Volume 100, Number 4, IN PRESS

Review
Brady S. Reive, Victor Lau, Carla L. Sánchez-Lafuente, Alexandre Henri-Bhargava, Lisa E. Kalynchuk, Marie-Ève Tremblay, Hector J. Caruncho (Handling Associate Editor: Marta Balietti)
The Inflammation-Induced Dysregulation of Reelin Homeostasis Hypothesis of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation.

Review
Muluken A. Yenesew, Janina Krell-Roesch, Betelhem Fekadu, Dabere Nigatu, Aklilu Endalamaw, Alemtsehay Mekonnen, Mulugeta Biyadgie, Gizachew Y. Wubetu, Alemu T. Debiso, Kassu M. Beyene, Teshome S. Kelkile, Daniel A. Enquobahrie, Tesfaye B. Mersha, Danielle E. Eagan, Yonas E. Geda
Prevalence of Dementia and Cognitive Impairment in East Africa Region: A Scoping Review of Population-Based Studies and Call for Further Research
Abstract: Background: Population-based research on the prevalence and determinants of dementia, Alzheimer’s disease, and cognitive impairment is scarce in East Africa. Objective: To provide an overview of community- and population-based studies among older adults on the prevalence of dementia and cognitive impairment in East Africa, and identify research gaps. Methods: We carried out a literature search using three electronic databases (PubMed, Scopus, Google Scholar) using pertinent search terms. Results: After screening 445 publications, we identified four publications on the population-based prevalence of dementia, and three on cognitive impairment. Prevalence rates varied from 6-23% for dementia, and 6-43% for cognitive impairment, among participants aged ≥ 50-70 years. Old age and a lower education level were risk factors for dementia and cognitive impairment. Physical inactivity, lack of a ventilated kitchen, and history of central nervous system infections and chronic headache were associated with increased odds of dementia. Female sex, depression, having no spouse, increased lifetime alcohol consumption, low income, rural residence, and low family support were associated with increased odds of cognitive impairment. Potential misclassification and non-standardized data collection methods are research gaps that should be addressed in future studies. Conclusions: Establishing collaborative networks and partnering with international research institutions may enhance the capacity for conducting population-based studies on dementia and cognitive impairment in East Africa. Longitudinal studies may provide valuable insights on incidence, as well as potential risk and protective factors of dementia and cognitive impairment, and may inform the development of targeted interventions including preventive strategies in the region.

Systematic Review
Mariane Gomes Machado1, Thais Helena Machado1, Paulo Caramelli2, Jessica Abdo Gonçalves Tosatti3, Sirley Alves da Silva Carvalho1, Luciana Macedo de Resende (Handling Associate Editor: Maëlenn Guerchet)
Effects of Hearing Aid Use on Individuals Diagnosed with Hearing Loss and Dementia: A Systematic Review
Abstract: Background: The assumption that hearing rehabilitation could improve quality of life and reduce dementia risk in people with hearing loss is a subject that needs further studies, especially clinical trials. It is necessary to determine the effects of hearing aid use, as part of hearing rehabilitation, among people diagnosed with dementia. Objective: To systematically review the literature to evaluate the effects of hearing aid use on cognition and quality of life of people with dementia. Methods: Protocol for this systematic review was registered (CRD42023387187). The Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Scopus, CINAHL, and Web of Science databases, as well as grey literature, including Google Scholar and ResearchGate, were systematically searched for clinical trials using MeSH terms. The PICOS principle was used to develop the inclusion criteria: population (P): adults and older adults, individuals diagnosed with dementia and hearing loss; intervention (I): rehabilitation with hearing aids; control (C): not using a hearing aid; outcome (O): cognitive and/or quality of life assessment using validated tests; study design (S): clinical trial. Results: The initial search yielded 576 studies, five of which met the inclusion criteria for qualitative analyses. Two of the included studies were randomized clinical trials, and three were crossover clinical trials, demonstrating the lack of studies on the subject. Four studies included participants with Alzheimer's disease. Quality of life was found to improve with the use of hearing aids, and hearing rehabilitation was not shown to affect cognitive outcomes. Conclusions: Hearing aid use appears to have a positive impact on quality of life.

Systematic Review
Rebecca J. Lepping, Benjamin J. Hess, Jasmine M. Taylor, Deanna Hanson-Abromeit, Kristine N. Williams
Inconsistent Music-Based Intervention Reporting in Dementia Studies: A Systematic Mapping Review
Abstract: Background: Recent research has shown beneficial results for music-based interventions (MBIs) for persons living with Alzheimer’s disease and related dementias (AD/ADRD), but reports often lack sufficient detail about the MBI methodology, which reduces replicability. A detailed checklist for best practices in how to report MBIs was created in 2011 by Robb and colleagues to remedy the lack of detail in MBI descriptions. The implementation of the checklist specifically in AD/ADRD research has not been established. Given the complexity of music and the variety of uses for research and health, specific MBI descriptions are necessary for rigorous replication and validation of study results. Objective: This systematic mapping review utilized the “Checklist for Reporting Music-Based Interventions” to evaluate the current state of MBI descriptive specificity in AD/ADRD research. Methods: Research articles testing MBIs and reviews of MBI efficacy published between January 2015 and August 2023 were scored using the checklist and the results were summarized. Results: Forty-eight studies were screened, and reporting was inconsistent across the 11 checklist criteria. Ten out of 48 studies fully reported more than 5 of the 11 criteria. Only one of the 11 scoring criteria was at least partially reported across 47 of 48 studies. Conclusions: Thorough reporting of intervention detail for MBIs remains limited in AD/ADRD MBI research. This impedes study validation, replication, and slows the progress of research and potential application of music in practice. Greater implementation of the reporting guidelines provided by Robb and colleagues would move the field of MBI research for AD/ADRD forward more quickly and efficiently.

Commentary
Che-Yuan Wu, Walter Swardfager
Phosphodiesterase-5 Inhibitors and Dementia Risk: Confounding by Indication in Real-World Studies
Abstract: Pharmacoepidemiologic studies using routinely collected data allow researchers to propose drugs for repurposing trials for dementia prevention or treatment. A recent cohort study reported a 54% lower dementia risk among users of sildenafil compared to users of certain cardiovascular medications. We caution that “confounding by indication” can arise when outcomes are compared between a drug of interest and an inappropriate comparator. Here, we emphasize important considerations in selecting an active comparator. We assess the implications of substantial risk of confounding by indication in pharmacoepidemiologic studies linking phosphodiesterase-5 inhibitors to lower dementia risk.

Marta Rodini, Sabrina Bonarota, Laura Serra, Carlo Caltagirone, Giovanni Augusto Carlesimo
Could Accelerated Long-Term Forgetting Be a Feature of the Higher Rate of Memory Complaints Associated with Subjective Cognitive Decline? An Exploratory Study
Abstract: Background: Recently, subjective cognitive decline (SCD) was proposed as an early risk factor for future Alzheimer’s disease (AD). Objective: In this study, we investigated whether accelerated long-term forgetting (ALF), assessed with extended testing intervals than those adopted in clinical practice, might be a cognitive feature of SCD. Using an explorative MRI analysis of the SCD sample, we attempted to investigate the areas most likely involved in the ALF pattern. Methods: We recruited 31 individuals with SCD from our memory clinic and subdivided them based on their rate of memory complaints into mild SCDs (n=18) and severe SCDs (n=13). A long-term forgetting procedure, involving the recall of verbal and visuo-spatial material at four testing delays (i.e., immediate, 30 min, 24 h, and 7 days post-encoding) was used to compare the two sub-groups of SCDs with a healthy control group (HC; n =16). Results: No significant between-group difference was found on the standard neuropsychological tests, nor in the immediate and 30 min recall of the experimental procedure. By contrast, on the verbal test severe SCDs forgot significantly more than HCs in the prolonged intervals (i.e., 24 h and 7 days), with the greatest decline between 30 min and 24 h. Finally, in the whole SCD sample, we found significant associations between functional connectivity values within some cortical networks involved in memory (default mode network, salience network, and fronto-parietal network) and verbal long-term measures. Conclusions: Our preliminary findings suggest that long-term forgetting procedures could be a sensitive neuropsychological tool for detecting memory concerns in SCDs, contributing to early AD detection.

Andrew Sommerlad, Jessica Grothe, Sumiyo Umeda, Manabu Ikeda, Hideki Kanemoto, Gill Livingston, Melanie Luppa, Katherine P. Rankin, Steffi G. Riedel-Heller, Susanne Röhr, Maki Suzuki, Jonathan Huntley
Awareness of Social Functioning in People with Dementia and Its Association with Dementia Severity: Multi-Center Cross-Sectional Study
Abstract: Background: People with dementia commonly have impaired social functioning and may not recognize this. This lack of awareness may result in worse outcomes for the person and their family carers. Objective: We aimed to characterize awareness of social functioning in dementia and describe its association with dementia severity. Methods: Multi-center cross-sectional study of people aged >65 years with dementia and family informants recruited from Germany, Japan and the United Kingdom. We used the Social Functioning in Dementia (SF-DEM) scale, assessing “spending time with other people” (domain 1), “communicating with other people” (domain 2), and “sensitivity to other people” (domain 3), and calculated lack of awareness into social functioning as the discrepancy between patient and informant ratings. Results: 108 participants with dementia (50.9% women), mean age = 78.9 years, and mean MMSE score = 22.7. Patient and informant domain 1 ratings did not differ, but patient-rating was higher than carers for domain 2 (11.2 versus 10.1; p = 0.003) and domain 3 (9.7 versus 8.1; p < 0.001). Sixty people with dementia overestimated their overall social functioning, 30 underestimated, and 18 gave ratings congruent with their informant. Performance on the MMSE and its sub-domains was not associated with SF-DEM discrepancy score. Conclusions: We found that awareness of social functioning in dementia was a multidimensional concept, which varies according to subdomains of social functioning. Clinicians should help family members understand and adapt by explaining their relative with dementia’s lack of awareness about aspects of their social functioning.

Anna Marin*, Katherine W. Turk*, Kylie Schiloski, Ana Vives-Rodriguez, Cheongmin Suh, Prayerna Uppal, Brigid Dwyer, Rocco Palumbo, Andrew E. Budson *These authors contributed equally to this work
The Use of Event Related Potentials to Predict Amyloid PET Status Among Patients from a Memory Disorders Clinic
Abstract: Background: Amyloid positron emission tomography (PET) scans provide in vivo evidence of Alzheimer’s disease (AD); however, their high cost limits their use in standard clinical care. Event related potentials (ERPs) may represent an inexpensive and non-invasive additional method for detecting AD pathology. Objective: We investigated whether ERPs, along with neuropsychological data, serve as predictors of amyloid PET status in patients with memory complaints. Methods: Veterans aged 50–100 were recruited from a memory disorders clinic. Participants underwent a neuropsychological battery and an ERP auditory oddball protocol. Twenty-eight patients had a positive amyloid PET scan, and thirty-nine patients had a negative scan. Results: ERP-P200 target amplitude and P200 standard latency were predictors of amyloid PET status. When submitting to ROC analysis, P200 standard latency exhibited the highest specificity and sensitivity in predicting amyloid PET positivity, correctly classifying the amyloid PET status for 86% of patients. Conclusions: ERP-P200 measures, are strong indicators of amyloid-β presence in patients from a memory disorder clinic. Increased P200 amplitude and decreased P200 latency in patients with a positive amyloid PET scan may be attributed to hyperactivation of perceptual bottom-up processes compensating for AD-related synaptic loss in the fronto-parietal networks.

Jeremy A. Elman, Nicholas J. Schork, Aaditya V. Rangan and for the Alzheimer’s Disease Neuroimaging Initiative
Exploring the Genetic Heterogeneity of Alzheimer’s Disease: Evidence for Genetic Subtypes
Abstract: Background: Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. Objective: We investigated genetic heterogeneity in AD risk through a multi-step analysis. Methods: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases=2,739, controls=5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases=500, controls=470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n=399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. Results: PCA revealed three distinct clusters ("constellations") driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. Conclusions: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.

Sarah Therrien, Mia Anthony, Adam Turnbull, F. Vankee Lin
Risk-Taking Behavior Differs Between Older Adults with and without Mild Cognitive Impairment
Abstract: Background: Adequately evaluating risk and making decisions is vital but understudied for older adults living independently but with compromised cognition, as seen in those with mild cognitive impairment (MCI), specifically those with amnestic MCI (aMCI) which is associated with higher risk of conversion to Alzheimer’s disease. Objective: We propose to comprehensively evaluate risk-taking behaviors across domains important for everyday activities between an aMCI group and their cognitively healthy counterparts (HC). Methods: A case-control study design. Data on risk-taking behaviors via the Domain-Specific Risk-Taking Scale (DOSPERT), and candidate confounding mental health factors (i.e., neurodegeneration, depression, and fatigue) were collected. Analyses on group difference and interaction between group and confounding factors on risk-taking behaviors were conducted. Results: The aMCI group showed a higher likelihood of risk-taking than HC (t=4.38, df=73, p<0.001). Moderation analysis showed fatigue (F=5.91, p=0.018) and presence of depression (F=4.52, p=0.037), but not neurodegeneration, as significant moderators for group and DOSPERT total score, controlling for sex. In post-hoc analyses, there was a significant relationship between both fatigue (B=-7.83, SE=3.65, t=-2.14, p=0.036), and presence of depression (B=-20.80, SE=9.97, t=-2.09, p=0.041), with DOSPERT total score for HC but not for aMCI. There were no significant relationships between neurodegeneration, fatigue, or depression with any specific risk-taking domains after correction for multiple comparisons. Conclusions: Our results show differences in risk-taking behavior between older adults with and without intact cognition, and overall decision-making is affected by fatigue and depression in HC but not aMCI, together suggesting the importance of cognition in the ability to adjust risk-taking behaviors.

Ryan A. Mace, Christopher Lyons, Joshua E. Cohen, Christine Ritchie, Stephen Bartels, Olivia I. Okereke, Bettina B. Hoeppner, Judson A. Brewer, Ana-Maria Vranceanu (Handling Associate Editor: Jeroen Bruinsma)
Optimizing the Implementation of a Lifestyle Dementia Prevention Intervention for Older Patients in an Academic Healthcare System
Abstract: Background: Interventions that promote healthy lifestyles are critical for the prevention of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). However, knowledge of the best practices for implementing AD/ADRD prevention in healthcare settings remains limited. Objective: We aimed to qualitatively identify barriers and facilitators to implementing a clinical trial of a novel lifestyle intervention (My Healthy Brain) in our medical center for older patients with subjective cognitive decline who are at-risk for AD/ADRD. Methods: We conducted focus groups with 26 healthcare professionals (e.g., physicians, psychology, nursing) from 5 clinics that treat older patients (e.g., memory care, psychiatry). Our qualitative analysis integrated two implementation frameworks to systematically capture barriers and facilitators to AD/ADRD prevention (Consolidated Framework for Implementation Science Research) that impact implementation outcomes of acceptability, appropriateness, and feasibility (Proctor’s framework). Results: We found widespread support for an RCT of My Healthy Brain and AD/ADRD prevention. Participants identified barriers related to patients (stigma, technological skills), providers (dismissiveness of “worried well”, doubting capacity for behavior change), clinics (limited time and resources), and the larger healthcare system (underemphasis on prevention). Implementation strategies guided by Expert Recommendations for Implementing Change (ERIC) included: developing tailored materials, training staff, obtaining buy-in from leadership, addressing stigmatized language and practices, identifying “champions,” and integrating with workflows and resources. Conclusions: The results will inform our recruitment, enrollment, and retention procedures to implement the trial of My Healthy Brain. Our study provides a blueprint for addressing multi-level barriers to the implementation of AD/ADRD prevention for older patients in medical settings.

Hongqi Wang*, Jilai Li, Wenjun Tu, Zhiqun Wang, Yiming Zhang, Lirong Chang, Yan Wu, Xia Zhang* *These authors contributed equally to this work.
Identification of Blood Biomarkers Related to Energy Metabolism and Construction of Diagnostic Prediction Model Based on Three Independent Alzheimer’s Disease Cohorts
Abstract: Background: Blood biomarkers are crucial in the diagnosis and therapy of Alzheimer's disease (AD). Energy metabolism disturbances are closely related to AD. However, research on blood biomarkers related to energy metabolism is still insufficient. Objective: This study aims to explore the diagnostic and therapeutic significance of energy metabolism related genes in AD. Methods: The AD cohorts were obtained from GEO database and single center. Machine learning algorithms were used to identify key genes. GSEA were used for functional analysis. Six algorithms were utilized to establish and evaluate diagnostic models. Key genes related drugs were screened through network pharmacology. Results: We identified 4 energy metabolism genes, NDUFA1, MECOM, RPL26, and RPS27. These genes were confirmed closely relation to multiple energy metabolic pathways and different types of T cell immune infiltration. Additionally, transcription factors INSM2 and 4 lncRNAs were involved in regulating 4 genes. Further analysis showed that all biomarkers were downregulated in the AD cohorts and not affected by aging and gender. More importantly, we constructed a diagnostic prediction model of 4 biomarkers, which has been validated by various algorithms for its diagnostic performance. Furthermore, we found that valproic acid mainly interacted with these biomarkers through hydrogen bonding, salt bonding, and hydrophobic interaction. Conclusions: We constructed a predictive model based on 4 energy metabolism genes, which may be helpful for the diagnosis of AD. The 4 validated genes could serve as promising blood biomarkers for AD. Their interaction with valproic acid may play a crucial role in the therapy of AD.

Robin van den Kieboom, Liselore Snaphaan , Ruth Mark, Marcel van Assen, Inge Bongers
The Effects of Neuropsychiatric Symptom Clusters in People with Dementia on Family Caregiver Burden
Abstract: Background: Neuropsychiatric symptoms are a robust risk factor for caregiver burden in family dementia caregivers. By grouping these symptoms, clinical interpretations regarding neuropsychiatric symptoms may facilitated because different groups of symptoms may require a different approach for intervention, thereby reducing caregiver burden. Objective: As clustering of neuropsychiatric symptoms could be clinically relevant, we aimed to explore the effects of these clusters on burden in family dementia caregivers. Methods: 152 family dementia caregivers were included. Caregiver burden was measured using the Ervaren Druk door Informele Zorg (EDIZ) / Self-Perceived Pressure from Informal Care, a Dutch questionnaire. Caregivers also reported the neuropsychiatric symptoms and functional impairments in daily activities of the people with dementia they cared for. Multiple regression analyses were used in this cross-sectional study. Results: Adjusted for functional impairments and sociodemographic variables, neuropsychiatric symptoms were associated with more caregiver burden (p < 0.001). However, this association did not differ between the three neuropsychiatric symptom clusters (p = 0.745). Conclusions: Neuropsychiatric symptoms were associated with more family caregiver burden, but no conclusive evidence was found that this association differed for the three clusters. Clustering of neuropsychiatric symptoms is, however, worth exploring further in future studies with more participants. If specific links are found these could be targeted in clinical practice in order to prevent, reduce and/or postpone caregiver burden.

Wan Wang*, Zhenping Gong*, Yadan Wang, Ying Zhao, Yaru Lu, Ruihua Sun, Haohan Zhang, Junkui Shang, Jiewen Zhang *These authors contributed equally to this work.
Mutant NOTCH3ECD Triggers Defects in Mitochondrial Function and Mitophagy in CADASIL Cell Models
Abstract: Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy.

Manjot Brar, Ríona Mc Ardle, Alexander Hagan, Amani Al-Oraibi, Matilda Hanjari, Blossom Stephan, Carol Brayne, Louise Lafortune, Manpreet Bains, Nadeem Qureshi*, Louise Robinson* (Handling Associate Editor: Jaime Perales) *These authors contributed equally to this work.
Attitudes and Preferences Towards Screening for Dementia with a Focus on Ethnic Minority and Low Socio-Economic Groups: A Systematic Review of Research Studies Written in the English Language
Abstract: Background: Increased understanding of dementia risk-reduction and early detection of Alzheimer’s disease and related disorders has spurred interest in the identification of risks for dementia, underlying putative biologies, or dementia itself. Implementation of such approaches require acceptability to the public. Research prior to 2012 indicated limited acceptability for population dementia screening. The changing landscape of dementia prevention research may influence recent perceptions. Additionally, perspectives from underserved populations, such as ethnic minorities and low socio-economic groups, are lacking. Objective: In this systematic review, we sought published studies since 2012 on attitudes and preferences of people with dementia, carers and the general public from ethnic minorities and low socio-economic groups regarding dementia screening. Methods: This review was preregistered on PROSPERO (CRD42023384115) and followed PRISMA guidelines. Key search terms were entered into five databases. Articles were included if they focused on population or risk screening for dementia via primary/community care-based assessments, and which included majority ethnic minority or low socio-economic groups or discretely considered these groups in data analysis. Data were synthesized narratively. Results: Seven studies reported perspectives of ethnic minorities regarding dementia screening; one study included people from low socio-economic groups. Results indicated that participants from ethnic minorities were willing to undergo dementia screening. Predictors of willingness included belief in benefits, desire to boost diversity, and to implement lifestyle changes. Unwillingness was associated with anxiety regarding results. Conclusions: Although there seems to be high acceptability for screening in the studied groups, more research is necessary to explore the practical considerations for screening such as cultural and economic barriers, trust, and post-screening actions.

Bao-Lin Han, Ling-Zhi Ma, Shuang-Ling Han, for the Alzheimer’s Disease Neuroimaging Initiative, Yin-Chu Mi, Jia-Yao Liu, Ze-Hu Sheng, Hui-Fu Wang, Lan Tan (Handling Associate Editor: Yong Liu)
Explore the Role of Frailty as a Contributor to the Association Between AT(N) Profiles and Cognition in Alzheimer’s Disease
Abstract: Background: The relationship between Alzheimer’s disease (AD)-related pathology and cognition was not exactly consistent. Objective: To explore whether the association between AD pathology and cognition can be moderated by frailty. Methods: We included 1711 participants from the Alzheimer’s Disease Neuroimaging Initiative database. Levels of cerebrospinal fluid amyloid-β, p-tau, and t-tau were identified for AD-related pathology based on the amyloid-β/tau/neurodegeneration (AT[N]) framework. Frailty was measured using a modified Frailty Index-11 (mFI-11). Regression and interaction models were utilized to assess the relationship among frailty, AT(N) profiles, and cognition. Moderation models analyzed the correlation between AT(N) profiles and cognition across three frailty levels. All analyses were corrected for age, sex, education, and APOE ε4 status. Results: In this study, frailty (odds ratio [OR] = 1.71, p < 0.001) and AT(N) profiles (OR = 2.00, p < 0.001) were independently associated with cognitive status. The model fit was improved when frailty was added to the model examining the relationship between AT(N) profiles and cognition (p < 0.001). There was a significant interaction between frailty and AT(N) profiles in relation to cognitive status (OR = 1.12, pinteraction = 0.028). Comparable results were obtained when Mini-Mental State Examination scores were utilized as the measure of cognitive performance. The association between AT(N) profiles and cognition was stronger with the levels of frailty. Conclusions: Frailty may diminish patients’ resilience to AD pathology and accelerate cognitive decline resulting from abnormal AD-related pathology. In summary, frailty contributes to elucidating the relationship between AD-related pathology and cognitive impairment.

Darlingtina Esiaka, Obinna Odo, Elizabeth Luth (Handling Associate Editor: Lilah Besser)
Unraveling the Threads: Sleep Difficulties, Neighborhood Physical Disorder, and Subjective Cognitive Decline in Older Americans
Abstract: Background: Research suggests that the neighborhood in which people live can be a risk or protective factor for various health outcomes, including cognitive decline to Alzheimer’s disease. Similar to the impact of neighborhood on health outcomes, sleep difficulties have been linked to cognitive function in older adults. However, few studies have examined how neighborhood physical disorders moderate the effects of sleep on subjective cognitive decline (SCD). Objective: The study examined the moderating effect of neighborhood factors on the relationship between sleep difficulties and SCD. Methods: Data were obtained from 2,494 respondents (1,065 males and 1,429 females) from Wave 11 of the National Health and Aging Trends (NHATS) data. Sleep difficulties were operationalized as the absence of difficulties in falling and staying asleep. Neighborhood physical disorder (e.g., vandalism, graffiti) was based on interviewer observations of respondents’ neighborhoods. SCD was operationalized as subjective reports of increasing or worse memory loss in the past 12 months and present memory rating. We utilized Linear regression to test neighborhood physical disorder as a moderator of the relationship between sleep difficulties and SCD. Results: We found a significant interaction between sleep difficulties and neighborhood physical disorder on SCD (β=0.03, SE=0.01, 95% CI[0.00,0.51], p<0.001). Participants who reported higher average sleep difficulties and higher levels of neighborhood physical disorder were more likely to report SCD. Conclusions: Our findings add to inform future health interventions and policy recommendations that address modifiable sources of cognitive decline and risk of Alzheimer’s disease.

Jeremy A. Syrjanen, Janina Krell-Roesch, Walter K. Kremers, Julie A. Fields, Eugene L. Scharf, David S. Knopman, Ronald C. Petersen, Maria Vassilaki, Yonas E. Geda
Association of Anxiety and Unspecified Emotional Distress Obtained from a Medical Records Linkage System with Incident Cognitive Outcomes in a Population-Based Setting
Abstract: Background: Studies that assess cognition prospectively and study in detail anxiety history in the participants' medical records within the context of brain aging and Alzheimer’s disease are limited. Objective: To examine the associations of anxiety and unspecified emotional distress (UED) acquired throughout a person’s life with prospectively collected cognitive outcomes. Methods: Mayo Clinic Study of Aging participants who were cognitively unimpaired at baseline were included. Anxiety and UED data were abstracted from the medical record using the Rochester Epidemiology Project (REP) resources and were run separately as predictors in our models. The data were analyzed using Cox proportional hazards models for the outcomes of incident mild cognitive impairment (MCI) and dementia and using linear mixed effects models for the outcomes of global and domain specific cognitive z-scores and included key covariates. Results: The study sample (n=1,808) had a mean (standard deviation) age of 74.5 (7.3) years and 51.4% were male. Anxiety was associated with increased risk of MCI and dementia and was associated with lower baseline cognitive z-scores and accelerated decline over time in the global, memory, and attention domains. UED was associated with faster decline in all domains except visuospatial but did not show evidence of association with incident cognitive outcomes. These results varied by medication use and timing of anxiety. Conclusions: Anxiety and UED both showed inverse associations with cognition. Utilization of anxiety and UED data from across the life course, as available, from the REP system adds robustness to our results.

Ruo-Tong Wang, Zhen Sun, Chen-Chen Tan, Lan Tan, Wei Xu, for the Alzheimer’s Disease Neuroimaging Initiative
Dynamic Features of Body Mass Index in Late Life Predict Cognitive Trajectories and Alzheimer’s Disease: A Longitudinal Study
Abstract: Background: The causal relationships of late-life body mass index (BMI) with Alzheimer's disease (AD) remains debated. Objective: We aimed to assess the associations of dynamic BMI features (ΔBMIs) with cognitive trajectories, AD biomarkers, and incident AD risk. Methods: We analyzed an 8-year cohort of 542 non-demented individuals who were aged ≥ 65 years at baseline and had BMI measurements over the first 4 years. ΔBMIs were defined as changing extent (change ≤ or > 5%), variability (standard deviation), and trajectories over the first 4 years measured using latent class trajectory modeling. Linear mixed-effect models were utilized to examine the influence of ΔBMIs on changing rates of AD pathology biomarkers, hippocampus volume, and cognitive functions. Cox proportional hazards models were used to test the associations with AD risk. Stratified analyzes were conducted by the baseline BMI group and age. Results: Over the 4-year period, compared to those with stable BMI, individuals who experienced BMI decreases demonstrated accelerated declined memory function (p = 0.006) and amyloid-β deposition (p = 0.034) while BMI increases were associated with accelerated hippocampal atrophy (p = 0.036). Three BMI dynamic features, including stable BMI, low BMI variability, and persistently high BMI, were associated with lower risk of incident AD (p < 0.005). The associations were validated over the 8-year period after excluding incident AD over the first 4 years. No stratified effects were revealed by the BMI group and age. Conclusions: High and stable BMI in late life could predict better cognitive trajectory and lower risk of AD.

Jian Yu*, Wenyu Tang*, Zubaidan Sulaiman, Xin Ma, Jiayi Wang, Zhongyong Shi, Qidong Liu, Zhongcong Xie, Yuan Shen, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Xuemin Xu) *These authors contributed equally to this work.
The Association Between Surgery and Mild Cognitive Impairment: Insight from a Case-Control Study
Abstract: Background: Surgery may be associated with postoperative cognitive impairment in elder participants, yet the extent of its association with mild cognitive impairment (MCI) remains undetermined. Objective: To determine the relationship between surgery and MCI. Methods: The data of participants from the Alzheimer’s Disease Neuroimaging Initiative were analyzed, including individuals with MCI or normal cognition. We focused on surgeries conducted after the age of 45, categorized by the number of surgeries, surgical risk, and the age at which surgeries occurred. Multivariable logistic regression was employed to determine the association between surgery and the development of MCI. Results: The study is comprised of 387 individuals with MCI and 578 cognitively normal individuals. The overall surgery exposure (adjusted OR = 1.14, [95% CI 0.83, 1.56], p = 0.43) and the number of surgeries (adjusted OR = 0.92 [0.62, 1.36], p = 0.67 for single exposure, adjusted OR = 1.12 [0.71, 1.78], p = 0.63 for two exposures, adjusted OR = 1.38 [0.95, 2.01], p = 0.09 for three or more exposures compared to no exposure as the reference) were not associated with the development of MCI. However, high-risk surgeries (adjusted OR = 1.79 [1.00, 3.21], p = 0.049) or surgeries occurring after the age of 75 (adjusted OR = 2.01 [1.03, 3.90], p = 0.041) were associated with a greater risk of developing MCI. Conclusions: High risk surgeries occurring at an older age contribute to the development of MCI, indicating a complex of mechanistic insights for the development of postoperative cognitive impairment.

Morag E. Taylor*, Luuk Kerckhaert*, Jacqueline C.T. Close, Kimberley S. van Schooten, Stephen R. Lord *These authors contributed equally to this work.
The Impact of misaligned perceived and objective fall risk in cognitively impaired older people
Abstract: Background: Cognitive impairment (CI) may impair the ability to accurately perceive physical capacity and fall risk. Objective: We investigated perceived (measured as concern about falls) and physiological fall risk in community-dwelling older people with CI, and the impact of misaligned perceptions on fall risk factors and falls. Methods: Participants (n=293) with mild-moderate CI were classified into four groups based on validated physiological and perceived fall risk assessments: 1) vigorous: low perceived and physiological fall risk; 2) anxious: high perceived and low physiological fall risk; 3) unaware: low perceived and high physiological fall risk; and 4) aware: high perceived and physiological fall risk. Groups were compared with respect to neuropsychological and physical function, activity and quality of life measures, and prospective falls (12-months). Results: The anxious (IRR=1.70, 95%CI=1.02-2.84), unaware (IRR=2.00, 95%CI=1.22-3.26), and aware (IRR=2.53, 95%CI=1.67-3.84) groups had significantly higher fall rates than the vigorous group but fall rates did not significantly differ among these groups. Compared with the vigorous group: the anxious group had higher depression scores and reduced mobility and quality of life; the unaware group had poorer global cognition, executive function and mobility and lower physical activity levels; and the aware group had an increased prevalence of multiple physical and cognitive fall risk factors. Conclusions: Fall rates were increased in participants who had increased perceived and/or physiological fall risk. Contrasting fall risk patterns were evident in those who under- and over-estimated their fall risk. Understanding these characteristics will help guide fall risk assessment and prevention strategies in community-dwelling older people with CI.

Tetsuo Kashibayashi, Hideki Kanemoto, Ryuichi Takahashi, Ryoko Fujito, Yoshihiro Chadani, Kenji Tagai, Shunichiro Shinagawa, Kazunari Ishii, Manabu Ikeda, Hiroaki Kazui
Neural Basis of Agitated Behaviors in Patients with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: Aggression, a common symptom of Alzheimer’s disease (AD), can impose a significant burden on caregivers, necessitating early institutionalization. Objective: The current study examined the neural basis of aggression and its expression mechanism, to advance the development of effective treatment strategies for aggression in patients with AD. Methods: The study sample included 257 patients; 180 were diagnosed with AD and 77 with amnestic mild cognitive impairment (aMCI). Factor analysis of the neuropsychiatric inventory (NPI) aggression scores was performed, and the correlation between each factor and cerebral blood flow (CBF) was examined via diagnosis of AD or aMCI using statistical parametric mapping. Results: Refusal of care was correlated with reduced CBF in the right hippocampus of patients with AD while no specific related regions could be identified in patients with aMCI. Violent behavior was associated with decreased CBF in the right temporal pole and medial frontal lobe of patients with AD and aMCI. Conclusions: These findings suggest that aggression, measured using NPI includes two distinct symptoms, refusal of care and violent behavior, having different underlying neural bases.

Shannon Halloway, Annabelle Santos Volgman, Lisa L. Barnes, Michael E. Schoeny, JoEllen Wilbur, Susan J. Pressler, Deepika Laddu, Shane A. Phillips, Sachin Vispute, Gabriel Hall, Shamatree Shakaya, Madison Goodyke, Claire Auger, Kelly Cagin, Jeffrey A. Borgia, Zoe A. Arvanitakis
The MindMoves Trial: Cross-Sectional Analyses of Baseline Vascular Risk and Cognition in Older Women with Cardiovascular Disease
Abstract: Background: Vascular diseases, including atherosclerotic cardiovascular disease (ASCVD) and stroke, increase the risk of Alzheimer’s disease and cognitive impairment. Serum biomarkers, such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1), may be indicators of cognitive health. Objective: We examined whether vascular risk was associated with levels of cognition and serum biomarkers in older women with cardiovascular disease (CVD). Methods: Baseline data from a lifestyle trial in older women (n = 253) with CVD (NCT04556305) were analyzed. Vascular risk scores were calculated for ASCVD (ASCVD risk estimator) and stroke (CHA2DS2-VASc) based on published criteria. Cognition-related serum biomarkers included BDNF, VEGF, and IGF-1. Cognition was based on a battery of neuropsychological tests that assessed episodic memory, semantic memory, working memory, and executive function. A series of separate linear regression models were used to evaluate associations of vascular risk scores with outcomes of cognition and serum biomarkers. All models were adjusted for age, education level, and racial and ethnic background. Results: In separate linear regression models, both ASCVD and CHA2DS2-VASc scores were inversely associated with semantic memory (β = -0.22, p = 0.007 and β = -0.15, p = 0.022, respectively), with no significant findings for the other cognitive domains. There were no significant associations between vascular risk scores and serum biomarkers. Conclusions: Future studies should prospectively examine associations between vascular risk and cognition in other populations and additionally consider other serum biomarkers that may be related to vascular risk and cognition.

Davida Fromm, Sarah Grace Dalton, Alexander Brick, Gbenuola Olaiya, Sophia Hill, Joel Greenhouse, Brian MacWhinney (Handling Associate Editor: Kristy Nielson)
The Case of the Cookie Jar: Differences in Typical Language Use in Dementia
Abstract: Background: Findings from language sample analyses can provide efficient and effective indicators of cognitive impairment in older adults. Objective: This study used newly automated core lexicon analyses of Cookie Theft picture descriptions to assess differences in typical use across three groups. Methods: Participants included adults without diagnosed cognitive impairments (Control), adults diagnosed with Alzheimer’s disease (ProbableAD), and adults diagnosed with mild cognitive impairment (MCI). Cookie Theft picture descriptions were transcribed and analyzed using CLAN. Results: Results showed that the ProbableAD group used significantly fewer core lexicon words overall than the MCI and Control groups. For core lexicon content words (nouns, verbs), however, both the MCI and ProbableAD groups produced significantly fewer words than the Control group. The groups did not differ in their use of core lexicon function words. The ProbableAD group was also slower to produce most of the core lexicon words than the MCI and Control groups. The MCI group was slower than the Control group for only two of the core lexicon content words. All groups mentioned a core lexicon word in the top left quadrant of the picture early in the description. The ProbableAD group was then significantly slower than the other groups to mention a core lexicon word in the other quadrants. Conclusions: This standard and simple-to-administer task reveals group differences in overall core lexicon scores and the amount of time until the speaker produces the key items. Clinicians and researchers can use these tools for both early assessment and measurement of change over time.