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Dementia is among the leading causes of cognitive and functional loss and disability in older adults. Past studies suggested sex differences in health conditions and progression of cognitive decline. Existing studies on the temporal trajectory of health conditions for patient characterization after dementia diagnosis are scarce and ambiguous. Thus, there's limited and unclear research on how health conditions change over time after a dementia diagnosis. To this end, we aim to analyze the shift in medical conditions and examine sex-specific changes in patterns of chronic health conditions after dementia diagnosis. We centered our analysis on a 15-year window around the point of dementia diagnosis, encompassing the 5 years leading up to the diagnosis and the 10 years following it. We introduce (i) MedMet, a network metric to quantify the contribution of each medical condition, and (ii) growth and decay function for temporal trajectory analysis of medical conditions. Our experiments demonstrate that certain health conditions are more prevalent among females than males. Thus, our findings underscore the pressing need to examine differences between men and women, which could be important for healthcare utilization after a dementia diagnosis.

This paper presents a machine learning-based prediction for dementia, leveraging transfer learning to reuse the knowledge learned from prediction of mild cognitive impairment, a precursor of dementia. We also examine the impacts of temporal aspects of longitudinal data and sex differences. The methodology encompasses key components such as setting the duration window, comparing different modeling strategies, conducting comprehensive evaluations, and examining the sex-specific impacts of simulated scenarios. The findings reveal that cognitive deficits in females, once detected at the mild cognitive impairment stage, tend to deteriorate over time, while males exhibit more diverse decline across various characteristics without highlighting specific ones. However, the underlying reasons for these sex differences remain unknown and warrant further investigation.

Background and Objectives: Treatment options for Alzheimer disease (AD) are limited and have focused mainly on symptomatic therapy and improving quality of life. Recently, lecanemab, an anti-β-amyloid monoclonal antibody (mAb), received accelerated approval by the US Food and Drug Administration for treatment in the early stages of biomarker-confirmed symptomatic AD. An additional anti-β-amyloid mAb, aducanumab, was approved in 2021, and more will potentially become available in the near future. Research on the applicability and generalizability of the anti-β-amyloid mAb eligibility criteria on adults with biomarkers available in the general population has been lacking. The study's primary aim was to apply the clinical trial eligibility criteria for lecanemab treatment to participants with early AD of the population-based Mayo Clinic Study of Aging (MCSA) and assess the generalizability of anti-amyloid treatment. The secondary aim of this study was to apply the clinical trial eligibility criteria for aducanumab treatment in MCSA participants., Methods: This cross-sectional study aimed to apply the clinical trial eligibility criteria for lecanemab and aducanumab treatment to participants with early AD of the population-based MCSA and assess the generalizability of anti-amyloid treatment., Results: Two hundred thirty-seven MCSA participants (mean age [SD] 80.9 [6.3] years, 54.9% male, and 97.5% White) with mild cognitive impairment (MCI) or mild dementia and increased brain amyloid burden by PiB PET comprised the study sample. Lecanemab trial's inclusion criteria reduced the study sample to 112 (47.3% of 237) participants. The trial's exclusion criteria further narrowed the number of potentially eligible participants to 19 (overall 8% of 237). Modifying the eligibility criteria to include all participants with MCI (instead of applying additional cognitive criteria) resulted in 17.4% of participants with MCI being eligible for lecanemab treatment. One hundred four participants (43.9% of 237) fulfilled the aducanumab clinical trial's inclusion criteria. The aducanumab trial's exclusion criteria further reduced the number of available participants, narrowing those eligible to 12 (5.1% of 237). Common exclusions were related to other chronic conditions and neuroimaging findings., Discussion: Findings estimate the limited eligibility in typical older adults with cognitive impairment for anti-β-amyloid mAbs., (© 2023 American Academy of Neurology.)

The study included 1,738 Mayo Clinic Study of Aging participants (≥50 years old; 1,460 cognitively unimpaired and 278 with mild cognitive impairment (MCI)) and examined the cross-sectional association between cerebrovascular (CVD) imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) and Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) scores, as well as their association with MCI. High (abnormal) WMH burden was significantly associated with having BDI-II>13 and BAI > 7 scores, and both (CVD imaging biomarkers and depression/anxiety) were significantly associated with MCI when included simultaneously in the model, suggesting that both were independently associated with the odds of MCI., Competing Interests: Maria Vassilaki has received research funding from F. Hoffmann-La Roche Ltd and Biogen and consulted for F. Hoffmann-La Roche Ltd; currently, she receives research funding from NIH; she has equity ownership in Johnson and Johnson, Medtronic, Merck, and Amgen. Jonathan Graff-Radford receives support from the NIH, serves on the DSMB for StrokeNET, and is an investigator in clinical trials sponsored by Esai and the Alzheimer’s Treatment and Research Institute at USC. Prashanthi Vemuri receives NIH funding. Eugene L Scharf is a consultant for Boston Scientific but receives no compensation. Mary M. Machulda receives NIH funding. Julie A. Fields serves as a consultant for Medtronic, Inc. and receives research support from the NIH. Walter K. Kremers receives research support from the NIH. Val J. Lowe serves as a consultant for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). Clifford R. Jack Jr. has no financial conflicts to disclose; he receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. David S. 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. He receives funding from the NIH. Ronald C. Petersen serves as a consultant for Roche, Inc., Eisai, Inc., Genentech, Inc. Eli Lilly, Inc., and Nestle, Inc., served on a DSMB for Genentech, receives royalties from Oxford University Press and UpToDate, and receives NIH funding. Yonas E. Geda receives funding from NIH and the BARROW Neurological Foundation. All other authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

Introduction: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults., Methods: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aβ42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q)., Results: Lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior., Discussion: CSF Aβ42, t-tau/Aβ42, and p-tau/Aβ42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Hearing loss is increasingly recognized as a chronic disease state with important health sequelae. Although considered a central component of routine audiometric testing, the degree to which various patient factors influence speech discrimination is poorly characterized to date. The primary objective of the current work was to describe associations of cognitive performance, sociodemographic factors, and pure-tone audiometry with speech discrimination in older adults., Study Design: Prospective study., Setting: Olmsted County, Minnesota., Patients: There were 1,061 study participants 50 years or older at enrollment in the population-based Mayo Clinic Study of Aging between November 2004 and December 2019 who underwent formal audiometric and cognitive testing included in the current investigation., Main Outcome Measures: The primary outcome measure was word recognition scores (WRSs; measured as <100% vs 100% as well as continuous), with pure-tone averages (PTAs; 0.5, 1, 2, and 3 kHz), age, sex, years of education, state area deprivation index (ADI) quintiles, and global cognition z scores as explanatory features., Results: The mean (SD) age among the 1,061 participants was 76 (9) years with 528 (50%) males. Participant age [OR (95% CI) for a 10-year increase of 1.8 (1.4-2.3), p < 0.001], male sex [OR = 2.6 (1.9-3.7), p < 0.001], and PTA [OR for a 10-dB hearing loss increase of 2.4 (2.1-2.8), p < 0.001] were all significantly associated with <100% WRSs, with the greatest explanatory ability attributable to the PTA. Years of education ( p = 0.9), state ADI quintile ( p = 0.6), and global cognitive performance ( p = 0.2) were not associated with WRS. The multivariable model demonstrated strong predictive ability for less than perfect WRSs, with a c index of 0.854. Similar results were seen for WRSs analyzed as continuous, with the multivariable model resulting in an R2 value of 0.433., Conclusions: Although PTA exhibited the greatest influence on speech discrimination, advancing age and male sex both independently increased the likelihood of having worse speech discrimination among older adults, even after accounting for years of education, neighborhood-level socioeconomic disadvantage, and cognitive function. These findings help identify patient factors that can be instrumental when designing screening programs for adult-onset hearing loss., Competing Interests: Conflicts of interest: R.C.P. has been a consultant for Roche, Biogen, Merck, Eisai, Genentech, and Nestle; receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate; and receives research support from the U.S. National Institutes of Health. N.S.R. is on the advisory board of Neosensory and receives funding from the National Institutes of Health and the National Institute on Aging. M.V. has received research funding from F. Hoffmann-La Roche and Biogen in the past, consults for F. Hoffmann-La Roche, receives research funding from the National Institutes of Health, and has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, AbbVie, and Amgen. All other authors declare no competing interests., (Copyright © 2023, Otology & Neurotology, Inc.)

Introduction: We examined associations between plasma-derived biomarkers of Alzheimer's disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults., Methods: Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment., Results: P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41-3.00, p  < 0.001), p-tau217 (OR 1.70, 95% CI 1.10-2.61, p  = 0.016), and t-tau (OR 1.44, 95% CI 1.08-1.92, p  = 0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20-3.11, p  = 0.007 and OR 2.04, 95% CI 1.21-3.42, p  = 0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45-3.93, p  = 0.001 and OR 2.30, 95% CI 1.33-3.98, p  = 0.003, respectively). Aβ42/Aβ40 and NfL were not associated with NPS., Conclusion: Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment., Highlights: We studied 1005 community-dwelling persons aged ≥ 50 yearsHigher plasma tau levels are associated with increased neuropsychiatric symptomsAβ42/Aβ40 and NfL are not associated with neuropsychiatric symptomsClinicians should treat neuropsychiatric symptoms in persons with high plasma-derived tau., Competing Interests: Walter K. Kremers receives research funding from the Department of Defense, the National Institutes of Health (NIH), Astra Zeneca, Biogen, and Roche. Alicia Algeciras‐Schimnich serves on advisory boards for Roche Diagnostics and Fujirebio Diagnostics. Jeffrey L. Dage is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents, and/or compositions of matter related to measurement of p‐tau217. Jeffrey L. Dage has served as a consultant for Genotix Biotechnologies Inc, Gates Ventures, Karuna Therapeutics, AlzPath Inc, Cognito Therapeutics, Inc., and received research support from ADx Neurosciences, AlzPath, Roche Diagnostics, and Eli Lilly and Company in the past 2 years. Jeffrey L. Dage has received speaker fees from Eli Lilly and Company. Argonde C. van Harten served as a consultant for Roche Diagnostics. Julie A. Fields receives research funding from the NIH. David S. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network (DIAN) study and is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. Clifford R. Jack Jr. serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Ronald C. Petersen consults for Roche, Merck, Genentech, and Biogen, and GE Healthcare and receives royalties from Oxford University Press for the publication of Mild Cognitive Impairment. Maria Vassilaki has received in the past research funding from Roche and Biogen; she currently consults for Roche; receives research funding from NIH; and has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, and Amgen. Yonas E. Geda receives funding from the NIH and Roche and served on the Lundbeck Advisory Board. No other disclosures were reported. Author disclosures are available in the supporting information.All participants gave their written informed consent to participate in the Mayo Clinic Study of Aging, in accordance with the ethical standards set by the Mayo Clinic and Olmsted Medical Center institutional review boards., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Total joint arthroplasty (TJA) implants are composed of metal components. Although they are regarded safe, the long-term immunological effects of chronic exposure to the specific implant materials are unknown. We recruited 115 hip and/or knee TJA patients (mean age 68 years) who provided a blood draw for measurement of chromium, cobalt, titanium concentrations, inflammatory markers and systemic distribution of immune cells. We examined differences between the immune markers and the systemic concentrations of chromium, cobalt and titanium. CD66-b neutrophils, early natural killer cells (NK), and eosinophils were present in higher percentages in patients with chromium and cobalt concentrations greater than the median. The opposite pattern was observed with titanium where the percentages of CD66-b neutrophils, early NK, and eosinophils were higher in patients with undetectable titanium. Cobalt concentrations were positively correlated with a higher percentage of gamma delta T cells. Both chromium and cobalt concentrations were positively correlated with higher percentages of plasmablasts. Titanium concentrations were positively correlated with higher CD4 effector memory T cells, regulatory T cell count and Th1 CD4 helper cells. In this exploratory study, we observed altered distribution of immune cells in TJA patients with elevated systemic metal concentrations. Although these correlations were not strong, these exploratory findings warrant further investigation into the role of increased metals circulating in blood and its role in immune modulation., Competing Interests: MV received funding in the past from F. Hoffmann-La Roche Ltd. and Biogen and consulted for F. Hoffmann-La Roche Ltd., outside of this study. MV has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, Merck, AbbVie and Amgen and is receiving research funding from NIH. KP has received consulting fees from Akna Health. DL has received research funding from NIH; Royalties and Consulting Fees from Zimmer and Biomet; serves on the American Joint Replacement Registry and Orthopaedic Research and Education Foundation; has stock in Acuitive Technologies and Ketai Medical Devices. HMK reported receiving research funding from NIH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peterson, O’Byrne, Brennan, Jannetto, Pavelko, Lewallen, Vassilaki and Maradit Kremers.)

Introduction: We investigated the association of the area deprivation index (ADI) with cognitive decline, mild cognitive impairment (MCI), and dementia in older adults (≥50 years old). ADI is a neighborhood socioeconomic disadvantage measure assessed at the census block group level., Methods: The study included 4699 participants, initially without dementia, with available ADI values for 2015 and at least one study visit in 2008 through 2018. Using logistic regression and Cox proportional hazards models with age as the time scale, we assessed the odds for MCI and the risk for dementia, respectively., Results: In cognitively unimpaired (CU) adults at baseline, the risk for progression to dementia increased for every decile increase in the ADI state ranking (hazard ratio = 1.06, 95% confidence interval (1.01-1.11), P = .01). Higher ADI values were associated with subtly faster cognitive decline., Discussion: In older CU adults, higher baseline neighborhood socioeconomic deprivation levels were associated with progression to dementia and slightly faster cognitive decline., Highlights: The study used area deprivation index, a composite freely available neighborhood deprivation measure. Higher levels of neighborhood deprivation were associated with greater mild cognitive impairment odds. Higher neighborhood deprivation levels were associated with higher dementia risk., (© 2022 the Alzheimer's Association.)

Objective: This study examined associations between physical activity (PA) and neuropsychiatric symptoms (NPS) in older adults free of dementia., Methods: This cross-sectional study included 3,222 individuals ≥70 years of age (1,655 men; mean±SD age=79.2±5.6; cognitively unimpaired, N=2,723; mild cognitive impairment, N=499) from the population-based Mayo Clinic Study of Aging. PA (taken as a presumed predictor) in midlife (i.e., when participants were 50-65 years of age) and late life (i.e., the year prior to assessment) was assessed with a self-reported, validated questionnaire; PA intensity and frequency were used to calculate composite scores. NPS (taken as presumed outcomes) were assessed with the Neuropsychiatric Inventory Questionnaire, Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). Regression analyses included midlife and late-life PA in each model, which were adjusted for age, sex, education, apolipoprotein E ɛ4 status, and medical comorbidity., Results: Higher late-life PA was associated with lower odds of having apathy (OR=0.89, 95% CI=0.84-0.93), appetite changes (OR=0.92, 95% CI=0.87-0.98), nighttime disturbances (OR=0.95, 95% CI=0.91-0.99), depression (OR=0.94, 95% CI=0.90-0.97), irritability (OR=0.93, 95% CI=0.89-0.97), clinical depression (OR=0.92, 95% CI=0.88-0.97), and clinical anxiety (OR=0.90, 95% CI=0.86-0.94), as well as lower BDI-II (β estimate=-0.042, 95% CI=-0.051 to -0.033) and BAI (β estimate=-0.030, 95% CI=-0.040 to -0.021) scores. Higher midlife PA was associated only with higher BDI-II scores (β estimate=0.011, 95% CI=0.004 to 0.019). Sex modified the associations between PA and NPS., Conclusions: Late-life PA was associated with a lower likelihood of clinical depression or anxiety and subclinical NPS. These findings need to be confirmed in a cohort study.

Background: In middle-aged and particularly older adults, body mass index (BMI) is associated with various health outcomes. We examined associations between physical activity (PA) and longitudinal BMI change in persons aged ≥ 50 years., Methods: The sample included 5159 community-dwelling individuals aged ≥ 50 years (50.5% males, mean (SD) age 73.0 (10.2) years at baseline) who were enrolled in the Mayo Clinic Study of Aging (MCSA). Participants had information on PA within one year of baseline assessment, BMI at baseline, and potential follow-up assessments (mean (SD) follow-up 4.6 (3.7) years). Linear mixed-effect models were used to calculate the association between PA (moderate-vigorous physical activity, MVPA; and all PA composite score) and the longitudinal change in BMI, adjusted for baseline age, sex, education and medical comorbidities. In addition to interactions between years since baseline and PA, we also included 2- and 3-way interactions with baseline age to further assess whether age modifies the trajectory of BMI over time., Results: We observed a decrease in BMI among participants engaging at a mean amount of PA (i.e., , Mvpa: 2.7; all PA: 6.8) and with a mean age (i.e., 73 years) at baseline (MVPA: estimate = -0.047, 95% CI -0.059, -0.034; all PA: estimate = -0.047, 95% CI -0.060, -0.035), and this decline is accelerated with increasing age. Participants with a mean age (i.e., 73 years) that engage at an increased amount of MVPA or all PA at baseline (i.e., one SD above the mean) do not decrease as fast with regard to BMI (MVPA: estimate = -0.006; all PA: estimate = -0.016), and higher levels of MVPA or all PA at baseline (i.e., two SD above the mean) were even associated with an increase in BMI (MVPA: estimate = 0.035; all PA: estimate = 0.015). Finally, MVPA but not all PA is beneficial at slowing BMI decline with increasing age., Conclusion: PA, particularly at moderate-vigorous intensity, is associated with slower decline in longitudinal BMI trajectories. This implies that engaging in PA may be beneficial for healthy body weight regulation in middle and late adulthood., (© 2023. The Author(s).)

Objective: To examine interactions between Neuropsychiatric symptoms (NPS) with Pittsburgh Compound B (PiB) and fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting cognitive trajectories., Methods: We conducted a longitudinal study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, MN, involving 1581 cognitively unimpaired (CU) persons aged ≥50 years (median age 71.83 years, 54.0% males, 27.5% APOE ɛ4 carriers). NPS at baseline were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Brain glucose hypometabolism was defined as a SUVR ≤ 1.47 (measured by FDG-PET) in regions typically affected in Alzheimer's disease. Abnormal cortical amyloid deposition was measured using PiB-PET (SUVR ≥ 1.48). Neuropsychological testing was done approximately every 15 months, and we calculated global and domain-specific (memory, language, attention, and visuospatial skills) cognitive z-scores. We ran linear mixed-effect models to examine the associations and interactions between NPS at baseline and z-scored PiB- and FDG-PET SUVRs in predicting cognitive z-scores adjusted for age, sex, education, and previous cognitive testing., Results: Individuals at the average PiB and without NPS at baseline declined over time on cognitive z-scores. Those with increased PiB at baseline declined faster (two-way interaction), and those with increased PiB and NPS declined even faster (three-way interaction). We observed interactions between time, increased PiB and anxiety or irritability indicating accelerated decline on global z-scores, and between time, increased PiB and several NPS (e.g., agitation) showing faster domain-specific decline, especially on the attention domain., Conclusions: NPS and increased brain amyloid deposition synergistically interact in accelerating global and domain-specific cognitive decline among CU persons at baseline., (© 2023 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

Background: Multiple algorithms with variable performance have been developed to identify dementia using combinations of billing codes and medication data that are widely available from electronic health records (EHR). If the characteristics of misclassified patients are clearly identified, modifying existing algorithms to improve performance may be possible., Objective: To examine the performance of a code-based algorithm to identify dementia cases in the population-based Mayo Clinic Study of Aging (MCSA) where dementia diagnosis (i.e., reference standard) is actively assessed through routine follow-up and describe the characteristics of persons incorrectly categorized., Methods: There were 5,316 participants (age at baseline (mean (SD)): 73.3 (9.68) years; 50.7% male) without dementia at baseline and available EHR data. ICD-9/10 codes and prescription medications for dementia were extracted between baseline and one year after an MCSA dementia diagnosis or last follow-up. Fisher's exact or Kruskal-Wallis tests were used to compare characteristics between groups., Results: Algorithm sensitivity and specificity were 0.70 (95% CI: 0.67, 0.74) and 0.95 (95% CI: 0.95, 0.96). False positives (i.e., participants falsely diagnosed with dementia by the algorithm) were older, with higher Charlson comorbidity index, more likely to have mild cognitive impairment (MCI), and longer follow-up (versus true negatives). False negatives (versus true positives) were older, more likely to have MCI, or have more functional limitations., Conclusions: We observed a moderate-high performance of the code-based diagnosis method against the population-based MCSA reference standard dementia diagnosis. Older participants and those with MCI at baseline were more likely to be misclassified.

Background: Hearing loss has been identified as a potential major modifiable risk factor for developing dementia. This study examined associations between formal behavioural pure-tone and speech audiometry assessed by an audiologist with development of dementia in the Mayo Clinic Study of Aging (MCSA)., Methods: The MCSA is a prospective population-based study examining the incidence, prevalence, and risk factors of mild cognitive impairment and dementia in Olmsted County, Minnesota, USA. Participants undergo clinical examinations with neuropsychological testing at enrolment and every 15 months. Participants were 50 years or older at enrolment between Nov 29, 2004, and Dec 23, 2019, who underwent formal behavioural audiometric evaluation by an audiologist due to concerns about hearing loss or as a part of annual comprehensive health assessments. Associations of pure-tone average (PTA) and word recognition scores (WRS) with the development of dementia were evaluated using Cox proportional hazards regression with age as the timescale, and associations with changes in cognitive testing scores over time were evaluated using linear mixed-effects models., Findings: Among 1200 eligible participants, the mean age at enrolment was 79 years (SD 9), 593 (49%) were men, and 207 developed dementia during a mean of 7·0 years (SD 3·7) of follow-up. After adjusting for sex, years of education, smoking status, diabetes, hypertension, apolipoprotein E ε4 carriership, and hearing rehabilitation (defined as hearing aid or cochlear implant use), neither PTA (hazard ratio [HR] per 10-decibels hearing level increase of 0·99 (95% CI 0·89-1·12; p=0·91) nor WRS (HR per 10% decrease of 0·98, 95% CI 0·89-1 ·07; p=0·65) was significantly associated with the development of dementia. However, both PTA and WRS were significantly associated with poorer performance in cognitive testing over time: participants with a PTA higher than 25 decibels hearing level or a WRS lower than 100% had significantly worse declines in cognitive testing scores. Informant-based hearing difficulties assessed by the participant's study partner were significantly associated with the development of dementia (HR 1·95, 95% CI 1·45-2·62; p<0·0001)., Interpretation: In this prospective population-based study, subjective informant-based hearing difficulties were associated with development of dementia, whereas objective measures on formal behavioural audiometry were predictive of poorer performance on cognitive testing over time but not the development of dementia. Other factors related to central processing might potentiate the effects of peripheral hearing loss detected on behavioural audiometric testing., Funding: National Institute of Health, the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic, the GHR Foundation, the Mayo Foundation for Medical Education and Research, the Liston Award, the Schuler Foundation, the Rochester Epidemiology Project medical records linkage system, and the National Institute on Aging., Competing Interests: Declaration of interests RCP has been a consultant for Roche, Biogen, Merck, Eisai, Genentech, and Nestle; receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate; and receives research support from the US National Institutes of Health. NSR is on the advisory board of Neosensory and receives funding from the National Institute of Health and the National Institute on Aging. MV has received research funding from F. Hoffmann-La Roche and Biogen in the past, consults for F. Hoffmann-La Roche, receives research funding from the National Institutes of Health, and has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, AbbVie, and Amgen. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We investigated the longitudinal relationship between cortical amyloid deposition, anxiety, and depression and the risk of incident mild cognitive impairment (MCI)., Methods: We followed 1440 community-dwelling, cognitively unimpaired individuals aged ≥ 50 years for a median of 5.5 years. Clinical anxiety and depression were assessed using Beck Anxiety and Depression Inventories (BAI, BDI-II). Cortical amyloid beta (Aβ) was measured by Pittsburgh compound B positron emission tomography (PiB-PET) and elevated deposition (PiB+) was defined as standardized uptake value ratio ≥ 1.48. We calculated Cox proportional hazards models with age as the time scale, adjusted for sex, education, and medical comorbidity., Results: Cortical Aβ deposition (PiB+) independent of anxiety (BAI ≥ 10) or depression (BDI-II ≥ 13) increased the risk of MCI. There was a significant additive interaction between PiB+ and anxiety (joint effect hazard ratio 6.77; 95% confidence interval 3.58-12.79; P = .031) that is, being PiB+ and having anxiety further amplified the risk of MCI., Discussion: Anxiety modified the association between PiB+ and incident MCI., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The secondary use of electronic health records (EHRs) faces challenges in the form of varying data quality-related issues. To address that, we retrospectively assessed the quality of functional status documentation in EHRs of persons participating in Mayo Clinic Study of Aging (MCSA). We used a convergent parallel design to collect quantitative and qualitative data and independently analyzed the findings. We discovered a heterogeneous documentation process, where the care practice teams, institutions, and EHR systems all play an important role in how text data is documented and organized. Four prevalent instrument-assisted documentation (iDoc) expressions were identified based on three distinct instruments: Epic smart form, questionnaire, and occupational therapy and physical therapy templates. We found strong differences in the usage, information quality (intrinsic and contextual), and naturality of language among different type of iDoc expressions. These variations can be caused by different source instruments, information providers, practice settings, care events and institutions. In addition, iDoc expressions are context specific and thus shall not be viewed and processed uniformly. We recommend conducting data quality assessment of unstructured EHR text prior to using the information., Competing Interests: Maria Vassilaki has received research funding from F. Hoffmann-La Roche Ltd and Biogen in the past and consults for F. Hoffmann-La Roche Ltd; she receives research funding from NIH and has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, AbbVie and Amgen. RCP is a consultant for Roche, Inc., Biogen, Inc., Merck, Inc., Eisai, Inc., Genentech, Inc. and Nestle, Inc.; receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003), UpToDate and receives research support from the National Institute of Health., (© 2022 Fu, Vassilaki, Ibrahim, Petersen, Pagali, St Sauver, Moon, Wang, Fan, Liu and Sohn.)

Area deprivation index (ADI), a tool used to capture the multidimensional neighborhood socioeconomic disadvantage across populations, is highly relevant to the field of aging and Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). ADI is specifically relevant in the context of resilience, a broad term used to explain why some older adults have better cognitive outcomes than others. The goal of this mini-review is three-fold: (1) to summarize the current literature on ADI and its link to cognitive impairment outcomes; (2) suggest possible mechanisms through which ADI may have an impact on AD/ADRD outcomes, and (3) discuss important considerations when studying relations between ADI and cognitive as well as brain health. Though difficult to separate both the upstream factors that emerge from high (worse) ADI and all the mechanisms at play, ADI is an attractive proxy of resilience that captures multifactorial contributors to the risk of dementia. In addition, a life-course approach to studying ADI may allow us to capture resilience, which is a process developed over the lifespan. It might be easier to build, preserve or improve resilience in an environment that facilitates instead of hindering physical, social, and cognitively beneficial activities. Neighborhood disadvantage can adversely impact cognitive impairment risk but be at the same time a modifiable risk factor, amenable to policy changes that can affect communities., Competing Interests: MV received research funding from F. Hoffmann-La Roche Ltd and Biogen in the past and consults for F. Hoffmann-La Roche Ltd; she currently receives research funding from NIH/NIA and has equity ownership in Abbott Laboratories, Johnson and Johnson, Medtronic, AbbVie, and Amgen. RP was a consultant for Roche, Inc., Biogen, Inc., Merck, Inc., Eisai, Inc., Genentech, Inc. and Nestle, Inc.; receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003), UpToDate and receives research support from the National Institute of Health. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the authors, PV., (Copyright © 2022 Vassilaki, Petersen and Vemuri.)

Dementia is one of the most prevalent health problems in the aging population. Despite the significant number of people affected, dementia diagnoses are often significantly delayed, missing opportunities to maximize life quality. Early identification of older adults at high risk for dementia may help to maximize current quality of life and to improve planning for future health needs in dementia patients. However, most existing risk prediction models predominantly use static variables, not considering temporal patterns of health status. This study used an attention-based time-aware model to predict incident dementia that incorporated longitudinal temporal health conditions. The predictive performance of the time-aware model was compared with three traditional models using static variables and demonstrated higher predictive power.

Dementia is one of the major health challenges in aging populations, with 50 million people diagnosed worldwide. However, dementia is often underdiagnosed or delayed resulting in missed opportunities for appropriate care plans. Identifying early signs of dementia is essential for better life quality of aging populations. Monitoring early signs of individual health changes could help clinicians diagnose dementia in its early stages with more effective treatment plans. However, rare data for dementia cases compared to the normal (i.e., imbalance class distribution) make it challenging to develop robust supervised learning models. In order to alleviate this issue, we investigated one-class classification (OCC) techniques, which use only majority class (i.e., normal cases) in model development to detect dementia signals from older adult clinical visits. The OCC models identify abnormality of older adults' longitudinal health conditions to predict incident dementia. The predictive performance of the OCC was compared with a recent streaming clustering-based technique and demonstrated higher predictive power. Our analysis showed that OCC has a promising potential to increase power in predicting dementia.

Background and Objectives: To identify clinicopathologic factors contributing to mild cognitive impairment (MCI) reversion to normal cognition., Methods: We analyzed 3 longitudinal cohorts in this study: the Mayo Clinic Study of Aging (MCSA), the Religious Orders Study and Memory and Aging Project (ROSMAP), and the National Alzheimer's Coordinating Center (NACC). Demographic characteristics and clinical outcomes were compared between patients with MCI with or without an experience of reversion to normal cognition (referred to as reverters and nonreverters, respectively). We also compared longitudinal changes in cortical thickness, glucose metabolism, and amyloid and tau load in a subcohort of reverters and nonreverters in MCSA with MRI or PET imaging information from multiple visits., Results: We identified 164 (56.4%) individuals in MCSA, 508 (66.8%) individuals in ROSMAP, and 280 (34.1%) individuals in NACC who experienced MCI reversion to normal cognition. Cox proportional hazards regression models showed that MCI reverters had an increased chance of being cognitively normal at the last visit in MCSA (HR 3.31, 95% CI 2.14-5.12), ROSMAP (HR 3.72, 95% CI 2.50-5.56), and NACC (HR 9.29, 95% CI 6.45-13.40) and a reduced risk of progression to dementia (HR 0.12, 95% CI 0.05-0.29 in MCSA; HR 0.41, 95% CI 0.32-0.53 in ROSMAP; and HR 0.29, 95% CI 0.21-0.40 in NACC). Compared with MCI nonreverters, reverters had better-preserved cortical thickness (β = 0.082, p <0.001) and glucose metabolism (β = 0.119, p = 0.001) and lower levels of amyloid, albeit statistically nonsignificant (β = -0.172 , p = 0.090). However, no difference in tau load was found between reverters and nonreverters (β = 0.073, p = 0.24)., Discussion: MCI reversion to normal cognition is likely attributed to better-preserved cortical structure and glucose metabolism., (© 2022 American Academy of Neurology.)

Background and Objectives: To investigate the association of the Financial Capacity Instrument-Short Form (FCI-SF) performance and timing total scores with brain β-amyloid and cortical thickness in cognitively unimpaired (CU) (at baseline) older adults., Methods: A total of 309 participants (aged 70 years or older) of the Mayo Clinic Study of Aging underwent 11 C-Pittsburgh compound B PET amyloid imaging and MRI, and completed the FCI-SF. Abnormal amyloid PET was defined as standardized uptake value ratio ≥1.48 in an Alzheimer disease (AD)-related region of interest and reduced AD signature cortical thickness as ≤2.68 mm (neurodegeneration). A cohort of 218 (of the 309) participants had follow-up visits (every 15 months) with FCI-SF data for longitudinal analysis (number of visits including baseline, median [range]: 2 [2-4]). In the analysis, we used linear regression and mixed-effects models adjusted for age, sex, education, apolipoprotein E ε4 allele status, global cognitive z score, and previous FCI-SF testing., Results: Participants' mean age (SD) was 80.2 (4.8) years (56.3% male individuals). In cross-sectional analysis, abnormal amyloid PET (vs normal) was associated with a lower FCI-SF total score and slower total composite time. In longitudinal analysis, FCI-SF total score declined faster (difference in annualized rate of change, beta coefficient [β] [95% confidence interval (CI)] = -1.123 [-2.086 to -0.161]) and FCI-SF total composite time increased faster (difference in annualized rate of change, β [95% CI] = 16.274 [5.951 to 26.597]) for participants with neurodegeneration at baseline (vs those without). Participants who exhibited both abnormal amyloid PET and neurodegeneration at baseline had a greater increase in total composite time when compared with the group without abnormal amyloid and without neurodegeneration (difference in annualized rate of change, β [95% CI] = 16.750 [3.193 to 30.307])., Discussion: Performance and processing speed on the FCI-SF were associated with imaging biomarkers of AD pathophysiology in CU (at baseline) older adults. Higher burdens of imaging biomarkers were associated with longitudinal worsening on FCI-SF performance. Additional research is needed to delineate further these associations and their predictive utility at the individual person level., (© 2022 American Academy of Neurology.)

Background: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population., Objective: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer's disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA)., Methods: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years)., Results: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02)., Conclusion: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.

more than 44 million people have been diagnosed with dementia worldwide, and this number is estimated to triple by next three decades. Given this increasing trend of older adults with cognitive impairment (CI; dementia and mild cognitive impairment) and its significant underdiagnosis, early identification of CI and understanding its progression is a critical step towards a better quality of life for the aging population. Early alert of individual health changes could facilitate better ways for clinicians to diagnose CI in its early stages and come up with more effective treatment plans. However, there is a lack of approaches to characterize patient health conditions accounting for temporal information in an unsupervised manner. Limited CI cases and its costly ascertainment in clinical settings also make unsupervised learning more promising in CI research. In this paper, a streaming clustering model was used to determine distinct patterns of older adults' health changes from their clinical visits in Mayo Clinic Study of Aging. The streaming clustering was also examined to study its ability to generate early alerts for potential incidents of CI. Our analysis demonstrated that temporal characteristics incorporated in a streaming clustering model has a promising potential to increase power in predicting CI.

Objective: The authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction., Methods: About 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status., Results: Participants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ 2  = 11.83, degree of freedom [df] = 1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ 2  = 29.68, df = 1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ 2  = 34.13, df = 1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ 2  = 21.92, df = 1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ 2  = 15.39, df = 1)., Conclusion: Combined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

About 44.4 million people have been diagnosed with dementia worldwide, and it is estimated that this number will be almost tripled by 2050. Predicting mild cognitive impairment (MCI), an intermediate state between normal cognition and dementia and an important risk factor for the development of dementia is crucial in aging populations. MCI is formally determined by health professionals through a comprehensive cognitive evaluation, together with a clinical examination, medical history and often the input of an informant (an individual that know the patient very well). However, this is not routinely performed in primary care visits, and could result in a significant delay in diagnosis. In this study, we used deep learning and machine learning techniques to predict the progression from cognitively unimpaired to MCI and also to analyze the potential for patient clustering using routinely-collected electronic health records (EHRs). Our analysis of EHRs indicates that temporal characteristics of patient data incorporated in a deep learning model provides increased power in predicting MCI.

Objective: To investigate whether timing, number, and frequency of mentally stimulating activities in midlife and late life are associated with the risk of incident mild cognitive impairment (MCI)., Methods: We conducted a prospective cohort study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, including 2,000 individuals aged ≥70 years who were cognitively unimpaired at baseline and were followed for a median of 5.0 years. Participants completed a self-reported survey on timing, number, and frequency of engagement in 5 mentally stimulating activities (reading books, computer use, social activities, playing games, craft activities) at baseline., Results: The risk of incident MCI was significantly reduced for participants who engaged in social activities (hazard ratio [95% confidence interval] 0.80 [0.64-0.99]) and playing games (0.80 [0.66-0.98]) in both late life and midlife combined. Using a computer was associated with a decreased risk regardless of timing (not late life but midlife: 0.52 [0.31-0.88]; late life but not midlife: 0.70 [0.56-0.88]; late life and midlife: 0.63 [0.51-0.79]). Craft activities were associated with a reduced risk of incident MCI only when carried out in late life but not midlife (0.58 [0.34-0.97]). Furthermore, engaging in a higher number of activities in late life was associated with a significantly reduced risk of incident MCI (any 2 activities: 0.72 [0.53-0.99], any 3: 0.55 [0.40-0.77], any 4: 0.44 [0.30-0.65], all 5: 0.57 [0.34-0.96])., Conclusion: Engaging in a higher number of mentally stimulating activities, particularly in late life, is associated with a decreased risk of MCI among community-dwelling older persons., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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., Competing Interests: Conflict of interestThe authors declare no conflict of interest related to this manuscript., (© The Author(s) 2019.)

Background: Evidence for an infectious origin of obesity is emerging. We explored whether common viruses were associated with obesity and metabolic traits., Methods: We used cross-sectional (n = 674) and prospective (n = 440) data from children participating at the 4 and 6 years of age follow-up in the Rhea birth cohort. Presence of IgG antibodies to ten polyomaviruses (BKPyV, JCPyV, KIPyV, WUPyV, HPyV6, HPyV7, TSPyV, MCPyV, HPyV9, and HPyV10) and four herpesviruses (EBV, CMV, HSV-1, and HSV-2) were measured at age 4. Body mass index, waist circumference, and skinfold thickness were measured at age 4 and 6. Data on serum lipids, leptin, and adiponectin were also available. Multivariable linear regression models were used to explore the associations., Results: At 4 years of age, seroprevalence to polyomaviruses ranged from 21.0% for HPyV9 to 82.0% for HPyV10. Seroprevalence for EBV, CMV, HSV-1, and HSV-2 was 53.0%, 26.0%, 3.6%, and 1.5% respectively. BKPyV seropositivity was associated with lower BMI SD score at age 4 [-0.21 (95% CI: -0.39, -0.03)] and 6 [-0.27 (95% CI:-0.48, -0.05)], waist circumference at age 4 [-1.12 cm (95% CI: -2.10, -0.15)] and 6 [-1.73 cm (95% CI: -3.33, -0.12)], sum of four skinfolds [-2.97 mm (95% CI: -5.70, -0.24)], and leptin levels at age 4 [ratio of geometric means, 0.83 (95% CI: 0.70, 0.98)]. CMV seropositivity was associated with higher BMI SD score at age 4 [0.28 (95% CI: 0.11, 0.45)] and 6 [0.24 (95% CI: 0.03, 0.45)] and sum of four skinfolds at age 6 [4.75 mm (95% CI: 0.67, 8.83)]. Having "2-3 herpesviruses infections" (versus "0 herpesvirus infections") was associated with higher BMI SD score [0.32, (95% CI: 0.12, 0.53)], waist circumference [1.22 cm (95% CI: 0.13, 2.31)], and sum of four skinfolds [3.26 mm (95% CI: 0.18, 6.35)] at age 4. Polyomaviruses burden was not associated with outcomes., Conclusions: A higher herpesviruses burden and CMV seropositivity were associated with obesity traits in childhood.

Background: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma., Objective: We sought to assess the hypothesis that these associations are explained by reduced airway patency., Methods: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma., Results: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma., Conclusions: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)