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Objective: To estimate the extent to which varus malalignment, a source of abnormal intra-articular stresses in the medial tibiofemoral compartment and risk factor for progression of knee osteoarthritis (OA), may have diminished the structure-modifying benefit of doxycycline in knee OA.Methods: Post hoc treatment group comparisons from a randomized, placebo-controlled trial of the effect of doxycycline (100mg, twice daily) on medial joint space narrowing (JSN) in subgroups of varus and non-varus OA knees. Subjects (N=379 with X-ray follow-up) were obese 45-64-year-old women with unilateral knee OA at baseline. JSN was measured manually in semiflexed anteroposterior (AP) radiographs acquired with standardized fluoroscopic positioning. The anatomic-axis angle (AAA) was measured in each baseline radiograph and transformed to an estimate of the mechanical-axis angle (MAA(est)) using a validated regression equation. Knees with MAA(est)<178 degrees were classified as varus.Results: In our original comparison with placebo, doxycycline slowed the rate of medial JSN in OA knees by 38% at 16 months and by 33% at 30 months. Among non-varus OA knees, 16-month JSN in the doxycycline group was 44% slower than in the placebo group (0.09 vs 0.16 mm/year, P=0.080), and 39% slower at month 30 (0.10 vs 0.17 mm/year, P=0.026). JSN in varus knees (0.20-0.27 mm/year) was more rapid than in non-varus knees (P=0.083) and unaffected by doxycycline.Conclusion: Varus malalignment negated the slowing of structural progression of medial-compartment OA by doxycycline. To our knowledge, this is the first report documenting that static varus angulation can negate a pharmacologic structure-modifying effect. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the reliability and validity of the Perceptions About Medications for Diabetes (PAM-D) instrument.Methods: The item pool was generated from a literature review and 18 focus groups of Type 2 diabetes patients. Surveys were mailed to 1,000 low-income diabetes patients; 362 were returned; 65 of 100 re-test surveys were returned.Results: This paper uses data from 343 Type 2 respondents. Mean age and age diagnosed were 59 and 48, respectively; 72% female; 52% African American; 51% were taking oral antihyperglycemic agents [OHA] monotherapy, 18% insulin monotherapy, and 28% insulin plus OHA. The initial 66 items were reduced to 37 across nine scales: scheduling flexibility, portability convenience, regimen inconvenience, medication effectiveness, difficulty remembering medications, gastrointestinal, hypoglycemia-related, and weight/edema physical side effects, and emotional side effects. Scale reliabilities ranged from 0.71 to 0.92 (coefficient alpha) and from 0.54 to 0.83 (test-retest coefficient, 37-81-day interval); factor loadings ranged from 0.35 to 0.86 (median, 0.67); significant scale differences across medication groups (insulin, OHA, insulin plus OHA) were consistent with a priori hypotheses.Conclusions: The PAM-D has substantial reliability and validity in a low-income, inner-city population of Type 2 diabetes patients and may be valuable for understanding multidimensional perceptions driving patients' treatment preferences. [ABSTRACT FROM AUTHOR]

Background: This is a community-based longitudinal epidemiological comparative study of elderly African Americans in Indianapolis and elderly Yoruba in Ibadan, Nigeria.Method: A two-stage study was designed in which community-based individuals were first screened using the Community Screening Interview for Dementia. The second stage was a full clinical assessment, which included use of the Geriatric Depression Scale, of a smaller sub-sample of individuals selected on the basis of their performance in the screening interview. Prevalence of depression was estimated using sampling weights according to the sampling stratification scheme for clinical assessment.Results: Some 2627 individuals were evaluated at the first stage in Indianapolis and 2806 in Ibadan. All were aged 69 years and over. Of these, 451 (17.2%) underwent clinical assessment in Indianapolis, while 605 (21.6%) were assessed in Ibadan. The prevalence estimates of both mild and severe depression were similar for the two sites (p=0.1273 and p=0.7093): 12.3% (mild depression) and 2.2% (severe depression) in Indianapolis and 19.8% and 1.6% respectively in Ibadan. Some differences were identified in association with demographic characteristics; for example, Ibadan men had a significantly higher prevalence of mild depression than Indianapolis men (p<0.0001). Poor cognitive performance was associated with significantly higher rates of depression in Yoruba (p=0.0039).Conclusion: Prevalence of depression was similar for elderly African Americans and Yoruba despite considerable socioeconomic and cultural differences between these populations. [ABSTRACT FROM AUTHOR]

Background: Assessing function is a crucial element in the diagnosis of dementia. This information is usually obtained from key informants. However, reliable informants are not always available.Methods: A 10-item semi-structured home interview (the CHIF, or Clinician Home-based Interview to assess Function) to assess function primarily by measuring instrumental activities of daily living directly was developed and tested for inter-rater reliability and validity as part of the Indianapolis-Ibadan dementia project. The primary validity measurements were correlations between scores on the CHIF and independently gathered scores on the Blessed Dementia Scale (from informants) and the Mini-mental State Examination (MMSE). Sensitivities and specificities of scores on the CHIF and receiver operator characteristic (ROC) curves were constructed with dementia as the dependent variable.Results: Inter-rater reliability for the CHIF was high (Pearson's correlation coefficient 0.99 in Indianapolis and 0.87 in Ibadan). Internal consistency, in both samples, was good (Cronbach's alpha 0.95 in Indianapolis and 0.83 in Ibadan). Scores on the CHIF correlated well with the Blessed Dementia scores at both sites (-0.71, p < 0.0001 for Indianapolis and -0.56, p < 0.0001 for Ibadan) and with the MMSE (0.75, p < 0.0001 for Indianapolis and 0.44, p < 0.0001 for Ibadan). For all items at both sites, the subjects without dementia performed significantly better than those with dementia. The area under the ROC curve for dementia diagnosis was 0.965 for Indianapolis and 0.925 for Ibadan.Conclusion: The CHIF is a useful instrument to assess function directly in elderly participants in international studies, particularly in the absence of reliable informants. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee. [ABSTRACT FROM AUTHOR]

Background: The Neuropsychiatric Inventory (NPI) has been used to assess behavioral symptoms of dementia in the United States, Taiwan, Japan, and Italy.Method: This report evaluates the use of the NPI to assess behavioral symptoms of dementia in a population of Yoruba, Nigerians aged 65 years and older who are subjects in the Indianapolis-Ibadan Dementia Project. In this study, the NPI, Blessed Dementia Scale, and Mini-Mental State Examination (MMSE) were used to assess Nigerian subjects with dementia. For this study the NPI was translated, back translated, and harmonized into Yoruba.Results: The harmonized version of the NPI showed good interrater and test-retest reliability. The Cronbach alpha on 40 subjects was .80 for total severity score, .73 for frequency, and .73 for distress, indicating good internal consistency. The MMSE correlated with the NPI total score and severity scores of delusion, hallucination, and agitation, whereas the Blessed correlated with the NPI total score and severity scores of depression, anxiety, and nighttime behavior.Conclusions: The NPI was found to be a reliable tool to assess behavioral symptoms and caregiver distress of dementia in the Yoruba. Behavioral disturbances were as common in the Yoruba patients with dementia as in studies in other countries that have used the NPI, but the pattern of behavioral disturbances and caregiver response varied among the countries. [ABSTRACT FROM AUTHOR]

BACKGROUND: It has not been demonstrated that the implementation of computerized quality improvement strategies can improve client-centered outcomes in public community based, long-term care (CBLTC) programs. OBJECTIVES: To test and evaluate 2 innovative computer-assisted, client-centered quality improvement strategies for public community-based, long-term care. The first strategy, the Normative Treatment Planning (NTP) program, assesses needs, prescribes services, and evaluates outcomes. The second strategy, the Client Feedback System (CFS) program, provides service vendors with feedback on client perceptions of services. RESEARCH DESIGN: A 2 x 2 factorial design with the 2 strategies using cluster randomization. SUBJECTS: A total of 2222 clients (86% of eligible program clients) enrolled in Indiana's state case management program and/or the Medicaid home and community-based services waiver program for the aged and disabled as of January 1, 1995. MEASURES: Outcomes of needs met and client satisfaction were measured through telephone surveys every 6 months for 2 years. RESULTS: A total of 1006 participants (45%) completed the 2-year evaluation study. For the group using only the NTP program, perception of needs met and client satisfaction were significantly better than the control group over the 2 years. During this period, the group using only the CFS program had significantly better client satisfaction than the control group. However, the effect sizes of the significant differences were small, and no statistically significant effects were found for the group using both programs. CONCLUSIONS: Client-centered quality improvement strategies can be implemented to enable public CBLTC programs to meet client needs better and increase client satisfaction. [ABSTRACT FROM AUTHOR]

The specialised structure of the centromere is critical for effective chromosome segregation, but its repetitive nature makes it vulnerable to rearrangements. Centromere fragility can drive tumorigenesis, but protective mechanisms preventing fragility are still not fully understood. The PBAF chromatin remodelling complex is frequently misregulated in cancer, but its role in cancer is incompletely characterized. Here, we identify PBAF as a protector of centromere and pericentromere structure with profound consequences for genome stability. A conserved feature of isogenic cell lines lacking PBRM1, a subunit of PBAF, is compromised centromere and pericentromere integrity. PBAF is present at these regions, and binding patterns of PBAF and H3K9 methylation change when PBRM1 is absent. PBRM1 loss creates a dependence on the spindle assembly checkpoint, which represents a therapeutic vulnerability. Importantly, we find that even in the absence of any perturbations, PBRM1 loss leads to centromere fragility, thus identifying a key player in centromere protection., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Older adults commonly experience chronic medical conditions and are at risk of cognitive impairment as a result of age, chronic comorbidity, and medications prescribed to manage multiple chronic conditions. Anticholinergic medications are common treatments for chronic conditions and have been repeatedly associated with poor cognitive outcomes, including delirium and dementia, in epidemiologic studies. However, no study has definitively evaluated the causal relationship between anticholinergics and cognition in a randomized controlled trial design. Utilizing our prior experience in deprescribing anticholinergic medications in various clinical environments, we designed an outpatient deprescribing intervention to prospectively test the potential causal relationship between anticholinergics and cognition in primary care older adults., Methods: This cluster randomized clinical trial will be conducted to evaluate the impact of an anticholinergic deprescribing intervention compared to usual care on outcomes of cognition and safety in primary care older adults. Participants will include those aged 65 years and over, receiving primary care in the greater Indianapolis area, using a strong anticholinergic within the last 2 weeks or with evidence of high-risk exposure in the past year. Those excluded will have a diagnosis of Alzheimer's disease or related dementia, or serious mental illness. The trial plans to enroll 344 participants who will be cluster-randomized at the level of primary care physician to avoid contamination. Participants will complete outcome assessments every 6 months up to 2 years by blinded outcome assessors. The primary outcome of the study is a composite measure of cognition that includes domains assessing executive cognitive function, language, and memory. Secondary outcomes include patient-reported measures of pain intensity, depression, anxiety, sleep disturbance, and health-related quality of life., Discussion: The R2D2 trial will be the largest and longest prospective randomized trial testing the impact of an anticholinergic-specific deprescribing intervention on cognition in primary care older adults. Results could influence deprescribing methodology and provide new insight on the relationship between anticholinergics and cognition., Trial Registration: ClinicalTrials.gov NCT04270474. Registered on February 17, 2020., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures have received and maintained ethical approval from the Institutional Review Board of the Indiana University (IRB# 1811254189; Federal-Wide Assurance Number, FWA00003544). The trial has also been registered at ClinicalTrials.gov (Identifier: NCT04270474). Consent for publication: Not applicable—no identifying images or other personal or clinical details of individual participants are presented here or will be presented in reports of the trial results. The participant information materials and informed consent form are available from the corresponding author on request. Competing interests: Dr. Boustani serves as a Chief Scientific Officer and co-Founder of Blue Agilis; the Chief Health Officer of DigiCare Realized, Inc; and the Chief Health Officer of Mozyne Health, Inc. He has equity interest in Blue Agilis, Inc; DigiCare Realized, Inc; and Mozyne Health, Inc. He sold his equity in Preferred Population Health Management LLC and MyShift, Inc (previously known as RestUp, LLC). He serves as an advisory board member or consultant for Eli Lilly and Co; Eisai, Inc; Merck & Co Inc; Biogen Inc; and Genentech Inc. These conflicts have been reviewed by Indiana University and has been appropriately managed to maintain objectivity. All other authors report no conflicts of interest., (© 2024. The Author(s).)

Objective: We assessed the concordance of patient-reported race and ethnicity for emergency department (ED) patients compared with what was recorded in the electronic health record., Methods: We conducted a single-center, prospective, observational study of 744 ED patients (English- and/or Spanish-speaking), asking them to describe their race and ethnicity. We compared the distributions of ethnicity and race between patient-reported and electronic health record data using McNemar's test. We calculated percent agreement and Cohen's kappa, with 95% confidence intervals (CI), for the concordance of patient-reported race and ethnicity with electronic health record data., Results: Of 744 ED patients, 731 participants who completed the survey reported their ethnicity, resulting in 98.2% of electronic health records obtained ethnicities matched self-reported data (kappa = 0.95; 95% CI: 0.92 to 0.98). For those who self-reported as Hispanic, only 92.3% agreement was observed between the self-reported and electronic health record values. For all patients who had race recorded, 85.4% agreement was observed (kappa = 0.75; 95% CI 0.71 to 0.79). High rates of agreement were observed for Black or African American patients (98.7%) and White patients (96.6%), with low rates for those who identified as "More than one race" (22.9%) or "Other" race (1.8%). In the subset of Hispanic patients, low rates of agreement (25.0%) were observed for race (kappa = 0.10; 95% CI 0.01 to 0.19)., Conclusions: Documentation discordance regarding race and ethnicity exists between electronic health records and self-reported data for our ED patients, particularly for ethnically Hispanic and Latino/a patients. Future efforts should focus on ensuring that demographic information in the electronic health record is accurately collected., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: We examined the burden of neuropsychiatric symptoms (NPSs) in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD) and adjusted for age effects via the inclusion of cognitively unimpaired (CU) individuals., Methods: Cross-sectional data from 2940 EOAD, 8665 LOAD, and 8775 age-stratified CU individuals (early-CU, n = 2433; late-CU, n = 6342) from the National Alzheimer's Coordinating Center database were included. Fisher's exact tests compared EOAD and LOAD on the presence and severity of NPSs. Multiple logistic regression models included an age*diagnosis interaction to examine age effects., Results: Presence (ps < 0.0001) and severity (ps < 0.05) of NPS were greater in EOAD than in LOAD. However, after adjusting for base rates in NPS in CU individuals (age effects), only elation and eating behaviors were more frequent in EOAD (ps < 0.05) and nighttime behaviors more frequent and severe in LOAD (ps < 0.05)., Discussion: Few NPSs were specific to the EOAD versus LOAD. Previous findings of greater NPS burden in EOAD may partially reflect age effects., Highlights: Adjusting for age effect, elation and eating problems are more frequent in EOAD. Adjusting for age effect, sleep disturbances are more frequent and severe in LOAD. Age effects underlie higher neuropsychiatric symptom presentation in EOAD than in LOAD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: More than 80% of patients who present to the emergency department (ED) with acute heart failure (AHF) are hospitalized. With more than 1 million annual hospitalizations for AHF in the US, safe and effective alternatives are needed. Care for AHF in short-stay units (SSUs) may be safe and more efficient than hospitalization, especially for lower-risk patients, but randomized clinical trial data are lacking., Objective: To compare the effectiveness of SSU care vs hospitalization in lower-risk patients with AHF., Design, Setting, and Participants: This multicenter randomized clinical trial randomly assigned low-risk patients with AHF 1:1 to SSU or hospital admission from the ED. Patients received follow-up at 30 and 90 days post discharge. The study began December 6, 2017, and was completed on July 22, 2021. The data were analyzed between March 27, 2020, and November 11, 2023., Intervention: Randomized post-ED disposition to less than 24 hours of SSU care vs hospitalization., Main Outcomes and Measures: The study was designed to detect at least 1-day superiority for a primary outcome of days alive and out of hospital (DAOOH) at 30-day follow-up for 534 participants, with an allowance of 10% participant attrition. Due to the COVID-19 pandemic, enrollment was truncated at 194 participants. Before unmasking, the primary outcome was changed from DAOOH to an outcome with adequate statistical power: quality of life as measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). The KCCQ-12 scores range from 0 to 100, with higher scores indicating better quality of life., Results: Of the 193 patients enrolled (1 was found ineligible after randomization), the mean (SD) age was 64.8 (14.8) years, 79 (40.9%) were women, and 114 (59.1%) were men. Baseline characteristics were balanced between arms. The mean (SD) KCCQ-12 summary score between the SSU and hospitalization arms at 30 days was 51.3 (25.7) vs 45.8 (23.8) points, respectively (P = .19). Participants in the SSU arm had 1.6 more DAOOH at 30-day follow-up than those in the hospitalization arm (median [IQR], 26.9 [24.4-28.8] vs 25.4 [22.0-27.7] days; P = .02). Adverse events were uncommon and similar in both arms., Conclusions and Relevance: The findings show that the SSU strategy was no different than hospitalization with regard to KCCQ-12 score, superior for more DAOOH, and safe for lower-risk patients with AHF. These findings of lower health care utilization with the SSU strategy need to be definitively tested in an adequately powered study., Trial Registration: ClinicalTrials.gov Identifier: NCT03302910.

Background: Despite the need to increase engagement of underrepresented groups (URG) in Alzheimer's disease and related dementias (ADRD) studies, enrollment remains low., Objective: Compare referral sources across racial and ethnic groups among participants enrolled in ADRC studies., Methods: Data for this cross-sectional secondary analysis were extracted from the National Alzheimer's Coordinating Center Uniform Data Set. We performed mixed effects logistic regression models using generalized estimating equations for professional referral versus non-professional referral by racial and ethnic group, adjusted for age, gender, education, visit year, and Clinical Dementia Rating scale (CDR) with a random effect for study site., Results: Included in the analysis were 48,330 participants across 46 ADRCs (mean [SD] age, 71.3 [10.5] years; 20,767 female [57%]; 4,138 Hispanic [8.6%]; 1,392 non-Hispanic Asian [2.9%]; 6,766 non-Hispanic Black [14%] individuals; and 676 individuals [1.4%] of other races. Non-Hispanic Black and Asian participants had lower odds of being referred by a professional contact compared to non-Hispanic White participants (Black: adjusted OR = 0.61, 95% CI = 0.44-0.86, p = 0.005; Asian: adjusted OR = 0.65, 95% CI, p = 0.004). In participants who had completed an MRI, there was no significant difference in referral source across ethnic and racial groups., Conclusions: Further studies are needed to better understand the systemic and structural factors that contribute to differences in referral sources and disparities in recruitment of URG into ADRD studies.

Pediatric and neonatal critical care providers involved in transport run calls involving patients diagnosed with Tetralogy of Fallot, which can occasionally be a challenge for some providers. Making up around 10% of all congenital heart defects, inevitably makes Tetralogy of Fallot (TOF) the most common of all the cyanotic congenital heart diseases. There are some transport teams that do not have the capability and invasive equipment that a referring hospital may have to manage these high acuity low volume patients. This makes it imperative to have a good working knowledge of this condition, and more importantly, the ability to recognize it when encountered so that you will then be able treat these patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play., Methods: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes., Results: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (β = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (β = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|β|s > 0.12, SEs <0.09, p s FDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (βs > 0.14, SEs <0.06, p s FDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts., Discussion: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Treating pediatric patients with diabetic ketoacidosis (DKA) during transport can be complex and multifactorial. Cerebral edema is a frequent occurrence in pediatric patients with DKA; however, the signs often occur in a subtle manner. Overzealous correction of their blood glucose may result in cerebral edema as well as a cascade of electrolyte abnormalities. Pediatric patients with diabetes mellitus are prone to developing DKA. Serious complications from DKA in pediatrics often present acutely and rapidly., (Copyright © 2023 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD)., Method: A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately., Results: APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P < 0.0001)., Conclusion: The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)