baseline cognition, the em PRS c̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The em PRS s̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the em PRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The em PRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel em PRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

Published
2018
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32. Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden.

Author

Rainey-Smith SR, Mazzucchelli GN, Villemagne VL, Brown BM, Porter T, Weinborn M, Bucks RS, Milicic L, Sohrabi HR, Taddei K, Ames D, Maruff P, Masters CL, Rowe CC, Salvado O, Martins RN, and Laws SM

Subjects
Aged, Aged, 80 and over, Australia, Brain diagnostic imaging, Cross-Sectional Studies, Female, Humans, Male, Polymorphism, Single Nucleotide, Positron-Emission Tomography, Amyloid beta-Peptides metabolism, Aquaporin 4 genetics, Brain metabolism, Sleep physiology, Sleep Wake Disorders physiopathology
Abstract

The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.

Published
2018
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33. KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ε4-positive cognitively normal adults with high Aβ-amyloid burden.

Author

Porter T, Burnham SC, Doré V, Savage G, Bourgeat P, Begemann K, Milicic L, Ames D, Bush AI, Maruff P, Masters CL, Rowe CC, Rainey-Smith S, Martins RN, Groth D, Verdile G, Villemagne VL, and Laws SM

Subjects
Aged, Amyloid beta-Peptides metabolism, Female, Hippocampus metabolism, Hippocampus pathology, Humans, Male, Apolipoproteins E genetics, Cognitive Dysfunction genetics, Intracellular Signaling Peptides and Proteins genetics, Phosphoproteins genetics, Polymorphism, Single Nucleotide
Abstract

A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer's disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.

Published
2018
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34. Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study.

Author

Porter T, Burnham SC, Milicic L, Savage G, Maruff P, Lim YY, Li QX, Ames D, Masters CL, Rainey-Smith S, Rowe CC, Salvado O, Groth D, Verdile G, Villemagne VL, and Laws SM

Subjects
Aged, Aged, 80 and over, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease psychology, Biomarkers cerebrospinal fluid, Brain diagnostic imaging, Cognitive Dysfunction cerebrospinal fluid, Cognitive Dysfunction psychology, Disease Progression, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neuropsychological Tests, Peptide Fragments cerebrospinal fluid, Prognosis, Prospective Studies, Risk Assessment, Alzheimer Disease diagnosis, Amyloid beta-Peptides cerebrospinal fluid, Cognition physiology, Cognitive Dysfunction diagnosis, Memory, Episodic, tau Proteins cerebrospinal fluid
Abstract

Background: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood., Objective: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline., Methods: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC)., Results: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype., Conclusions: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Published
2018
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35. Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer's Disease: A 6-Year Prospective Cohort Study.

Author

Pietrzak RH, Laws SM, Lim YY, Bender SJ, Porter T, Doecke J, Ames D, Fowler C, Masters CL, Milicic L, Rainey-Smith S, Villemagne VL, Rowe CC, Martins RN, and Maruff P

Subjects
Aged, Alzheimer Disease diagnosis, Brain metabolism, Cognition physiology, Disease Progression, Female, Humans, Hypothalamo-Hypophyseal System metabolism, Male, Prospective Studies, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Pituitary-Adrenal System metabolism
Abstract

Background: Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer's disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention., Methods: Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults., Results: Results revealed that Aβ+ older adults experienced faster decline than Aβ- older adults in all cognitive domains (Cohen's d at 6-year assessment = 0.37-0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type., Conclusions: In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD., (Published by Elsevier Inc.)

Published
2017
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