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Introduction: AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function., Methods: In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired)., Results: (1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition., Discussion: The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.M. Mielke served as a consultant to Brain Protection Company, Biogen, and LabCorp and receives research support from the National Institutes of Health and the Department of Defense. She is a Senior Associate Editor forAlzheimer's and Dementia: The Journal of the Alzheimer's Association. Dr. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for Lecanemab on December 2, 2022 but received no compensation directly or indirectly. He receives funding from the NIH. Maria Vassilaki has received research funding from F. Hoffmann-La Roche Ltd and Biogen in the past and consulted for F. Hoffmann-La Roche Ltd; she currently receives research funding from NIH and have equity ownership in Johnson and Johnson, Merck, Medtronic, and Amgen. P. Vemuri received speaking fees from Miller Medical Communications, LLC, and receives research support from the National Institutes of Health. J. Graff-Radford receives NIH funding and serves on the data and safety monitoring board board for Neurology. He has received payment for speaking at the American Academy of Neurology Annual meeting. C.R. Jack serves on an independent data monitoring board for Roche, but he receives no personal compensation from any commercial entity. He receives research support from the National Institutes of Health, the GHR Foundation and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. R.C. Petersen is a consultant for Roche, Inc., Eli Lilly and Co. Nestle, Inc. and Eisai, Inc. He receives royalties from Oxford University Press and UpToDate and receives research support from the National Institutes of Health. V. J. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, Elly Lilly and Company and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). D. Shir, T.G. Lesnick, S. Przybelski, A.J. Fought, and M.M. Machulda have no conflicts to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10 -8 , β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults., Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status., Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores., Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition., Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

Our goal was to evaluate the utility of diffusion tensor imaging (DTI) for predicting future cognitive decline in mild cognitive impairment (MCI) in conjunction with Alzheimer's disease (AD) biomarkers (amyloid positron emission tomography and AD signature neurodegeneration) in 132 MCI individuals ≥60 year old with structural magnetic resonance imaging, DTI, amyloid positron emission tomography, and at least one clinical follow-up. We used mixed-effect models to evaluate the prognostic ability of fractional anisotropy of the genu of the corpus callosum (FA-Genu), as a cerebrovascular disease marker, for predicting cognitive decline along with AD biomarkers. We contrasted the value of white matter hyperintensities, a traditional cerebrovascular disease marker as well as FA in the hippocampal cingulum bundle with the FA-Genu models. FA-Genu significantly predicted cognitive decline even after accounting for AD biomarkers. WMH was not associated with cognitive decline in the model with both WMH and FA-Genu. DTI specifically FA-Genu provides unique complementary information to AD biomarkers and has significant utility for prediction of cognitive decline in MCI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We evaluated the hypothesis that the rate of postoperative decline in global cognition is greater in older adults exposed to general anesthesia with nitrous oxide (N2O) compared to general anesthesia without N2O., Methods: Longitudinal measures of cognitive function were analyzed in nondemented adults, 70-91 years of age, enrolled in the Mayo Clinic Study of Aging. Linear mixed-effects models with time-varying covariates assessed the relationship between exposure to surgery with general anesthesia (surgery/GA) with or without N2O and the rate of long-term cognitive changes. Global cognition and domain-specific cognitive outcomes were defined using z scores, which measure how far an observation is, in standard deviations, from the unimpaired population mean., Results: The analysis included 1819 participants: 280 exposed to GA without N2O following enrollment and before censoring during follow-up (median [interquartile range {IQR}] follow-up of 5.4 [3.9-7.9] years); 256 exposed to GA with N2O (follow-up 5.6 [4.0-7.9] years); and 1283 not exposed to surgery/GA (follow-up 4.1 [2.5-6.4] years). The slope of the global cognitive z score was significantly more negative following exposure to surgery/GA after enrollment (change in slope of -0.062 [95% confidence interval {CI}, -0.085 to -0.039] for GA without N2O, and -0.058 [95% CI, -0.080 to -0.035] for GA with N2O, both P < .001). The change in slope following exposure to surgery/GA did not differ between those exposed to anesthesia without versus with N2O (estimated difference -0.004 [95% CI, -0.035 to 0.026], P = .783)., Conclusions: Exposure to surgery/GA is associated with a small, but statistically significant decline in cognitive z scores. Cognitive decline did not differ between anesthetics with and without N2O. This finding provides evidence that the use of N2O in older adults does not need to be avoided because of concerns related to decline in cognition.

Objective: Research in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A-) in cognitively unimpaired (CU) older adults., Methods: We included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B-PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates., Results: Higher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A- but weaker in A- CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex., Conclusions: A faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Alzheimer's disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia., Methods: The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to three interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise, cognitive training, and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2 × 2 factorial phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n = 128). In this ACT Trial blood biomarkers study, we will enroll 120 ACT Trial participants with aMCI and measure blood biomarkers at baseline and at 3, 6, 12, and 18 months. The goals are to (1) determine the effect of interventions on blood biomarkers over 6 months, (2) evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months, and (3, exploratory) examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months., Discussion: This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among patients with aMCI subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia., Trial Registration: ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.

Introduction: Our aim was to examine whether surgery with regional anesthesia (RA) is associated with accelerated long-term cognitive decline comparable with that previously reported after general anesthesia (GA)., Methods: Longitudinal cognitive function was analyzed in a cohort of 1819 older adults. Models assessed the rate of change in global and domain-specific cognition over time in participants exposed to RA or GA., Results: When compared with those unexposed to anesthesia, the postoperative rate of change of the cognitive global z-score was greater in those exposed to both RA (difference in annual decline of -0.041, P = .011) and GA (-0.061, P < .001); these rates did not differ. In analysis of the domain-specific scores, an accelerated decline in memory was observed after GA (-0.065, P < .001) but not RA (-0.011, P = .565)., Conclusions: Older adults undergoing surgery with RA experience decline of global cognition similar to those receiving GA; however, memory was not affected., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: We aimed to (1) assess and compare baseline plasma and CSF neurofilament light (NfL) for cross-sectional and longitudinal associations with neuroimaging or cognition and (2) determine whether change in plasma NfL corresponded with change in these outcomes., Methods: Seventy-nine participants without dementia, median age 76 years, had plasma and CSF NfL, neuropsychological testing, and neuroimaging (MRI, amyloid PET, FDG-PET) at the same study visit, and a repeat visit (15 or 30 months later) with both plasma NfL and neuroimaging. Plasma NfL was measured on the Simoa-HD1 Platform and CSF NfL with an in-house ELISA. Linear mixed effects models were used to examine the associations between baseline plasma or CSF NfL and cognitive and neuroimaging outcomes adjusting for age, sex, and education. The relationship between change in plasma NfL and change in the outcomes was assessed using linear regression., Results: There were no cross-sectional associations between CSF or plasma NfL and any neuroimaging or cognitive measure. Longitudinally, higher baseline plasma NfL was associated with worsening in all neuroimaging measures, except amyloid PET, and global cognition. Higher baseline CSF NfL was associated with worsening in cortical thickness and diffusion MRI. The beta estimates for CSF NfL were similar to those for plasma NfL. Change in plasma NfL was associated with change in global cognition, attention, and amyloid PET., Conclusion: Elevated baseline plasma NfL is a prognostic marker of cognitive decline and neuroimaging measures of neurodegeneration, and has similar effect sizes to baseline CSF NfL. Change in plasma NfL also tracked with short-term cognitive change., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults., Methods: Tau- and amyloid-PET were performed in 579 CU participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49., Results: Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory z scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+., Conclusions: Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal., (© 2019 American Academy of Neurology.)

Plasma phosphatidylcholines (PCs) have been examined in the context of Alzheimer's disease dementia. However, their association with longitudinal changes in amyloid deposition remains unknown. This study investigated the associations of 8 plasma PC levels (PC aa [14:0&#95;14:0], PC aa [16:0&#95;16:0], PC aa [16:0&#95;18:2], PC aa [16:0&#95;22:6], PC aa [18:0&#95;18:0], PC aa [18:0&#95;18:1], PC aa [18:0&#95;20:4], PC aa [18:1&#95;18:1]) with cross-sectional and longitudinal measures of amyloid deposition, Alzheimer's disease-associated neurodegeneration (glucose metabolism and cortical thickness), and cognition (global- and domain-specific) of 1440 cognitively unimpaired participants (47% female, aged 50.7-95.3 years) in the Mayo Clinic Study of Aging. Longitudinally, higher baseline levels of PC aa [16:0&#95;18:2], PC aa [18:0&#95;18:1], and PC aa [18:1&#95;18:1] were associated with slower decline in performance on tests of global cognition and specific cognitive domains. Furthermore, higher baseline levels of plasma PC aa (14:0&#95;14:0) were associated with slower amyloid deposition and cortical thinning after multiple covariable adjustment (age, sex, education, medical comorbidity, dyslipidemia, statin use, and APOE4 allele presence). Our study findings support an independent association between plasma PC aa (14:0&#95;14:0) with slower amyloid deposition and cortical thinning among cognitively unimpaired older adults., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Research into cognitive resilience imaging markers may help determine the clinical significance of Alzheimer's disease pathology among older adults over 80 years (80+). In this study, we aimed to identify a fluorodeoxyglucose (FDG)-PET based imaging marker of cognitive resilience. We identified 457 participants ≥ 80 years old (357 cognitively unimpaired, 118 cognitively impaired at baseline, mean age of 83.5 ± 3.2 years) from the population-based Mayo Clinic Study of Aging (MCSA) with baseline MRI, Pittsburgh compound B-PET and FDG-PET scans and neuropsychological evaluation. We identified a subset of 'resilient' participants (cognitively stable 80+, n = 192) who maintained normal cognition for an average of 5 years (2-10 years). Global PIB ratio, FDG-PET ratio and cortical thickness from Alzheimer's disease signature regions were used as Alzheimer's disease imaging biomarker outcomes and global cognitive z-score was used as a cognitive outcome. First, using voxel-wise multiple regression analysis, we identified the metabolic areas underlying cognitive resilience in cognitively stable 80+ participants, which we call the 'resilience signature'. Second, using multivariate linear regression models, we evaluated the association of risk and protective factors with the resilience signature and its added value for predicting global cognition beyond established Alzheimer's disease imaging biomarkers in the full 80+ sample. Third, we evaluated the utility of the resilience signature in conjunction with amyloidosis in predicting longitudinal cognition using linear mixed effect models. Lastly, we assessed the utility of the resilience signature in an independent cohort using ADNI (n = 358, baseline mean age of 80 ± 3.8). Our main findings were: (i) FDG-PET uptake in the bilateral anterior cingulate cortex and anterior temporal pole was associated with baseline global cognition in cognitively stable 80+ (the resilience signature); (ii) established Alzheimer's disease imaging biomarkers did not predict baseline global cognition in this subset of participants; (iii) in the full MCSA 80+ and ADNI cohorts, amyloid burden and FDG-PET in the resilience signature were the stronger predictors of baseline global cognition; (iv) sex and systemic vascular health predicted FDG-PET in the resilience signature, suggesting vascular health maintenance as a potential pathway to preserve the metabolism of these areas; and (v) the resilience signature provided significant information about global longitudinal cognitive change even when considering amyloid status in both the MCSA and ADNI cohorts. The FDG-PET resilience signature may be able to provide important information in conjunction with other Alzheimer's disease biomarkers for the determination of clinical prognosis. It may also facilitate identification of disease targeting modifiable risk factors such as vascular health maintenance., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To examine the cross-sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI))., Design: Cross-sectional., Setting: Olmsted County, Minnesota., Participants: Population-based Mayo Clinic Study of Aging (MCSA) participants (aged ≥ 50, mean age 71.3 ± 10.2; 53.4% male; 28.3% apolipoprotein (APO)E ε4 allele carriers, 1,578 CU, 204 MCI) who underwent 11 C-Pittsburgh compound B ( 11 C-PiB) positron emission tomography (PET) (N=1,782)., Measurements: We defined an abnormal (high) 11 C-PiB-PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A-) and neurodegeneration (N+/N-). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ)., Results: Participants with a CDR-SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77-8.67, adjusting for age, sex, education, global cognitive z-score, and APOE ε4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04-2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A-N + in CU participants., Conclusion: The findings of this cross-sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. J Am Geriatr Soc 66:2274-2281, 2018., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Levels of insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, and their ratio in the blood may be useful for monitoring those at risk of cognitive and functional decline. However, the association between IGF measures and functional and cognitive outcomes has been mixed, and the associations may vary by sex. The present study investigated the cross-sectional, sex-specific associations between serum measures total IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio, gait speed, and cognition in 1320 cognitively unimpaired participants aged 50-95 years enrolled in the Mayo Clinic Study of Aging. We used multivariable linear regression models to determine the association between IGF measures and gait speed or cognitive test performance by sex. IGF measures were not associated with cognitive or functional performance among men. Among women, higher levels of log total IGF-1 and IGFBP-3 were associated with better performance in attention, visuospatial, and global cognitive domains, independent of the gait speed. These findings suggest that among women, IGF measures are associated with cognition, and these associations are independent of function., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In 1164 cognitively unimpaired persons, aged 50-95 years, from the population-based Mayo Clinic Study of Aging, we examined the relationships of baseline cognition and cognitive changes across the full range of cortical thickness of an Alzheimer signature region of interest and global β-amyloid levels measured by Pittsburgh compound B positron emission tomography (PIB PET) standardized uptake value ratio (SUVR). In machine-learning models accounting for both biomarkers simultaneously, worsening biomarker values were additive and associated with lower baseline global cognition and greater subsequent decline in global cognition. Associations between Alzheimer's disease signature cortical thickness or PIB PET β-amyloid SUVR and baseline cognition were mainly linear. Lower Alzheimer's disease signature cortical thickness values across the entire range of thickness predicted future decline in global cognitive scores, demonstrating its close relationship to cognitive functioning. PIB PET β-amyloid SUVR also predicted cognitive decline across its full range, even when cortical thickness was accounted for. PIB PET β-amyloid's relationship to cognitive decline was nonlinear, more prominent at lower β-amyloid levels and less prominent at higher β-amyloid levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: There is growing interest in white matter (WM) imaging with positron emission tomography (PET)., Objectives: We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding., Methods: In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences., Results: MS patients had lower memory ( p = 0.03) and language ( p = 0.02) performance; smaller thalamic volumes ( p = 0.003); and thinner temporal ( p = 0.001) and frontal ( p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls ( p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS ( p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities ( r = 0.65; p = 0.02) and NAWM ( r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS., Conclusion: PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures' integrity such as those involved in visuospatial performance.

Background: Little is known about the association of cortical Aβ with depression and anxiety among cognitively normal (CN) elderly persons., Methods: We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB-) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex., Results: Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00-1.06) and BAI (OR = 1.04; 1.01-1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83-2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.77; 0.97-3.22)., Conclusions: As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.

Objective: The objective of this study was to examine practice effects and longitudinal cognitive change in 190 clinically normal elderly classified according to a two-feature biomarker model for Alzheimer's disease., Methods: All participants completed neuropsychological testing, MRI, FDG-PET, and PiB-PET at their baseline evaluation. We divided participants into four groups based on neuroimaging measures of amyloid (A+ or A-) and neurodegeneration (N+ or N-) and reexamined cognition at 15- and 30-month intervals., Results: The A-N- group showed significant improvements in the memory and global scores. The A+N- group also showed significant improvements in the memory and global scores as well as attention. The A-N+ group showed a significant decline in attention at 30 months. The A+N+ group showed significant improvements in memory and the global score at 15 months followed by a significant decline in the global score at 30 months., Conclusion: Amyloidosis in the absence of neurodegeneration did not have an adverse impact on practice effects or the 30-month cognitive trajectories. In contrast, participants with neurodegeneration (either A-N+ or A+N+) had worse performance at the 30-month follow-up. Our results show that neurodegeneration has a more deleterious effect on cognition than amyloidosis in clinically normal individuals.

Introduction: Tau protein levels in plasma may be a marker of neuronal damage. We examined associations between plasma tau levels and Alzheimer's disease (AD)-related magnetic resonance imaging (MRI) and positron emission tomography (PET) neuroimaging measures among nondemented individuals., Methods: Participants included 378 cognitively normal (CN) and 161 mild cognitive impairment (MCI) individuals enrolled in the Mayo Clinic Study of Aging with concurrent neuropsychological measures and amyloid PET, fluorodeoxyglucose PET, and MRI. Baseline plasma tau levels were measured using the Quanterix Simoa-HD1 tau assay., Results: Plasma tau levels were higher in MCI compared with CN (4.34 vs. 4.14 pg/mL, P = .078). In regression models adjusted for age, gender, education, and APOE, higher plasma tau was associated with worse memory performance (b = -0.30, P = .02) and abnormal cortical thickness in an AD signature region (odds ratio = 1.80, P = .018)., Discussion: Plasma tau is associated with cortical thickness and memory performance. Longitudinal studies will better elucidate the associations between plasma tau, neurodegeneration, and cognition., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer's disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio < 1.32 in AD-related regions). Abnormal FDG-PET was associated with depression as measured by NPI-Q (OR = 2.12; 1.23-3.64); the point estimate was further elevated for APOE ɛ4 carriers (OR = 2.59; 1.00-6.69), though marginally significant. Additionally, we observed a significant association between abnormal FDG-PET and depressive and anxiety symptoms when treated as continuous measures. These findings indicate that NPS, even in community-based samples, can be an important additional tool to the biomarker-based investigation of presymptomatic AD.

Objective: To assess the cross-sectional association between multimorbidity and imaging biomarkers of brain pathology in the population-based Mayo Clinic Study of Aging (MCSA)., Methods: The study consisted of 1,449 MCSA participants who were cognitively normal at the time of MRI. A subset of the participants also had (11)C-Pittsburgh compound B (n = 689) and (18)fluorodeoxyglucose (n = 688) PET scans available. Information on multimorbidity (defined as ≥2 chronic conditions) in the 5 years prior to the first imaging study was captured from the medical record using ICD-9 codes for chronic conditions and the Rochester Epidemiology Project medical records linkage system. The cross-sectional association of multimorbidity and imaging biomarkers was examined using logistic and linear regression models., Results: Among 1,449 cognitively normal participants (mean age 79 years; 50.9% men), 85.4% had multimorbidity (≥2 chronic conditions). Multimorbidity and severe multimorbidity (≥4 chronic conditions) were associated with abnormal Alzheimer disease (AD) signature meta-region of interest (meta-ROI) (18)F-FDG hypometabolism (odds ratio [OR] 2.03; 95% confidence interval [CI] 1.10-3.77 and OR 2.22; 95% CI 1.18-4.16, respectively), and with abnormal AD signature MRI cortical thickness (OR 1.53; 95% CI 1.09-2.16 and OR 1.76; 95% CI 1.24-2.51, respectively), but was not associated with amyloid accumulation., Conclusions: Multimorbidity was associated with brain pathology through mechanisms independent of amyloid deposition and such neuronal injury and pathology was present before any symptomatic evidence of cognitive impairment. Longitudinal follow-up will provide insights into potential causal associations of multimorbidity with changes in brain pathology., (© 2016 American Academy of Neurology.)

Background: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD)., Objective: To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women., Methods: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated., Results: Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers., Conclusion: In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

Background: Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer's disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown., Objective: Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample., Methods: Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 and older enrolled in the Mayo Clinic Study of Aging., Results: Women had higher adiponectin than men (12,631 ng/mL versus 8,908 ng/mL, p < 0.001). Among women, higher adiponectin was associated with smaller HVa (B = -0.595; 95% CI -1.19, -0.005), poorer performance in language (B = -0.676; 95% CI -1.23, -0.121), and global cognition (B = -0.459; 95% CI -0.915, -0.002), and greater odds of a MCI diagnosis (OR = 6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR >1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B = -0.723; 95% CI -1.43, -0.014), poorer performance in memory (B = -1.02; 95% CI -1.73, -0.312), language (B = -0.896; 95% CI -1.58, -0.212), global cognition (B = -0.650; 95% CI -1.18, -0.116), and greater odds of MCI (OR = 19.34; 95% CI 2.72, 137.34)., Conclusion: Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline.

Introduction: Few studies have examined the effects of amyloid and apolipoprotein E (APOE) genotype on cognition among middle-aged individuals., Methods: We included 464 cognitively normal, test-naïve, participants with Pittsburgh compound B positron emission tomography amyloid imaging, mean age of 62.7 (range, 51-71 years), enrolled in the Mayo Clinic Study of Aging. Participants completed multiple cognitive assessments, including a standard neuropsychological battery and the CogState computerized battery, over 30 months of follow-up. Linear mixed models were used to examine the effects of amyloid and APOE genotype on baseline cognition and cognitive decline., Results: Elevated amyloid was not associated with tests of episodic memory but did predict declines on tests of executive function. APOE genotype was not associated with cognition. Among APOE ɛ4 noncarriers, higher amyloid was predictive of decline on tests of executive function and on one episodic memory test., Discussion: Elevated amyloidosis and APOE genotype do not appear to exert a dramatic influence on cognition in middle age., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Importance: The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain., Objective: To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers., Design, Setting, and Participants: A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated., Main Outcomes and Measures: Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures., Results: At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB- noncarriers). These associations were largely independent of APOE4., Conclusions and Relevance: In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.

Objective: To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment., Methods: We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ≤-0.5, -1, -1.5, and -2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately., Results: The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles., Conclusions: Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint., (© 2015 American Academy of Neurology.)

Background: Inexpensive, non-invasive tools for assessing Alzheimer-type pathophysiologies are needed. Computerized cognitive assessments are prime candidates., Methods: Cognitively normal participants, aged 51-71, with magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z-scores and neuroimaging., Results: Slower reaction times for CogState Identification and One Back, and lower memory and attention z-scores, were associated (P < .05) with FDG-PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z-scores with neuroimaging were small and of a similar magnitude., Conclusions: CogState subtests were cross-sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration., Methods: We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, (18)F-fluorodeoxyglucose ((18)F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A(+)] or negative [A(-)]) was determined by amyloid PET with (11)C Pittsburgh compound B. Neurodegeneration status (positive [N(+)] or negative [N(-)]) was determined by an Alzheimer's disease signature (18)F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A(-)N(-)], amyloid positive and neurodegeneration negative [A(+)N(-)], amyloid negative and neurodegeneration positive [A(-)N(+)], or amyloid positive and neurodegeneration positive [A(+)N(+)]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models., Findings: The study population consisted of 985 eligible participants. The population frequency of A(-)N(-) was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A(+)N(-) increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A(-)N(+) increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A(+)N(+) increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A(+)N(-) and A(+)N(+) were more frequent in APOE ɛ4 carriers than in non-carriers and that A(+)N(+) was more, and A(+)N(-) less frequent in men than in women., Interpretation: Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals., Funding: US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Importance: Intellectual lifestyle enrichment throughout life is increasingly viewed as a protective strategy against commonly observed cognitive decline in the older population., Objectives: To investigate the association of lifetime intellectual enrichment with baseline cognitive performance and rate of cognitive decline in an older population without dementia and to estimate the years of protection provided against cognitive impairment by these factors., Design, Setting, and Participants: Prospective analysis of individuals enrolled from October 1, 2004, and in 2008 and 2009 in the Mayo Clinic Study of Aging, a longitudinal, population-based study of cognitive aging in Olmsted County, Minnesota. We studied 1995 individuals without dementia (1718 cognitively normal individuals and 277 individuals with mild cognitive impairment) who completed intellectual lifestyle enrichment measures at baseline and underwent at least 1 follow-up visit., Main Outcomes and Measures: We studied the effect of lifetime intellectual enrichment by separating the variables into 2 nonoverlapping principal components: education/occupation score and mid/late-life cognitive activity based on self-report questionnaires. A global cognitive z score served as the summary cognition measure. Linear mixed-effects models were used to investigate the associations of demographic and intellectual enrichment measures with global cognitive z score trajectories., Results: Baseline cognitive performance was lower in older individuals; individuals with lower education/occupation score, lower mid/late-life cognitive activity, and APOE genotype; and men (P < .001). The interaction between the 2 intellectual enrichment measures was significant (P < .03) such that the beneficial effect of mid/late-life cognitive activity on baseline cognitive performance was reduced with increasing education/occupation score. Only baseline age, mid/late-life cognitive activity, and APOE4 genotype were significantly associated with longitudinal change in cognitive performance from baseline (P < .05). For APOE4 carriers with high lifetime intellectual enrichment (75th percentile of education/occupation score and midlife to late-life cognitive activity), the onset of cognitive impairment was approximately 8.7 years later compared with low lifetime intellectual enrichment (25th percentile of education/occupation score and mid/late-life cognitive activity)., Conclusions and Relevance: Higher education/occupation scores were associated with higher levels of cognition. Higher levels of mid/late-life cognitive activity were also associated with higher levels of cognition, but the slope of this association slightly increased over time. Lifetime intellectual enrichment might delay the onset of cognitive impairment and be used as a successful preventive intervention to reduce the impending dementia epidemic.

Objective: The authors conducted a prospective cohort study to estimate the risk of incident mild cognitive impairment in cognitively normal elderly (aged ≥70 years) individuals with or without neuropsychiatric symptoms at baseline. The research was conducted in the setting of the population-based Mayo Clinic Study of Aging., Method: A classification of normal cognitive aging, mild cognitive impairment, and dementia was adjudicated by an expert consensus panel based on published criteria. Hazard ratios and 95% confidence intervals were computed using Cox proportional hazards model, with age as a time scale. Baseline Neuropsychiatric Inventory Questionnaire data were available for 1,587 cognitively normal persons who underwent at least one follow-up visit., Results: The cohort was followed to incident mild cognitive impairment (N=365) or censoring variables (N=179) for a median of 5 years. Agitation (hazard ratio=3.06, 95% CI=1.89-4.93), apathy (hazard ratio=2.26, 95% CI=1.49-3.41), anxiety (hazard ratio=1.87, 95% CI=1.28-2.73), irritability (hazard ratio=1.84, 95% CI=1.31-2.58), and depression (hazard ratio=1.63, 95% CI=1.23-2.16), observed initially, increased risk for later mild cognitive impairment. Delusion and hallucination did not. A secondary analysis, limited in significance by the small number of study participants, showed that euphoria, disinhibition, and nighttime behaviors were significant predictors of nonamnestic mild cognitive impairment but not amnestic mild cognitive impairment. By contrast, depression predicted amnestic mild cognitive impairment (hazard ratio=1.74, 95% CI=1.22-2.47) but not nonamnestic mild cognitive impairment., Conclusions: An increased incidence of mild cognitive impairment was observed in community-dwelling elderly adults who had nonpsychotic psychiatric symptoms at baseline. These baseline psychiatric symptoms were of similar or greater magnitude as biomarkers (genetic and structural MRI) in increasing the risk of incident mild cognitive impairment.

Background: Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition., Methods: Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS., Results: Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment., Conclusion: These results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.

Background: The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals., Methods: The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70-89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions., Results: Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed., Conclusions: Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline.

The objective of this study was to examine practice effects and longitudinal cognitive change in a population-based cohort classified as clinically normal at their initial evaluation. We examined 1390 individuals with a median age of 78.1 years and re-evaluated them up to four times at approximate 15-month intervals, with an average follow-up time of 5 years. Of the 1390 participants, 947 (69%) individuals remained cognitively normal, 397 (29%) progressed to mild cognitive impairment (MCI), and 46 (3%) to dementia. The stable normal group showed an initial practice effect in all domains which was sustained in memory and visuospatial reasoning. There was only a slight decline in attention and language after visit 3. We combined individuals with incident MCI and dementia to form one group representing those who declined. The incident MCI/dementia group showed an unexpected practice effect in memory from baseline to visit 2, with a significant decline thereafter. This group did not demonstrate practice effects in any other domain and showed a downward trajectory in all domains at each evaluation. Modeling cognitive change in an epidemiologic sample may serve as a useful benchmark for evaluating cognitive change in future intervention studies.

Background: Evidence suggests that elevated systolic blood pressure (SBP) and pulse pressure (PP) in midlife is associated with increased risk for cognitive impairment later in life. There is mixed evidence regarding the effects of late life elevated SBP or PP on cognitive function, and limited information on the role of female gender., Methods/principal Findings: Effects of SBPand PPon cognitive abilities at baseline and over a 9-year period were evaluated in 337 non-demented community-dwelling female participants over age 70 in the Women's Health and Aging Study II using logistic and Cox proportional hazards regression analyses. Participants aged 76-80 years with SBP≥160 mmHg or PP≥84 mmHg showed increased incidence of impairment on Trail Making Test-Part B (TMT, Part B), a measure of executive function, over time when compared to the control group that included participants with normal and pre-hypertensive SBP (<120 and 120-139 mmHg) or participants with low PP (<68 mmHg) (HR = 5.05 [95%CI = 1.42, 18.04], [HR = 5.12 [95%CI = 1.11; 23.62], respectively). Participants aged 70-75 years with PP≥71 mmHg had at least a two-fold higher incidence of impairment on HVLT-I, a measure of verbal learning, over time when compared to participants with low PP (<68 mmHg) (HR = 2.44 [95%CI = 1.11, 5.39])., Conclusions/significance: Our data suggest that elevated SBP or PP in older non-demented women increases risk for late-life cognitive impairment and that PP could be used when assessing the risk for impairment in cognitive abilities. These results warrant further, larger studies to evaluate possible effects of elevated blood pressure in normal cognitive aging.

Background: Although several studies have investigated the association between cholesterol and dementia, few have examined cholesterol and decline across cognitive domains. We examined serum total and high-density lipoprotein (HDL) cholesterol, total-to-HDL ratio, and trajectories across cognitive domains., Methods: Participants were 436 community-residing women (70-79 years old) in the Women's Health and Aging Study II; they were screened to be physically high-functioning and cognitively intact at baseline. Cognition and other health-related variables were assessed at five intervals spanning 9 years. Cognitive assessments included Trail Making Test Parts A (TMT-A) and B (TMT-B), Hopkins Verbal Learning Test-Revised, Purdue Pegboard, and Mini-Mental State Examination (MMSE). The association between baseline levels of serum lipids and cognitive trajectories were evaluated using Generalized Estimating Equations (GEE). Covariates included age, education, race, vascular disease, serum creatinine, depression, and lipid-lowering medications., Results: In multivariate analyses, baseline higher total (p =.02) and HDL (p =.03) cholesterol were associated with better performance on the Purdue Pegboard. Using clinical cholesterol cutoffs, baseline serum total cholesterol levels >240 mg/dL were associated with the best performance (p =.02). Baseline lipids were not associated with any other cognitive tests; there were no Lipid x Time interactions., Conclusion: Higher baseline serum lipid levels predicted better performance over time on a measure of motor speed, but not memory or psychomotor or executive functioning in this population of elderly women. This association suggests that peripheral cholesterol levels, measured in late-life, may not be a good predictor of subsequent cognitive decline. Future research examining peripheral cholesterol over the life span and its relationship with cognition is needed.

Dual cognitive and mobility impairments are associated with an increased risk of dementia. Recent studies examining temporal trajectories of mobility and cognitive function in aging found that dual decline is associated with higher dementia risk than memory decline or gait decline only. Although initial data show that individuals with dual decline or impairment have excessive cardiovascular and metabolic risk factors, the causes of dual decline or what underlies dual decline with a high risk of dementia remain largely unknown. In December 2021, the National Institute on Aging Intramural and Extramural Programs jointly organized a workshop on Biology Underlying Moving and Thinking to explore the hypothesis that older persons with dual decline may develop dementia through a specific pathophysiological pathway. The working group discussed assessment methods for dual decline and possible mechanisms connecting dual decline with dementia risk and pinpointed the most critical questions to be addressed from a translational perspective.

This study aimed to explore the relationship of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with cognition in women with (HIV+) and without HIV (HIV-) infection. One thousand six hundred ninety participants (1,196 HIV+, 494 HIV-) in the Women's Interagency HIV Study (WIHS) with data available on anthropometric measures comprise the analytical sample. Cross-sectional analyses using linear regression models estimated the relationship between anthropometric variables and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score, CD4 count, insulin resistance, drug use, and race/ethnicity. Among HIV+ women, BMI

Objective: The Stricker Learning Span (SLS) is a computer-adaptive digital word list memory test specifically designed for remote assessment and self-administration on a web-based multi-device platform (Mayo Test Drive). We aimed to establish criterion validity of the SLS by comparing its ability to differentiate biomarker-defined groups to the person-administered Rey's Auditory Verbal Learning Test (AVLT). Method: Participants (N = 353; mean age = 71, SD = 11; 93% cognitively unimpaired [CU]) completed the AVLT during an in-person visit, the SLS remotely (within 3 months) and had brain amyloid and tau PET scans available (within 3 years). Overlapping groups were formed for 1) those on the Alzheimer's disease (AD) continuum (amyloid PET positive, A+, n = 125) or not (A-, n = 228), and those with biological AD (amyloid and tau PET positive, A+T+, n = 55) vs no evidence of AD pathology (A−T−, n = 195). Analyses were repeated among CU participants only. Results: The SLS and AVLT showed similar ability to differentiate biomarker-defined groups when comparing AUROCs (p 's >.05). In logistic regression models, SLS contributed significantly to predicting biomarker group beyond age, education, and sex, including when limited to CU participants. Medium (A− vs A+) to large (A−T− vs A+T+) unadjusted effect sizes were observed for both SLS and AVLT. Learning and delay variables were similar in terms of ability to separate biomarker groups. Conclusions: Remotely administered SLS performed similarly to in-person-administered AVLT in its ability to separate biomarker-defined groups, providing evidence of criterion validity. Results suggest the SLS may be sensitive to detecting subtle objective cognitive decline in preclinical AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Few studies have comprehensively examined the impact of reproductive factors (i.e., reproductive window, parity, hormonal contraception [HC], and menopausal hormone therapy [MHT]) on global and domain‐specific cognition in later life. METHODS: We studied a population‐based sample of 2458 women (median age 74.2 years) residing in Olmsted County, Minnesota; participants underwent a clinical evaluation and comprehensive cognitive testing. RESULTS: The length of a woman's reproductive window was not associated with cognition. Higher parity was associated with greater cognitive decline in all domains. Ever HC use was associated with less decline in all domains. Ever MHT use was associated with greater decline in global cognition and all domain‐specific z‐scores except visuospatial; results were driven by women who initiated MHT 5 or more years after menopause. Additional adjustments for APOE and vascular‐related covariates did not attenuate the results. DISCUSSION: Multiple reproductive risk factors are associated with cognitive decline in later life. Highlights: The length of a woman's reproductive window was not associated with cognition longitudinally.Greater parity was associated with greater cognitive decline longitudinally.Ever HC use was associated with less decline in global cognition and all domain‐specific z‐scores longitudinally (all p < 0.01).Ever MHT use was associated with greater decline in global cognition and all domain‐specific z‐scores except visuospatial longitudinally (all p < 0.01).The greatest cognitive decline was among women who initiated MHT more than 5 years after menopause. [ABSTRACT FROM AUTHOR]

Chronic pain is highly prevalent in older adults and is associated with poor functional outcomes. Furthermore, opioid analgesics are commonly utilized for the treatment of pain in older adults despite well-described adverse effects. Importantly, both chronic pain and opioid analgesics have been linked with impairments in cognitive function, though data are limited. In this manuscript we summarize the evidence and critical knowledge gaps regarding the relationships between pain, opioid analgesics, and cognition in older adults. Furthermore, we provide a conceptual framework to guide future research in the development, implementation, and evaluation of strategies to optimize analgesic outcomes in older adults while minimizing deleterious effects on cognition. [ABSTRACT FROM AUTHOR]

Background: Opioids are frequently prescribed to alleviate pain in older adults, yet the relationships between prescription opioids and long‐term cognitive function are unclear. Methods: In this analysis of the Mayo Clinic Study of Aging, a longitudinal population‐based cohort study of older adults with formal neuropsychological testing and cognitive evaluations performed every 15 months, the associations between prescription opioids, global and domain‐specific cognitive function, and mild cognitive impairment were evaluated through time‐dependent linear mixed effects and Cox proportional hazards models. Results: Four thousand two hundred eighteen participants (51% male) were included with enrollment between 11/1/2004 and 4/1/2019 and median age of 76 (interquartile range 72, 82) years. Two thousand nine hundred seventy‐seven subjects (71%) received at least 1 opioid prescription during a median follow‐up of 7.5 (5.0, 10.7) years. Overall, there was an estimated 0.096 reduction in the global cognitive Z‐score per year, including decreases of 0.050 in memory, 0.080 in language, 0.044 in visual–spatial cognition, and 0.112 in attention. In multivariable analyses, each receipt of an opioid prescription resulted in an additional −0.007 (95% CI −0.009, −0.005) change in global cognitive Z‐score (p < 0.001), with significant effects seen in the domains of memory (−0.005, 95% CI −0.007, −0.003; p < 0.001), language (−0.002, 95% CI −0.003, 0.000; p = 0.024) and attention (−0.004, 95% CI −0.006, −0.002; p < 0.001) but not visual–spatial function (0.000, 95% CI −0.001, 0.001; p = 0.897). Opioid prescriptions were associated with incident mild cognitive impairment (MCI) in adjusted analysis (hazard ratio 1.21, 95% CI 1.04, 1.42; p = 0.014). Conclusion: Prescription opioids are associated with small but statistically significant declines in long‐term cognitive function in older adults, which may represent effects of opioids or other related factors. [ABSTRACT FROM AUTHOR]

Introduction: Blood‐based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers. Methods: Plasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) were measured on the Quanterix Simoa HD‐1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years. All other data were collected during in‐person MCSA visits or abstracted from the medical record. Results: Among cognitively unimpaired (CU) participants, all plasma markers correlated with age. Linear regression models revealed multiple relationships. For example, higher Charlson Comorbidity Index and chronic kidney disease were associated with higher levels of all biomarkers. Some relationships differed between mild cognitive impairment and dementia participants. Discussion: Multiple variables affect plasma biomarkers of amyloid pathology and neurodegeneration among CU in the general population. Incorporating this information is critical for accurate interpretation of the biomarker levels and for the development of reference ranges. [ABSTRACT FROM AUTHOR]

IMPORTANCE: Hospitalizations are associated with cognitive decline in older adults. OBJECTIVE: To determine the association between hospitalization characteristics and the trajectory of cognitive function in older adults. DESIGN: Population‐based longitudinal study of cognitive aging. SETTING: Olmsted Medical Center and Mayo Clinic, the only centers in Olmsted County, Minnesota, with hospitalization capacity. PARTICIPANTS: Individuals without dementia at baseline, with consecutive cognitive assessments from 2004 through 2017, and at least one visit after the age of 60. MEASUREMENTS: The primary outcome was longitudinal changes in global cognitive z‐score. Secondary outcomes were changes in four cognitive domains: memory, attention/executive function, language, and visuospatial skills. Hospitalization characteristics analyzed included elective versus nonelective, medical versus surgical, critical care versus no critical care admission, and long versus short duration admissions. RESULTS: Of 4,587 participants, 1,622 had 1 and more hospital admission. Before hospitalization, the average slope of the global z‐score was −0.031 units/year. After hospitalization, the rate of annual global z‐score accelerated by −0.051 (95% CI = −0.057, −0.045) units, P <.001, resulting in an estimated annual slope after the first hospitalization of −0.082. The accelerated decline was found in all four cognitive domains (memory, visuospatial, language, and executive, all P <.001). The acceleration of the decline in global z‐score following hospitalization was greater for medical compared to surgical hospitalizations (slope change following hospitalization = −0.064 vs −0.034 for medical vs surgical, P <.001), and nonelective compared to elective admissions (slope change following hospitalization = −0.075 vs −0.037 for nonelective vs elective, P <.001). The acceleration of cognitive decline was not different for hospitalization with intensive care unit admission versus not. CONCLUSIONS: Hospitalization of older adults is associated with accelerated decline of global and domain‐specific cognitive domains, with the rate of decline dependent upon type of admission. The clinical impact of this accelerated decline will depend on the individual's baseline cognitive reserve and expected longevity. [ABSTRACT FROM AUTHOR]

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer's disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers.Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women.Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1-42 (Aβ1-42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs.Results: Only the number of microvesicles positive for Aβ1-42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045).Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition. [ABSTRACT FROM AUTHOR]

Introduction: We examined the association between androgen deprivation therapy (ADT) use and the risk of mild cognitive impairment (MCI) among prostate cancer patients.Methods: We included 241 cognitively unimpaired men, aged 70 to 90, with a history of prostate cancer before enrollment in the population-based Mayo Clinic Study of Aging. Using the Rochester Epidemiology Project medical records-linkage system, ADT use and length of exposure were abstracted. Follow-up visits occurred every 15 months and MCI diagnoses were made based on clinical consensus. Cox proportional hazards models, with age as the timescale, were used to examine the association between ADT use (yes/no) and length of exposure with the risk of MCI adjusting for education, apolipoprotein E, depression, and the Charlson Index score.Results: There was no association between any ADT use (27.8% of participants) and the risk of MCI in the multivariable model [hazard ratio (HR), 1.25; 95% confidence interval (CI), 0.75-2.10]. Although not significant, there was an ADT dose-response relationship for risk of MCI: <5 years versus no use (HR, 1.08; 95% CI, 0.60-1.96) and ≥5 years versus not use (HR, 1.89; 95% CI, 0.83-4.27).Conclusion: ADT use among prostate cancer patients was not associated with an increased risk of developing MCI. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to examine white matter hyperintensities (WMH) and fractional anisotropy (FA) in empirically derived incident mild cognitive impairment (MCI) subtypes. Methods: We evaluated 188 participants with incident MCI in the Mayo Clinic Study of Aging (MCSA) identified as having one of four cluster‐derived subtypes: subtle cognitive impairment, amnestic, dysnomic, and dysexecutive. We used linear regression models to evaluate whole brain and regional WMH volumes. We examined fractional anisotropy (FA) on a subset of 63 participants with diffusion tensor imaging. Results: Amnestic and dysexecutive subtypes had higher WMH volumes in differing patterns than cognitively unimpaired; the dysexecutive subtype had higher WMH than subtle cognitive impairment. There was widespread WM degeneration in long association and commissural fibers in the amnestic, dysnomic, and dysexecutive subtypes, and corpus callosum FA accounted for significant variability in global cognition. Discussion: White matter changes likely contribute to cognitive symptoms in incident MCI. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins' impact on markers of dementia risk.Objective: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition.Methods: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity.Results: Omega-6 derived 9-HODE was associated with increased WMH (p = 0.017) and reduced grey matter volume (p = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p = 0.035) and poorer performance on Trails-B (p = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p = 0.04) and poorer performance on Trails-B (p = 0.04). Arachidonic acid was associated with better performance on Trails-B (p = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p = 0.005).Conclusions: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk. [ABSTRACT FROM AUTHOR]

In this study derived from the population-based Mayo Clinic Study of Aging, we investigated whether non-exercise physical activity (PA) was associated with global and domain-specific cognitive trajectories (memory, language, visuospatial skills, attention) and whether the association differed by apolipoprotein E (APOE) ε4 genotype status. We included 2061 community-dwelling individuals aged ≥ 70 years (50.5% males, 26.7% APOE ε4 carriers) who were cognitively unimpaired at baseline and on whom serial cognitive data and self-reported information on non-exercise PA were available. We specifically inquired about non-exercise PA carried out at two time points, i.e., midlife (between 50 and 65 years of age) and late-life (within 1 year prior to assessment) and three intensity levels, i.e., light (e.g., laundry), moderate (e.g., scrubbing floors) and heavy (e.g., hard manual labor). Linear mixed-effect models revealed that engaging in midlife PA of moderate or heavy intensity was associated with significantly less-pronounced decline of z-scores in all cognitive domains. Similarly, participants that engaged in late-life moderate or heavy PA had less decline in visuospatial, attention and global z-scores than non-active peers. These associations varied depending on APOE ε4 carrier status, i.e., APOE ε4 non-carriers but not APOE ε4 carriers that engaged in late-life PA had less decline in cognitive z-scores. In contrast, engaging in midlife PA, irrespective of intensity, was significantly associated with less decline in memory function only among APOE ε4 carriers. [ABSTRACT FROM AUTHOR]