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1 Sex Differences in Associations Between APOE ε2 and Longitudinal Cognitive Decline
- Madeline Wood, Lisa Xiong, Yuen Yan Wong, Rachel F Buckley, Walter Swardfager, Mario Masellis, Andrew Lim, Emma Nichols, Renaud La Joie, Kaitlin Casaletto, Raj Kumar, Kristen Dams-O’Connor, Priya Palta, Kristen George, Claudia Satizabal, Lisa L Barnes, Julie A Schneider, Judy Pa, Adam Brickman, Sandra Black, Jennifer Rabin
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 405-406
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Objective:
Women have a greater lifetime risk of developing Alzheimer’s disease (AD) dementia than men, a sex/gender disparity that cannot be explained by female longevity alone. There is substantial evidence for sex differences in the effects of APOE £4 on risk for AD. While APOE e4 increases AD risk in both sexes, women who carry APOE e4 are disproportionately vulnerable to cognitive impairment and AD compared to their counterpart men. In contrast to APOE e4, APOE £2 is associated with slower cognitive decline and a lower risk of AD. Although a less robust literature, APOE e2 may also have sex-specific effects. Because APOE e2 is the rarest major APOE allele, well-powered studies are needed to examine sex-specific effects. The objective of the present study was to examine sex-specific associations of APOE e2 carriage with longitudinal cognitive decline in a large cohort of clinically unimpaired adults.
Participants and Methods:We used observational data from two sources: the National Alzheimer’s Coordinating Center (NACC) and the Rush Alzheimer’s Disease Center (ROS/MAP/MARS) studies. We included data from clinically unimpaired adults who were >50 years old at baseline who self-identified as non-Hispanic White (NHW) or non-Hispanic Black (NHB). Participants were categorized as APOE £2, £4, or £3/e3 carriers. APOE e2/e4 carriers were excluded. The same battery of neuropsychological tests was used to assess global cognition in participants from both data sources. Linear mixed models examined interactive associations of genotype (£2 or £4 vs. £3/£3), sex, and time on longitudinal cognition in NHW and NHB participants separately. Analyses were first performed in a pooled sample of NACC and ROS/MAP/MARS participants and if significant they were repeated separately in each data source.
Results:Across both data sources, 9,766 NHW (mean (SD) age=73.0(9.00) years, mean (SD) education=16.3(2.83) years, n(%) women=6,344(65.0)) and 2,010 NHB participants (mean(SD) age=71.3(7.59) years, mean(SD) education=14.9(3.10) years, n(%) women=1,583(78.8)) met inclusion criteria. Sex modified the association between APOE £2 and cognitive decline in NHW (ß=0.097, 95% CI: 0.023-0.172, pint=.01) but not NHB participants (ß=-0.011, 95% CI: -0.153-0.131, pint=.9). In sex-stratified analyses of NHW participants, APOE £2 (vs. £3/£3) carriage was associated with attenuated cognitive decline in men (ß=0.096, 95% CI: 0.037-0.155, p=.001), but not women (ß=-0.001, 95% CI: -0.044-0.043, p=.97). In analyses comparing men and women APOE £2 carriers, men exhibited slower cognitive decline than women (ß=0.120, 95% CI: 0.051-0.190, p=.001). Analyses performed separately in NACC and ROS/MAP revealed the same pattern of male-specific APOE £2 protection in NHW participants in both data sources.
Conclusions:In light of the longstanding view that APOE £2 protects against AD and dementia, our results provide evidence that APOE £2 is associated with attenuated cognitive decline in men but not women among NHW adults. This male-specific protection may contribute to sex differences in AD-related cognitive decline. Our findings have important implications for understanding the biological drivers of sex differences in AD risk, which is crucial for developing sex-specific strategies to prevent and treat AD dementia.
69 Evaluation of Ethnoracial Differences in Self- and Study-Partner Reported Subjective Cognitive Decline
- Talia L Robinson, Hannah M Klinger, Rachel F Buckley, Kacie D Deters, Yakeel T Quiroz, Dorene M Rentz, Reisa A Sperling, Rebecca E Amariglio
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 374-375
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Objective:
1) Evaluate the association of self- and study-partner report of subjective cognitive decline (SCD) to objective cognitive performance across ethnoracial groups. 2) Evaluate the concordance of self- and study partner report of SCD across ethnoracial groups.
Participants and Methods:Participants were 5241 non-Hispanic White (NHW), 267 non-Hispanic Black (NHB), 225 Hispanic, and 228 Asian participants screened for the A4 study (N=5961). Participants completed the Preclinical Alzheimer Cognitive Composite (PACC), and self- and study partner-report of SCD using the Cognitive Function Index (CFI). Analysis of variance was used to assess difference in key variables by ethnoracial group. Regression analyses were conducted to evaluate the association of SCD and objective performance by ethnoracial group, and the association between self-and study partner report of SCD by ethnoracial group.
Results:Asian participants reported the highest mean CFI relative to all other groups, while NHW reported the lowest (F(3,5957)=41.93, p <.001). Asian and NHW participants had higher PACC scores relative to NHB and Hispanic participants (F(3,5957)=41.93, p <.001). Regression analyses revealed higher CFI was associated with lower PACC score across groups, and this association was strongest in the Asian sample relative to other groups (F(10, 5897)=40.49, p<.001,R2=.06). Evaluation of study partner characteristics suggested NBH participants had the highest proportion on non-spousal study partners relative to other groups. Regression analyses revealed no differences in the association of self- and study partner report of SCD across ethnoracial groups (F(10, 5859)=132.9, p<.001, R2=0.18).
Conclusions:Results suggest that that SCD is associated with objective cognitive performance across racial groups, although the strength of this association appears to vary in this sample. There is also consistent concordance between self- and study partner report of SCD across groups, despite differences in study partner relationships. SCD may be considered a valid predictor of subtle cognitive change across groups in the A4 sample. Limitations include small group sizes relative to the large NHW sample. Future work with larger, more representative samples are needed to further validate these findings.
84 Feasibility and Validity of Remote Digital Assessment of Multi-Day Learning in Cognitively Unimpaired Older Adults
- Emma L. Weizenbaum, Daniel Soberanes, Stephanie Hsieh, Olivia R Schneider, Shruthi Srinivasan, Rachel F Buckley, Michael J Properzi, Dorene Rentz, Keith A Johnson, Reisa A Sperling, Kathryn V Papp, Rebecca E Amariglio
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 487-488
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Objective:
Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning across days on participants’ own devices. More rapid detection of diminished learning may provide a potentially valuable metric that is sensitive to cognitive change over short intervals. In this study we examine feasibility and predictive validity of a novel digital assessment that measures learning of the same material over 7 days in older adults.
Participants and Methods:The Boston Remote Assessment for Neurocognitive Health (BRANCH) (Papp et al., 2021) is a web-based assessment administered over 7 consecutive days repeating the same stimuli each day to capture multi-day-learning slopes. The assessment includes Face-Name (verbal-visual associative memory), Groceries-Prices (numeric-visual associative memory), and Digits-Signs (speeded processing of numeric-visual associations). Our sample consisted of200 cognitively unimpaired older adults enrolled in ongoing observational studies (mean age=74.5, 63% female, 87% Caucasian, mean education=16.6) who completed the tasks daily, at home, on their own digital devices. Participants had previously completed in-clinic paper-and-pencil tests to compute a Preclinical Alzheimer’s Cognitive Composite (PACC-5). Mixed-effects models controlling for age, sex, and education were used to observe the associations between PACC-5 scores and both initial performance and multi-day learning on the three BRANCH measures.
Results:Adherence was high with 96% of participants completing all seven days of consecutive assessment; demographic factors were not associated with differences in adherence. Younger participants had higher Day 1 scores all three measures, and learning slopes on Digit-Sign. Female participants performed better on Face-Name (T=3.35, p<.001) and Groceries-Prices (T=2.00, p=0.04) on Day 1 but no sex differences were seen in learning slopes; there were no sex differences on Digit-Sign. Black participants had lower Day 1 scores on Face-Name (T=-3.34, p=0.003) and Digit Sign (T=3.44, p=0.002), but no racial differences were seen on learning slopes for any measure. Education was not associated with any measure. First day performance on Face-Name (B=0.39, p<.001), but not learning slope B=0.008, p=0.302) was associated with the PACC5. For Groceries-Prices, both Day 1 (B=0.27, p<.001) and learning slope (B=0.02, p=0.03) were associated with PACC-5. The Digit-Sign scores at Day 1 (B=0.31, p<.001) and learning slope (B=0.06, p<.001) were also both associated with PACC-5.
Conclusions:Seven days of remote, brief cognitive assessment was feasible in a sample of cognitively unimpaired older adults. Although various demographic factors were associated with initial performance on the tests, multi-day-learning slopes were largely unrelated to demographics, signaling the possibility of its utility in diverse samples. Both initial performance and learning scores on an associative memory and processing speed test were independently related to baseline cognition indicating that these tests’ initial performance and learning metrics are convergent but unique in their contributions. The findings signal the value of measuring differences in learning across days as a means towards sensitively identifying differences in cognitive function before signs of frank impairment are observed. Next steps will involve identifying the optimal way to model multi-day learning on these subtests to evaluate their potential associations with Alzheimer’s disease biomarkers.
Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer’s Disease
- Roos J. Jutten, Sietske A.M. Sikkes, Rebecca E. Amariglio, Rachel F. Buckley, Michael J. Properzi, Gad A. Marshall, Dorene M. Rentz, Keith A. Johnson, Charlotte E. Teunissen, Bart N.M. Van Berckel, Wiesje M. Van der Flier, Philip Scheltens, Reisa A. Sperling, Kathryn V. Papp, for the Alzheimer Disease Neuroimaging Initiative, National Alzheimer’s Coordinating Center, the Harvard Aging Brain Study, and the Alzheimer Dementia Cohort
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- Journal:
- Journal of the International Neuropsychological Society / Volume 27 / Issue 5 / May 2021
- Published online by Cambridge University Press:
- 13 October 2020, pp. 426-438
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Objective:
Alzheimer’s disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer’s Association (NIA-AA) research framework.
Method:Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models.
Results:1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p < .001). Word List Delayed Recall (β = −.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p < .001) and 4 (β = −2.23, p < .001).
Conclusions:We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.
Between foraging and farming: strategic responses to the Holocene Thermal Maximum in Southeast Asia
- Marc F. Oxenham, Hiep Hoang Trinh, Anna Willis, Rebecca K. Jones, Kathryn Domett, Cristina Castillo, Rachel Wood, Peter Bellwood, Monica Tromp, Ainslee Kells, Philip Piper, Son Thanh Pham, Hirofumi Matsumura, Hallie Buckley
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Large, ‘complex’ pre-Neolithic hunter-gatherer communities thrived in southern China and northern Vietnam, contemporaneous with the expansion of farming. Research at Con Co Ngua in Vietnam suggests that such hunter-gatherer populations shared characteristics with early farming communities: high disease loads, pottery, complex mortuary practices and access to stable sources of carbohydrates and protein. The substantive difference was in the use of domesticated plants and animals—effectively representing alternative responses to optimal climatic conditions. The work here suggests that the supposed correlation between farming and a decline in health may need to be reassessed.
The influence of demographic factors on subjective cognitive concerns and beta-amyloid
- Sarah L. Aghjayan, Rachel F. Buckley, Patrizia Vannini, Dorene M. Rentz, Jonathan D. Jackson, Reisa A. Sperling, Keith A. Johnson, Rebecca E. Amariglio
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- Journal:
- International Psychogeriatrics / Volume 29 / Issue 4 / April 2017
- Published online by Cambridge University Press:
- 11 October 2016, pp. 645-652
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Background:
Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aβ) burden.
Methods:In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63–90 years (mean 73.7±6) with 6–20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aβ burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aβ burden and SCC. A post-hoc mediation model was implemented to further understand the relationship between Aβ burden and SCC via their relationship with education.
Results:Age (β = −0.84, p = 0.36) and sex (β = −0.55, p = 0.22) did not modify the relationship between SCC and Aβ burden. Fewer years of education was correlated with greater SCC (r = −0.12, p = 0.05), but the relationship between Aβ burden and SCC was stronger in those with more education (β = 1.16, p < 0.05). A partial mediation effect was found of Aβ burden on SCC via education (b = −0.12, 95% CI [−0.31, −0.02]).
Conclusions:These findings suggest that the association between SCC and Aβ burden becomes stronger with greater educational attainment. Thus, SCC may be of particular importance in highly educated CN individuals harboring amyloid pathology.
Autobiographical narratives relate to Alzheimer's disease biomarkers in older adults
- Rachel F. Buckley, Michael M. Saling, Muireann Irish, David Ames, Christopher C. Rowe, Victor L. Villemagne, Nicola T. Lautenschlager, Paul Maruff, S. Lance Macaulay, Ralph N. Martins, Cassandra Szoeke, Colin L. Masters, Stephanie R. Rainey-Smith, Alan Rembach, Greg Savage, Kathryn A. Ellis
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- Journal:
- International Psychogeriatrics / Volume 26 / Issue 10 / October 2014
- Published online by Cambridge University Press:
- 27 June 2014, pp. 1737-1746
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Background:
Autobiographical memory (ABM), personal semantic memory (PSM), and autonoetic consciousness are affected in individuals with mild cognitive impairment (MCI) but their relationship with Alzheimer's disease (AD) biomarkers are unclear.
Methods:Forty-five participants (healthy controls (HC) = 31, MCI = 14) completed the Episodic ABM Interview and a battery of memory tests. Thirty-one (HC = 22, MCI = 9) underwent β-amyloid positron emission tomography (PET) and magnetic resonance (MR) imaging. Fourteen participants (HC = 9, MCI = 5) underwent one imaging modality.
Results:Unlike PSM, ABM differentiated between diagnostic categories but did not relate to AD biomarkers. Personal semantic memory was related to neocortical β-amyloid burden after adjusting for age and apolipoprotein E (APOE) ɛ4. Autonoetic consciousness was not associated with AD biomarkers, and was not impaired in MCI.
Conclusions:Autobiographical memory was impaired in MCI participants but was not related to neocortical amyloid burden, suggesting that personal memory systems are impacted by differing disease mechanisms, rather than being uniformly underpinned by β-amyloid. Episodic and semantic ABM impairment represent an important AD prodrome.
Contributors
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- By Rob Aitken, Catrin Albrecht, Melvin E. Andersen, James C. Bonner, Matthew Boyles, Alison Buckley, Vincent Castranova, Michael P. DeLorme, Ken Donaldson, Rodger Duffin, Kirsten Gerloff, Helinor Johnston, Ali Kermanizadeh, Amie Lund, Laura MacCalman, Robert Maynard, Jacob D. McDonald, Robert R. Mercer, Fiona A. Murphy, Craig A. Poland, Jessica P. Ryman-Rasmussen, Roel P. F. Schins, Charanjeet Singh, Rachel Smith, Wenhui Song, Vicki Stone, Lang Tran, Klaus Unfried, Damien van Berlo, Julia Varet, David B. Warheit
- Edited by Ken Donaldson, University of Edinburgh, Craig Poland, Rodger Duffin, University of Edinburgh, James Bonner, North Carolina State University
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- The Toxicology of Carbon Nanotubes
- Published online:
- 05 July 2012
- Print publication:
- 21 June 2012, pp x-xiv
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Contributors
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- By Sonia Ancoli-Israel, Ragnar Asplund, Michel Billiard, Theresa M. Buckley, Rohit Budhiraja, Robert N. Butler, Daniel J. Buysse, Scott S. Campbell, Daniel P. Cardinali, Julie Carrier, Cynthia L. Comella, Jana R. Cooke, Pietro Cortelli, Agnès Demazieres, Glenna A. Dowling, Luigi Ferini-Strambi, Philip R. Gehrman, Nalaka Sudheera Gooneratne, David S. Hallegua, Patrick J. Hanly, David G. Harper, Orla P. Hornung, Magdolna Hornyak, Michal Karasek, Milton Kramer, Andrew D. Krystal, Malcolm H. Lader, Rachel Leproult, Kenneth L. Lichstein, Andrea H.S. Loewen, Rémy Luthringer, Laurin J. Mack, Evelyn Mai, Atul Malhotra, Jennifer L. Martin, Judy Mastick, Monique A.J. Mets, Andrew A. Monjan, Timothy H. Monk, Daniel Monti, Jaime M. Monti, Patricia J. Murphy, C. Ineke Neutel, Eric A. Nofzinger, Seithikurippu R. Pandi-Perumal, Scott B. Patton, Donald B. Penzien, Max H. Pittler, Giora Pillar, Marc J. Poulin, Louis J. Ptácek, Stuart F. Quan, Jeanetta C. Rains, Megan E. Ruiter, Bruce D. Rybarczyk, Colin M. Shapiro, Vijay Kumar Sharma, D. Warren Spence, Kai Spiegelhalder, Luc Staner, Stephanie A. Studenski, Nikola N. Trajanovic, Eve Van Cauter, Gregory S. Vander Wal, Joris C. Verster, Aleksandar Videnovic, Matthew P. Walker, Daniel J. Wallace, David K. Welsh, David P. White, Barbara Wider, Theresa B. Young, Stefano Zanigni
- Edited by S. R. Pandi-Perumal, Jaime M. Monti, Universidad de la República, Uruguay, Andrew A. Monjan, National Institute on Aging, Bethesda, Maryland
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- Book:
- Principles and Practice of Geriatric Sleep Medicine
- Published online:
- 04 August 2010
- Print publication:
- 26 November 2009, pp ix-xii
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