Directed exploration is elevated in affective disorders but reduced by an aversive interoceptive state induction.

Elevated anxiety and uncertainty avoidance are known to exacerbate maladaptive choice in individuals with affective disorders. However, the differential roles of state vs. trait anxiety remain unclear, and underlying computational mechanisms have not been thoroughly characterized. In the present study, we investigated how a somatic (interoceptive) state anxiety induction influences learning and decision-making under uncertainty in individuals with clinically significant levels of trait anxiety. A sample of 58 healthy comparisons (HCs) and 61 individuals with affective disorders (iADs; i.e., depression and/or anxiety) completed a previously validated explore-exploit decision task, with and without an added breathing resistance manipulation designed to induce state anxiety. Computational modeling revealed a pattern in which iADs showed greater information-seeking (i.e., directed exploration; Cohen's d =.39, p =.039) in resting conditions, but that this was reduced by the anxiety induction. The affective disorders group also showed slower learning rates across conditions (Cohen's d =.52, p =.003), suggesting more persistent uncertainty. These findings highlight a complex interplay between trait anxiety and state anxiety. Specifically, while elevated trait anxiety is associated with persistent uncertainty, acute somatic anxiety can paradoxically curtail exploratory behaviors, potentially reinforcing maladaptive decision-making patterns in affective disorders.

Longer time horizons are associated with reduced risk of mortality and disability in older adults.

OBJECTIVES: Longer time horizons are associated with positive health behaviors, but the associations of time horizons with disability and mortality are less understood. This study aims to test the hypothesis that longer time horizons are associated with decreased disability and mortality in older adults. METHOD: Participants were 1052 older adults (mean age = 81 ± 7 years) without dementia. Proportional hazard models adjusted for age, sex, and education were used to examine the associations of time horizons with risk of mortality and disability. RESULTS: During up to 11 years of follow up (mean = 5.7), 317 participants died. In fully adjusted models, longer time horizons were associated with reduced mortality risk (hazard rate [HR] = 0.78, 95% confidence interval [CI] = 0.68-0.89). About 36.7% of participants developed disability in instrumental activities of daily living (ADLs) and 49.3% developed disability in basic ADLs during follow up. Longer time horizons were associated with a reduced risk of disability in basic ADLs (HR = 0.89, 95% CI = 0.79-0.99) but not instrumental ADLs (HR = 0.90, 95% CI = 0.80-1.03). CONCLUSION: Longer time horizons are associated with a reduced risk of all-cause mortality and disability in basic ADLs among community-dwelling older adults, thus highlighting a potentially modifiable psychological risk factor for negative health outcomes in aging.

In vivo human knee varus-valgus loading apparatus for analysis of MRI-based intratissue strain and relaxometry.

The diagnosis of early-stage osteoarthritis remains as an unmet challenge in medicine and a roadblock to evaluating the efficacy of disease-modifying treatments. Recent studies demonstrate that unique patterns of intratissue cartilage deformation under cyclic loading can serve as potential biomarkers to detect early disease pathogenesis. However, a workflow to obtain deformation, strain maps, and quantitative MRI metrics due to the loading of articular cartilage in vivo has not been fully developed. In this study, we characterize and demonstrate an apparatus that is capable of applying a varus-valgus load to the human knee in vivo within an MRI environment to enable the measurement of cartilage structure and mechanical function. The apparatus was first tested in a lab environment, then the functionality and utility of the apparatus were examined during varus loading in a clinical 3T MRI system for human imaging. We found that the device enables quantitative MRI metrics for biomechanics and relaxometry data acquisition during joint loading leading to compression of the medial knee compartment. Integration with spiral DENSE MRI during cyclic loading provided time-dependent displacement and strain maps within the tibiofemoral cartilage. The results from these procedures demonstrate that the performance of this loading apparatus meets the design criteria and enables a simple and practical workflow for future studies of clinical cohorts, and the identification and validation of imaging-based biomechanical biomarkers.

ADOPTERs of Innovation in a Crisis: The History of Vera Gedroits, Kanehiro Takaki and the Russo-Japanese War of 1904-1905.

The 1904-1905 Russo-Japanese War was the first "modern" conflict, using rapid-firing artillery and machine guns, fought over imperial ambitions in Korea and Manchuria. During the war, Princess Vera Gedroits pioneered early laparotomy for penetrating abdominal wounds with unprecedented success. Her techniques were then adopted by the Russian Society of Military Doctors. However, Allied forces took 10 years to adopt operative management of penetrating abdominal wounds over conservative management. Gedroits was later appointed in Kyiv as the world's first female Professor of Surgery. Kanehiro Takaki, a Japanese Naval surgeon, showed in 1884 a diet of barley, meat, milk, bread, and beans, rather than polished white rice, eliminated beriberi in the Japanese Navy. Despite this success, the Japanese Army failed to change the white rice rations until March 1905. During the 1904-1905 Russo-Japanese War, an estimated 250,000 Japanese soldiers developed beriberi, of whom 27,000 died. Japan's 1905 defeat of Russia sowed the seeds of discontent with Tsar Nicholas' rule, culminating in the 1917 Russian Revolution. Although the Russian Navy was destroyed, Japan ceded North Sakhalin Island to Russia in peace negotiations, and Russia seized Manchuria, South Sakhalin, and the Kuril Islands in 1945. We highlight the contributions of Gedroits and Takaki, 2 intellectual prodigies who respectively pioneered rapid triage and surgical management of trauma and a cure for beriberi. We aim to show how both these surgeons challenged entrenched dogma and the cultural and political zeitgeist, and risked their professional reputations and their lives in being ADOPTERs of innovation during a crisis.

Individuals with Methamphetamine Use Disorder Show Reduced Directed Exploration and Learning Rates Independent of an Aversive Interoceptive State Induction.

Methamphetamine Use Disorder (MUD) is associated with substantially reduced quality of life. Yet, decisions to use persist, due in part to avoidance of anticipated withdrawal states. However, the specific cognitive mechanisms underlying this decision process, and possible modulatory effects of aversive states, remain unclear. Here, 56 individuals with MUD and 58 healthy comparisons (HCs) performed a decision task, both with and without an aversive interoceptive state induction. Computational modeling measured the tendency to test beliefs about uncertain outcomes (directed exploration) and the ability to update beliefs in response to outcomes (learning rates). Compared to HCs, those with MUD exhibited less directed exploration and slower learning rates, but these differences were not affected by aversive state induction. These results suggest novel, state-independent computational mechanisms whereby individuals with MUD may have difficulties in testing beliefs about the tolerability of abstinence and in adjusting behavior in response to consequences of continued use.

Computational identification of disease models through cross-species phenotype comparison.

The use of standardised phenotyping screens to identify abnormal phenotypes in mouse knockouts, together with the use of ontologies to describe such phenotypic features, allows the implementation of an automated and unbiased pipeline to identify new models of disease by performing phenotype comparisons across species. Using data from the International Mouse Phenotyping Consortium (IMPC), approximately half of mouse mutants are able to mimic, at least partially, the human ortholog disease phenotypes as computed by the PhenoDigm algorithm. We found the number of phenotypic abnormalities in the mouse and the corresponding Mendelian disorder, the pleiotropy and severity of the disease, and the viability and zygosity status of the mouse knockout to be associated with the ability of mouse models to recapitulate the human disorder. An analysis of the IMPC impact on disease gene discovery through a publication-tracking system revealed that the resource has been implicated in at least 109 validated rare disease-gene associations over the last decade.

Differences in Academic Qualifications for Leadership at Hand Surgery Fellowships in the United States.

Objective: In the United States, orthopaedic, general, and plastic surgery hand fellowship programs train hand surgeons. Currently, differences in the academic qualifications of hand surgery fellowship directors (HSFDs) are unknown. This study compares the academic qualifications of HSFDs by specialty. Methods: American Medical Association's Residency and Fellowship Database was queried for hand surgery fellowship training programs. Scholarly activity, academic characteristics, and training pedigrees were collected for each HSFD. Results: Ninety-two HSFDs (73 orthopaedic surgeons, 17 plastic surgeons, 2 general surgeons) were identified. Most were male (87%) and Caucasian (82%). Mean age was 55 ± 11 years and most were trained in orthopaedic surgery (80%). Ten percent of orthopaedic hand surgery fellowship programs were run by a plastic surgeon HSFD, which was greater than 0% of plastic surgery hand fellowship programs run by an orthopaedic surgeon HSFD (p < 0.05). Mean H-index was 15 ± 9 from an average of 57 ± 47 publications. Orthopaedic and plastic surgeon HSFDs had similar levels of scholarly activity (p > 0.05). Age correlated with higher H-index values (r = 0.38, p < 0.001). More plastic surgeon HSFDs were trained by their top five fellowship programs than orthopaedic surgeon HSFDs (65 vs. 27%, p < 0.05). Conclusion: Ultimately, HSFDs have strong research backgrounds and similar characteristics despite disparate training pathways. Women and racial minority groups are largely underrepresented among leadership positions at hand surgery fellowships. These benchmarks can help inform future diversity initiatives.

Benchmarking Accomplishments of Presidents Elected to Hand Surgery Societies in the United States.

Objective: Qualifications needed to achieve national leadership positions in hand surgery are poorly defined. This study compares the academic accomplishments, demographics, and training backgrounds of presidents elected to serve the American Society for Surgery of the Hand (ASSH) and the American Association for Hand Surgery (AAHS). Methods: The ASSH and AAHS provided names of elected Presidents (1990-2022, n = 64). Curriculum vitae and academic web sites were used to collect demographic, training, bibliometric, and National Institutes of Health (NIH) funding data of presidents. Results: Presidents were predominately male (95%), Caucasian (90%), and orthopaedic surgery residency-trained (66%). Only 9% were racial minorities (8% Asian, 2% Hispanic, and 0% African American). The average age at appointment was 59 ± 7 years old, which was an average of 23 years from completion of hand surgery fellowship. More presidents received plastic surgery residency training in AAHS than ASSH (50 vs. 19%). The most represented hand surgery fellowships were Mayo Clinic (14%), University of Louisville (11%), and Duke University (9%). Twenty-one presidents participated in a travel fellowship (33%). Thirty presidents served as Department Chair or Division Chief at time of election (47%). The average h-index was 34 ± 18 resulting from 164 ± 160 peer-reviewed manuscripts and was similar between the two organizations. Eleven presidents had NIH grant funding (18%) and there were no differences in procurement or funding totals between the two organizations. Conclusion: Presidents of American hand surgery societies obtain high levels of scholarly activity regardless of training specialty. Women and racial minorities remain underrepresented at the highest levels of leadership.

Impact of Orthopedic Hand Surgery Fellowship Training on Hand Surgery Cases Performed by Plastic Surgeons in the United States.

Objective: Multiple pathways exist for hand surgery training in the United States. Plastic surgeons often select Orthopedic Hand Surgery Fellowships to complement their skills and bridge perceived deficiencies in bone and joint cases. This study aims to quantify the impact of this approach on operative hand experience. Materials and methods: Case logs were analyzed for plastic surgery residents and orthopaedic hand surgery fellows (2016-2017 to 2019-2020). Reported hand surgery cases were compared between residency and fellowship using Student's t-tests. In total, 606 plastic surgery residents and 393 orthopaedic hand surgery fellows were included in this study. One year of Orthopedic Hand Surgery Fellowship training afforded more than twice the volume of hand surgery cases than Plastic Surgery Residency training (886.1 ± 234.7 vs. 428.1 ± 147.2, p < 0.001). Results: Case categories with the greatest positive fold difference in case volume encountered during Orthopedic Surgery Hand Fellowship were tumor (138.2 ± 63.2 vs. 22.1 ± 11.8, p < 0.001), joint reconstruction (108.7 ± 21.6 vs. 18.8 ± 11.5, p < 0.001), nerve decompression (158.4 ± 63.1 vs. 53.0 ± 32.6, p < 0.001), Dupuytren's (18.4 ± 10.5 vs. 7.6 ± 6.4, p < 0.001), and fracture management (132.8 ± 21.7 vs. 59.6 ± 24.1, p < 0.001). Conclusion: Orthopedic Hand Surgery Fellowship training doubles the operative hand case volume encountered during Plastic Surgery Residency. Significant increases are especially encountered for select case categories including bone and joint cases.

The effects of supplemental instruction derived from peer leaders on student outcomes in undergraduate human anatomy.

Supplemental instruction (SI) confers student success, as represented by grades, knowledge retention, and student engagement. However, studies often report professional, not undergraduate, program findings. To measure these effects, students studying human anatomy at a university in Ontario, Canada, attended structured (peer-assisted) or unstructured (nonpeer-assisted) SI sessions and completed a pre-/post-survey. Fifty-eight learners (39 systems (SYS) and 19 musculoskeletal (MSK) anatomy) completed both surveys and had responses analyzed. Both cohorts, maintained initial perceptions across pre-/post-analyses (MSK p = 0.1376 and SYS p = 0.3521). Resource usage was similar across both cohorts with discrepancies in skeletal model and textbook use. No MSK learner ranked any lab resources as "not at all useful." MSK learners felt more prepared to write a graded assessment (p = 0.0269), whereas SYS learners did not (p = 0.0680). Stratification of learners in MSK and SYS revealed learners spending between 30 and 60 min in SI sessions during the study period had the highest grades compared to students who spent less than 30 (p = 0.0286) or more than 60 (p = 0.0286) min attending SI sessions, respectively. Most learners in MSK (89.4%) and SYS (66%) concluded that they preferred structured over unstructured SI. Sentiment/thematic analysis using a generative AI-driven large language model revealed learners held positive perceptions of SI, emphasizing structured learning, resources, personalized learning, and support offered as the most prevalent themes surrounding SI. Ultimately, this study provides evidence that supports SI for improving student outcomes related to perceived preparedness for completing assessments and preferred teaching/learning styles in undergraduate human anatomy.

Does the State Impact Hope? The Impact of Direct and Vicarious Police Contact on the Optimism of Youth in Large Cities.

A growing body of research has begun to examine the implications of police contact for youth. Largely emphasizing serious police contact (arrest, court involvement, and incarceration), this scholarship has generally found that police contact is associated with negative health and educational outcomes. In this study, we build on this work by examining the implications of direct and vicarious police contact for youth attitudes towards the future, both generally and with respect to graduating college. Using multivariate regression models that incorporated a wide range of control variables and data from the Fragile Families and Child Wellbeing Study, we found that youth who experienced police stops without an arrest were less optimistic in general and with respect to college graduation. We found the same for youth who experienced vicarious police contact, but for youth who experienced arrest we only found a significant reduction in optimism with respect to college graduation. Therefore, based on our findings and prior scholarship, we argue that social workers should push policymakers to move beyond the status quo and to make significant changes to how they go about promoting public safety.

Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. METHODS: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. RESULTS: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence. CONCLUSION: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.

Where east meets west: Phylogeography of the high Arctic North American brant goose.

Genetic variation in Arctic species is often influenced by vicariance during the Pleistocene, as ice sheets fragmented the landscape and displaced populations to low- and high-latitude refugia. The formation of secondary contact or suture zones during periods of ice sheet retraction has important consequences on genetic diversity by facilitating genetic connectivity between formerly isolated populations. Brant geese (Branta bernicla) are a maritime migratory waterfowl (Anseriformes) species that almost exclusively uses coastal habitats. Within North America, brant geese are characterized by two phenotypically distinct subspecies that utilize disjunct breeding and wintering areas in the northern Pacific and Atlantic. In the Western High Arctic of Canada, brant geese consist of individuals with an intermediate phenotype that are rarely observed nesting outside this region. We examined the genetic structure of brant geese populations from each subspecies and areas consisting of intermediate phenotypes using mitochondrial DNA (mtDNA) control region sequence data and microsatellite loci. We found a strong east-west partition in both marker types consistent with refugial populations. Within subspecies, structure was also observed at mtDNA while microsatellite data suggested the presence of only two distinct genetic clusters. The Western High Arctic (WHA) appears to be a secondary contact zone for both Atlantic and Pacific lineages as mtDNA and nuclear genotypes were assigned to both subspecies, and admixed individuals were observed in this region. The mtDNA sequence data outside WHA suggests no or very restricted intermixing between Atlantic and Pacific wintering populations which is consistent with published banding and telemetry data. Our study indicates that, although brant geese in the WHA are not a genetically distinct lineage, this region may act as a reservoir of genetic diversity and may be an area of high conservation value given the potential of low reproductive output in this species.

Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.

INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline. METHODS: This study consists of 1,118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time. RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition (ß = -0.064 (SE = 0.028), p-value = 0.023) and on episodic memory (ß = -0.097 (SE = 0.036), p-value = 0.007). CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce rate of cognitive decline in individuals with high concentrations of NfL.

Post-COVID postural orthostatic tachycardia syndrome (POTS): a new phenomenon.

Background: The impact of COVID-19 has been far-reaching, and the field of neurology is no exception. Due to the long-hauler effect, a variety of chronic health consequences have occurred for some post-COVID patients. A subset of these long-hauler patients experienced symptoms of autonomic dysfunction and tested positive for postural orthostatic tachycardia syndrome (POTS) via autonomic testing. Methods: We conducted a chart review of a convenience sample from patients seen by neurologists at our tertiary care center for suspicion of post-COVID POTS. Patients included in our study had clearly defined POTS based on clinical criteria and positive tilt table test, were 81.25% female, and had an average age of approximately 36. Out of 16 patients, 12 had a confirmed positive COVID test result, with the remaining 4 having strong clinical suspicion for COVID infection. Our analysis examined the most bothersome 3 symptoms affecting each patient per the neurologist's note at their initial visit for post-COVID POTS, clinical presentation, comorbidities, neurological exam findings, autonomic testing results, and COMPASS-31 autonomic questionnaire and PROMIS fatigue survey results. Results: Palpitations (68.75%) and fatigue (62.5%) were the most common of the impactful symptoms reported by patients in their initial Cleveland Clinic neurology visit. The most frequent comorbidities in our sample were chronic migraines (37.5%), irritable bowel syndrome (IBS) (18.75%), and Raynaud's (18.75%). Neurological exam findings and autonomic testing results other than tilt table yielded variable findings without clear trends. Survey results showed substantial autonomic symptom burden (COMPASS-31 autonomic questionnaire average score 44.45) and high levels of fatigue (PROMIS fatigue survey average score 64.64) in post-COVID POTS patients. Conclusion: Our sample of post-COVID POTS patients are similar to the diagnosed POTS general population including in comorbidities and autonomic testing. Fatigue was identified by patients as a common and debilitating symptom. We hope that our study will be an early step toward further investigation of post-COVID POTS with focus on the trends identified in this chart review.

Unique transcriptional signatures correlate with behavioral and psychological symptom domains in Alzheimer's disease.

Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.

The structure and development of explore-exploit decision making.

A critical component of human learning reflects the balance people must achieve between focusing on the utility of what they know versus openness to what they have yet to experience. How individuals decide whether to explore new options versus exploit known options has garnered growing interest in recent years. Yet, the component processes underlying decisions to explore and whether these processes change across development remain poorly understood. By contrasting a variety of tasks that measure exploration in slightly different ways, we found that decisions about whether to explore reflect (a) random exploration that is not explicitly goal-directed and (b) directed exploration to purposefully reduce uncertainty. While these components similarly characterized the decision-making of both youth and adults, younger participants made decisions that were less strategic, but more exploratory and flexible, than those of adults. These findings are discussed in terms of how people adapt to and learn from changing environments over time.Data has been made available in the Open Science Foundation platform (osf.io).

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

BACKGROUND AND OBJECTIVES: The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. METHODS: This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. RESULTS: The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (ß = 0.021, 95% CI 0.007-0.034) and episodic memory (ß = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. DISCUSSION: Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.