Volume 96, Number 2, IN PROGRESS

Review
Dale E. Bredesen, Kat Toups, Ann Hathaway, Deborah Gordon, Henrianna Chung, Cyrus Raji, Alan Boyd, Benjamin D. Hill, Sharon Hausman-Cohen, Mouna Attarha, Won Jong Chwa, Alexei Kurakin, Michael Jarrett
Precision Medicine Approach to Alzheimer’s Disease: Rationale and Implications
Abstract: The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer’s disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

Review
Antonia González-Madrid, Camila Calfío, Andrea González, Valentina Lüttges and Ricardo B. Maccioni
Toward Prevention and Reduction of Alzheimer's Disease
Abstract: Different investigations lead to the urgent need to generate validated clinical protocols as a tool for medical doctors to orientate patients under risk for a preventive approach to control Alzheimer's disease. Moreover, there is consensus that the summation of risk factors for the disease can be modified according to lifestyle, thus controlling at least 40% of cases. Another fraction of cases derives from candidate genes and epigenetic components as a relevant factor in AD pathogenesis. At this point, it appears to be of critical relevance the search for molecular biomarkers that may provide information on probable pathological events and alert about early detectable risks to prevent symptomatic events of the disease. These precocious detection markers will then allow early interventions of non-symptomatic subjects at risk. Here, we summarize the status and potential avenues of prevention and highlight the usefulness of biological and reliable markers for AD.

Review
Yiming Liu, Yong Shen
Applications of Nanoparticles in Alzheimer’s Disease
Abstract: With the rapid aging of the global population, the prevalence of neurodegenerative diseases has become a significant concern, with Alzheimer's disease (AD) being the most common. However, the clinical trials of many drugs targeting AD have failed due to the challenges posed by the blood-brain barrier (BBB), which makes intracerebral administration of drugs difficult. However, nanoparticles (NPs) may aid in the delivery of such drugs. NPs are materials with sizes between 1-100 nm that offer several advantages, such as improving biocompatibility, prolonging half-life, transporting large molecules, crossing the BBB to deliver to the central nervous system, and exhibiting good targeting ability. In addition to drug delivery, NPs also have excellent diagnostic potential, and multifunctional NPs can integrate the advantages of diagnosis, targeting, and treatment. This mini-review article provides an overview of NPs, including the composition of the carrier, strategies for crossing the BBB, and different targets of AD pathology, with the aim of providing guidance for the development prospects of NPs.

Review
Solene Guilliot, Serge Gauthier, Jacques Touchon, Maria E. Soto
Lithium, a Treatment Option for Alzheimer’s Disease? A Review of Existing Evidence and Discussion on Future Perspectives
Abstract: After over 50 years of use, lithium-salts remain the first-line therapy for the management of bipolar disorder. Throughout this period, the potential for lithium salts has been extensively studied and numerous data favor its use in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). We reviewed existing evidence gathered from clinical case reports and studies on the effect of lithium on neuropsychological symptoms of AD and as a disease-modifying treatment acting on cognitive symptoms. The review summarizes the molecular pathways, involving GSK-3β inhibition and neuroprotection, through which lithium is proposed to exert its effect. Limitations to its current use in AD are discussed and future perspectives as a potential treatment option for AD are considered in regard to ongoing clinical trials using different forms of lithium.

Systematic Review
Clément Polin, Thibaut Gellé, Emilie Auditeau, Caroline Adou, Jean-Pierre Clément, Benjamin Calvet
Repetitive Behaviors in Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: Repetitive behaviors (RBs) are a well-known symptom of Alzheimer's disease (AD); however, they have been little studied and have not been the subject of any specific literature review. Objective: To conduct a systematic review of all studies to document RBs in AD. Methods: An extensive literature search combining five databases and a meta-analysis were conducted to investigate the frequency, nature, and cognitive correlates of RBs in AD. Results: Ten studies were included in the review. Seven studies out of ten investigated the frequency of RBs in patients with AD, which ranged from 52.3% to 87%. A meta-analysis showed an overall frequency of 66.3% (95% CI: 55.5; 77.1) of patients exhibiting RBs in AD, but important heterogeneity was observed between studies. Three studies investigated the predominant nature of RBs in AD. Verbal RBs, complex behavioral stereotypies, and simple motor stereotypies have been identified to different degrees depending on the level of dementia. Most verbal RBs are underpinned by episodic memory impairment, while simple motor stereotypies and complex behavioral stereotypies are mostly underpinned by executive dysfunction. Conclusions: The current review seems to suggest that there are two types of mechanisms underpinning RBs involved in AD. The first is observed especially in the mild stages of the disease and is mediated by episodic memory impairment. The second occurs later and is mediated by executive impairment. Additional studies should be conducted to improve the knowledge about RBs in AD and thus improve their management.

Short Communication
Svetlana Ukraintseva, Matt Duan, Amanda M. Simanek, Rachel Holmes, Olivia Bagley, Aravind L. Rajendrakumar, Arseniy P. Yashkin, Igor Akushevich, Alexander Tropsha, Heather Whitson, Anatoliy Yashin, Konstantin Arbeev
Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer’s Disease
Abstract: Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer’s disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.

Short Communication
Cody Karjadi*, Chonghua Xue*, Claire Cordella, Swathi Kiran, Ioannis Ch. Paschalidis, Rhoda Au, Vijaya B. Kolachalama (Handling Associate Editor: Ganesh Babulal) *These authors contributed equally to this work.
Fusion of Low-Level Descriptors of Digital Voice Recordings for Dementia Assessment
Abstract: Digital voice recordings can offer affordable, accessible ways to evaluate behavior and function. We assessed how combining different low-level voice descriptors can evaluate cognitive status. Using voice recordings from neuropsychological exams at the Framingham Heart Study, we developed a machine learning framework fusing spectral, prosodic, and sound quality measures early in the training cycle. The model's area under the receiver operating characteristic curve was 0.832 (± 0.034) in differentiating persons with dementia from those who had normal cognition. This offers a data-driven framework for analyzing minimally processed voice recordings for cognitive assessment, highlighting the value of digital technologies in disease detection and intervention.

Short Communication
Fred B. Ketchum, Claire M. Erickson, Kristin E. Basche, Nathaniel A. Chin, Hannah L. Rosario, Sterling C. Johnson, Lindsay R. Clark
Informing Disclosure: Efficacy of a Brief Educational Intervention on Research Participants’ Knowledge about Alzheimer’s Disease Biomarkers
Abstract: Recommendations for communicating Alzheimer’s disease (AD) biomarkers include pre-disclosure participant education and counseling, to allow individuals to make an informed decision. In a cohort of largely non-Hispanic White, cognitively unimpaired older adults from the Wisconsin Registry for Alzheimer’s Prevention, we conducted a structured amyloid PET disclosure process that included knowledge assessment and education. Baseline participant knowledge about AD biomarkers and research was high, but information needs existed around dementia causes, early AD symptoms, genetic information, and psychosocial consequences of disclosure. Knowledge scores increased after education, highlighting the potential of brief educational interventions to improve informed decision-making about biomarker disclosure.

Cheng-Chun Liu, Qing-Hua Wang, Jia-Yan Xin, Yu-Hao Liu, Fan Zeng, Dong-Wan Chen, Hui-Yun Li, Xu Yi, Gui-Hua Zeng, Yan-Jiang Wang, Yang Xiang, Yang Chen
Association of Adipokines with Alzheimer’s Disease in a Chinese Cohort
Abstract: Background: The correlation between plasma adipose factor levels and Alzheimer's patients is not entirely clear. Objective: We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin. Methods: A single-center, cross-sectional study recruited AD patients (n = 148) and cognitively normal (CN) controls (n = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD. Results: After adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95%CI: 0.272-0.638, p < 0.0001) and adiponectin (OR = 1.249, 95%CI: 1.151-1.354, p < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p < 0.0001) and was positively with CDR scores (p < 0.0001) and age (p < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p < 0.0001) and positively correlated with MMSE scores (p < 0.0001). Both adiponectin (p < 0. 0001) and leptin (p < 0. 0001) featured higher AUC than the random chance. Conclusions: Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD.

Daniel L. Alkon, Miao-Kun Sun, Alan J. Tuchman, Richard E. Thompson (Deputy Editor: Jesus Avila)
Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial
Abstract: Background: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. Objective: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. Methods: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints—patients randomized with respect to Treatment groups. Results: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.5 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p=0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. Conclusions: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients’ decline of -12.5 SIB points.

Jinghua Bian*, Yintong Li*, Yongna Li* (Handling Associate Editor: Damaris Aschwanden) *These authors contributed equally to this work.
Attentional Control in Subjective Cognitive Decline
Abstract: Background: Attention is an essential cognitive ability that is necessary in other cognitive processes. Only few studies have focused on decline in specific functions of attention in older adults with cognitive decline. No research explores the difference in the proactive and reactive mode of control between the healthy control (HC) and older adults with subjective cognitive decline (SCD). Objective: The current work investigated whether there was any decline in alerting, orienting, and executive control in SCD. Particularly, the present study further explored the impairment of the proactive and reactive control in SCD. Methods: We recruited 25 HC and 26 SCD. All participants first finish a set of neuropsychological assessments. They then completed an Attention Network Test for measuring the alerting, orienting, and executive control, the List-wide and the Item-specific Proportion Congruency Effect task for measuring the proactive and reactive mode of control, respectively. Results: No difference was found in alerting, orienting, and executive control measured by the between SCD and HC. The results also indicated no difference in the reactive control between SCD and HC. However, older adults with SCD performed worse in the proactive control as compared to HC. Conclusions: Older adults with SCD showed an impairment in the proactive control. The current findings help us better understand objective decline in cognitive domains other than memory and shed light on early assessment and prevention of AD.

Aron S. Buchman, Sue E. Leurgans, Namhee Kim, Sonal Agrawal, Shahram Oveisgharan, Andrea R. Zammit, Veronique VanderHorst, Sukrit Nag, David A. Bennett (Handling Associate Editor: Qu Tian)
Alzheimer’s Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia
Abstract: Background: Assessments of Alzheimer’s disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. Objective: Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. Methods: Autopsies were obtained in decedents with cognitive testing (n=300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n=14), brainstem (n=5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases. Results: Age at death was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. Conclusions: Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

Kathrin Heser*, Luca Kleineidam*, Michael Wagner, Melanie Luppa, Margrit Löbner, Birgitt Wiese, Anke Oey, Hans-Helmut König, Christian Brettschneider, Carolin van der Leeden, Hendrik van den Bussche, Angela Fuchs, Michael Pentzek, Siegfried Weyerer, Jochen Werle, Horst Bickel, Martin Scherer, Wolfgang Maier, Alfredo Ramirez, Steffi G. Riedel-Heller *These authors contributed equally to this work.
Family History of Dementia in Old-Age Participants with Subjective Memory Complaints Predicts Own Risk for Dementia in a Longitudinal Multi-Center Cohort Study
Abstract: Background: Subjective memory complaints and family history of dementia are possibly intertwined risk factors for the own subsequent dementia risk and Alzheimer's disease. However, their interaction has rarely been studied. Objective: To study the association between subjective memory complaints and family history of dementia with regard to the own subsequent risk of dementia. Methods: Cross-sectional and longitudinal analyses over a follow-up period of up to 13 years were conducted in a population sample of participants without dementia at baseline (n = 3,256, mean age = 79.62 years), using group comparisons and Cox proportional hazards models. Results: Cross-sectionally, participants with subjective memory complaints were significantly more likely to report family history of dementia. Longitudinally, family history of dementia (FH) was significantly associated with subsequent dementia in the subjective memory complaints (SMC) group, but not in those without SMC. A relative excess risk due to interaction analysis confirmed a significant FHxSMC-interaction. Conclusions: Family history of dementia was a predictor of incident dementia in those with SMC, which can serve as an additional, clinically relevant criterion to gauge the risk of dementia in older-aged subjects with SMC with and without objective cognitive impairment.

Jared C. Roach, Molly K. Rapozo, Junko Hara, Gwênlyn Glusman, Jennifer Lovejoy, William R. Shankle, Leroy Hood on behalf of the COCOA Consortium
A Remotely Coached Multimodal Lifestyle Intervention for Alzheimer’s Disease Ameliorates Functional and Cognitive Outcomes
Abstract: Background: Comprehensive treatment of Alzheimer’s disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer’s disease (AD). Objective: The Coaching for Cognition in Alzheimer’s (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. Methods: Participants with early-stage AD were randomized into two arms. Arm 1 (N=24) received standard of care. Arm 2 (N=31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. Results: The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. Conclusions: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

Zhihong Bian, Xinran Hu, Xia Liu, Haibo Yu, Yuting Bian, Hongming Sun, Yusuke Fukui, Ryuta Morihara, Hiroyuki Ishiura, Toru Yamashita
Protective Effects of Rivaroxaban on White Matter Integrity and Remyelination in a Mouse Model of Alzheimer's Disease Combined with Cerebral Hypoperfusion
Abstract: Background: Alzheimer's disease (AD) is characterized by cognitive dysfunction and memory loss that is accompanied by pathological changes to white matter. Some clinical and animal research revealed that AD combined with chronic cerebral hypoperfusion (CCH) exacerbates AD progression by inducing blood-brain barrier dysfunction and fibrinogen deposition. Rivaroxaban, an anticoagulant, has been shown to reduce the rates of dementia in atrial fibrillation patients, but its effects on white matter and the underlying mechanisms are unclear. Objective: The main purpose of this study was to explore the therapeutic effect of rivaroxaban on the white matter of AD+CCH mice. Methods: In this study, the therapeutic effects of rivaroxaban on white matter in a mouse AD+CCH model were investigated to explore the potential mechanisms involving fibrinogen deposition, inflammation, and oxidative stress on remyelination in white matter. Results: The results indicate that rivaroxaban significantly attenuated fibrinogen deposition, fibrinogen-related microglia activation, oxidative stress, and enhanced demyelination in AD+CCH mice, leading to improved white matter integrity, reduced axonal damage, and restored myelin loss. Conclusions: These findings suggest that long-term administration of rivaroxaban might reduce the risk of dementia.

Siqi Xia, Huaijun Chen, Tianchi Tang
Risk of Death from Alzheimer’s Disease Associated with Brain Tumor, Glioma, and Glioblastoma
Abstract: Background: No study has compared the risk of Alzheimer’s disease (AD) in patients with brain tumors, gliomas, or glioblastomas with the risk in patients with other tumors. Objective: To determine whether, compared with other tumors, brain tumors, gliomas, and glioblastomas increase the risk of AD. Methods: This study identified a case group of 24,441 patients from the Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed with only one primary tumor at age >20 years in 1975-2019 and died from AD at age >65 years as case group. The control group comprised 122,205 subjects from the SEER database who died from causes other than AD but otherwise had the same conditions as those in the case group. Results: There was a significantly lower prevalence of glioma (0.074% versus 0.14%, p=0.007) and glioblastoma (0.0082% versus 0.074%, p=0.001) in patients who died from AD than in those who died from other causes, while brain tumors were not significantly associated with AD death (p=0.227). When adjusted for factors including age at death, sex, race, tumor behavior, radiation therapy and tumor-directed surgery, glioblastoma was related to a significantly lower AD risk than other tumors (odds ratio: 0.19, 95% CI: 0.05-0.77). Additionally, patients who were older, female, American Indian/Alaska Native, had a benign tumor, radiation therapy and tumor-directed surgery had a significantly higher risk of dying from AD. Conclusions: Gliomas and glioblastomas were associated with a significantly lower risk of death from AD than other tumors.

Minjae Kim, Dahyun Yi*, Min Soo Byun, Hyejin Ahn, Joon Hyung Jung, Nayeong Kong, Yoonyoung Chang, Hyeji Choi, Jungmin Choi, Kyungtae Kim, Gijung Jung, Dong Young Lee*; for the KBASE research group *These authors contributed equally to this work.
Development of a Cognitive Composite for Preclinical Alzheimer’s Disease in Korean Older Adults
Abstract: Background: As tracking subtle cognitive declines in the preclinical stage of Alzheimer’s disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. Objective: We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults. Methods: A total 225 cognitively normal elderly individuals from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease, were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composites. Three candidate composites including Consortium to Establish a Registry for Alzheimer's Disease Word list recall (WLR), Logical memory (LM) II, and Mini-Mental status examination (MMSE) in common, and Letter fluency test (LF), category fluency test, or Stroop color and word test, were selected. Results: Student t-tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two-year follow-up period between Aβ positive and negative group (p=0.03). Linear mixed model analyses also showed that the Aβ x time interaction effect was significant only for Composite 1 (p=0.025). Based on the results, Composite 1 was chosen as the final cognitive composite for preclinical Alzheimer’s disease (CPAD). Conclusions: CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in Korean older adults. It also may be used for monitoring progression or treatment benefits in clinical practices.

Anqi Li, Jing Du, Yue Cai, Xuhui Chen, Kun Sun, Tengfei Guo, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ling-Qiang Zhu)
Body Mass Index Decrease Has a Distinct Association with Alzheimer’s Disease Pathophysiology in APOE ε4 Carriers and Non-Carriers
Abstract: Background: Body mass index (BMI) changes may be related to Alzheimer’s disease (AD) alterations, but it is unclear how the apolipoprotein E ε4 (APOE ε4) allele affects their association. Objective: To explore the association of BMI changes with AD pathologies in APOE ε4 carriers and non-carriers. Methods: In 862 non-demented ADNI participants with ≥2 BMI measurements, we investigated the relationships between BMI slopes and longitudinal changes in amyloid-β (Aβ) accumulation, neurodegeneration and cognition, and follow-up tau deposition in different Aβ and APOE ε4 statuses. Results: In Aβ+ APOE ε4 non-carriers, faster BMI declines were associated with faster rates of Aβ accumulation (standardized β (βstd) = -0.29, p = 0.001), AD meta regions of interest (metaROI) hypometabolism (βstd = 0.23, p = 0.026), memory declines (βstd = 0.17, p = 0.029), executive function declines (βstd = 0.19, p = 0.011), and marginally faster Temporal-metaROI cortical thinning (βstd = 0.15, p = 0.067) and higher follow-up Temporal-metaROI tau deposition (βstd = -0.17, p = 0.059). Among Aβ- individuals, faster BMI decreases were related to faster Aβ accumulation (βstd = -0.25, p = 0.023) in APOE ε4 carriers, whereas predicted faster declines in memory and executive function in both APOE ε4 carriers (βstd = 0.25, p = 0.008; βstd = 0.32, p = 0.001) and APOE ε4 non-carriers (βstd = 0.11, p = 0.030; βstd = 0.12, p = 0.026). Conclusions: This study highlights the significance of tracking BMI data in older adults by providing novel insights into how body weight fluctuations and APOE ε4 interact with AD pathology and cognitive decline.

Igor Akushevich, Arseniy Yashkin, Svetlana Ukraintseva, Anatoliy I. Yashin, Julia Kravchenko
The Construction of a Multidomain Risk Model of Alzheimer’s Disease and Related Dementias
Abstract: Background: Alzheimer’s disease (AD) and related dementia (ADRD) risk is affected by multiple dependent risk factors; however, there is no consensus about their relative impact in the development of these disorders. Objective: To rank the effects of potentially dependent risk factors and identify an optimal parsimonious set of measures for predicting AD/ADRD risk from a larger pool of potentially correlated predictors. Methods: We used diagnosis record, survey, and genetic data from the Health and Retirement Study to assess the relative predictive strength of AD/ADRD risk factors spanning several domains: comorbidities, demographics/socioeconomics, health-related behavior, genetics, and environmental exposure. A modified stepwise-AIC-best-subset blanket algorithm was then used to select an optimal set of predictors. Results: The final predictive model was reduced to 10 features for AD and 19 for ADRD; concordance statistics were about 0.85 for one-year and 0.70 for ten-year follow-up. Depression, arterial hypertension, traumatic brain injury, cerebrovascular diseases, and the APOE4 proxy SNP rs769449 had the strongest individual associations with AD/ADRD risk. AD/ADRD risk-related co-morbidities provide predictive power on par with key genetic vulnerabilities. Conclusions: Results confirm the consensus that circulatory diseases are the main comorbidities associated with AD/ADRD risk and show that clinical diagnosis records outperform comparable self-reported measures in predicting AD/ADRD risk. Model construction algorithms combined with modern data allows researchers to conserve power (especially in the study of disparities where disadvantaged groups are often grossly underrepresented) while accounting for a high proportion of AD/ADRD-risk-related population heterogeneity stemming from multiple domains.

Xiaolei Han, Lin Song, Yuanjing Li, Yi Dong, Rui Liu, Qi Han, Xiaojie Wang, Ming Mao, Lin Cong, Shi Tang, Tingting Hou, Qinghua Zhang, Cuicui Liu, Xiaodong Han, Lin Shi, Lars Nyberg, Lenore J. Launer, Yongxiang Wang, Yifeng Du, Chengxuan Qiu
Accelerometer-Measured Sedentary Behavior Patterns, Brain Structure, and Cognitive Function in Dementia-Free Older Adults: A Population-Based Study
Abstract: Background: Sedentary behavior is associated with cognitive impairment, but the neuropathological mechanisms underlying their associations are poorly understood. Objective: To investigate the associations of accelerometer-measured sedentary behavior patterns with brain structure and cognition, and further to explore the potential mechanisms. Methods: This community-based study included 2,019 older adults (age ≥60 years, 59% women) without dementia derived from participants in the baseline examination of MIND-China (2018-2020). We assessed sedentary parameters using an accelerometer and cognitive function using a neuropsychological test battery. Structural brain markers were assessed on the structural brain MRI scans in a subsample (n=1,009). Data were analyzed using the general linear, isotemporal substitution, and mediation models. Results: In the total sample (n=2,019), adjusting for multiple covariates and moderate-to-vigorous-intensity physical activity, longer mean sedentary bout duration was linearly related with lower z-scores of global cognition, verbal fluency, and memory (ptrend<0.05), whereas greater total sedentary time was linearly associated with lower z-scores of global cognition, verbal fluency, and memory only among individuals with long sedentary time (>10 h/day) (ptrend<0.05); Breaking up sedentary time with same amount of light-intensity physical activity was significantly associated with higher verbal fluency and memory z-scores (p<0.05). In the MRI subsample (n=1,009), separately entering structural brain MRI markers into the mediation models substantially attenuated the associations of mean sedentary bout duration with global cognition, verbal fluency, and memory z-scores. Conclusions: Prolonged uninterrupted sedentary time is associated with poor global cognition, memory, and verbal fluency among rural older adults, and structural brain markers could partially mediate the association.

Jiwei Jiang*, Yin Hong*, Wenyi Li, Anxin Wang, Shirui Jiang, Tianlin Jiang, Yanli Wang, Linlin Wang, Shiyi Yang, Qiwei Ren, Xinying Zou, Jun Xu (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this study.
Chain Mediation Analysis of the Effects of Nutrition and Cognition on the Association of Apolipoprotein E ε4 with Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract: Background: Apolipoprotein E (APOE) is the most recognized risk gene for cognitive decline and clinical progression of late-onset Alzheimer’s disease (AD); nonetheless, its association with neuropsychiatric symptoms (NPSs) remains inconclusive. Objective: To investigate the association of APOE ε4 with NPSs and explore nutritional status and cognition as joint mediators of this association. Methods: Between June 2021 and October 2022, patients with amnestic mild cognitive impairment (aMCI) or AD were recruited from the Chinese Imaging, Biomarkers, and Lifestyle Study. NPSs were assessed using the Neuropsychiatric Inventory, while global cognition and nutritional status were evaluated using the Mini-Mental State Examination (MMSE) and Mini-Nutritional Assessment (MNA), respectively. Simple mediation and multiple chain mediation models were developed to examine the mediating effects of the MNA and MMSE scores on the relationship between APOE ε4 and specific neuropsychiatric symptom. Results: Among 310 patients, 229 (73.87%) had NPSs, and 110 (35.48%) carried APOE ε4. Patients with APOE ε4 were more likely to have hallucinations (p=0.014), apathy (p=0.008), and aberrant motor activity (p=0.018). MNA and MMSE scores mediated the association between APOE ε4 and hallucinations (17.97% and 37.13%, respectively), APOE ε4 and apathy (30.73% and 57.72%, respectively), and APOE ε4 and aberrant motor activity (17.82% and 34.24%), respectively. Chain-mediating effects of MNA and MMSE scores on the association of APOE ε4 with hallucinations, apathy, and aberrant motor activity after adjusting for confounding factors were 6.84%, 11.54%, and 6.19%, respectively. Conclusions: Nutritional status and cognition jointly mediate the association between APOE ε4 and neuropsychiatric symptoms in patients with aMCI or AD.

Ahmed A. Bahrani, Erin L. Abner, Charles S. DeCarli, Justin M. Barber, Abigail C. Sutton, Pauline Maillard, Francisco Sandoval, Konstantinos Arfanakis, Yung-Chuan Yang, Arnold M. Evia, Julie A. Schneider, Mohamad Habes, Crystal G. Franklin, Sudha Seshadri, Claudia L. Satizabal, Arvind Caprihan, Jeffrey F. Thompson, Gary A. Rosenberg, Danny J.J. Wang, Kay B. Jann, Chenyang Zhao, Hanzhang Lu, Paul B. Rosenberg, Marilyn S. Albert, Doaa G. Ali, Herpreet Singh, Kristin Schwab, Steven M. Greenberg, Karl G. Helmer, David K. Powel, Brian T. Gold, Larry B. Goldstein, Donna M. Wilcock, Gregory A. Jicha (Handling Associate Editor: Melissa Lamar)
Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol
Abstract: Background: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer’s Disease. Objective: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. Methods: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. Results: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p<0.028) but was not associated with WMH regression. Conclusions: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Nigel L. Kravatz, Dristi Adhikari, Emmeline Ayers, Joe Verghese
Prodromal Motoric Cognitive Risk Syndrome and Everyday Function
Abstract: Background: Motoric cognitive risk syndrome (MCR), a pre-dementia syndrome characterized by subjective cognitive complaints and slow gait, is associated with disability in instrumental activities of daily living. It is unknown whether these functional limitations occur even before this pre-dementia syndrome is diagnosed. Objective: To assess profiles of complex and instrumental activities of daily living in the prodromal stages of MCR. Methods: We examined functional profiles in 46 older adults (mean age 79 years, 59% women) living in the community with normal cognition at baseline who developed MCR over follow-up (‘pre-MCR’) with 264 older adults (mean age 75 years, 57% women) who remained cognitively intact over the follow-up period. Results: Pre-MCR individuals had more limitations on complex everyday function at baseline compared to normal controls in multivariable logistic regression models (odds ratio 1.21). Pre-MCR cases at baseline had limitations in handling finances (odds ratio 3.0) and performing hobbies (odds ratio 5.5) as compared to normal controls. Pre-MCR cases had a greater difference in the number of complex functional limitations from baseline to MCR compared to the difference from baseline to final visit for the controls (1.2±3.0 versus 0.5±2.2, p<0.001). Conclusions: Limitations in complex everyday tasks arise in the prodromal stages of MCR and can assist in risk prognostication.

Weiqi Xue, Weifeng He, Mengyuan Yan, Huanyi Zhao, Jianbin Pi
Exploring Shared Biomarkers of Myocardial Infarction and Alzheimer’s Disease via Single-Cell/Nucleus Sequencing and Bioinformatics Analysis
Abstract: Background: Patients are at increased risk of dementia, including Alzheimer’s disease (AD), after myocardial infarction (MI), but the biological link between MI and AD is unclear. Objective: To understand the association between the pathogenesis of MI and AD and identify common biomarkers of both diseases. Methods: Using public databases, we identified common biomarkers of MI and AD. Least absolute shrinkage and selection operator (LASSO) regression and protein-protein interaction (PPI) network were performed to further screen hub biomarkers. Functional enrichment analyses were performed on the hub biomarkers. Single-cell/nucleus analysis was utilized to further analyze the hub biomarkers at the cellular level in carotid atherosclerosis and AD datasets. Motif enrichment analysis was used to screen key transcription factors. Results: 26 common differentially expressed genes were screened between MI and AD. Function enrichment analyses showed that these differentially expressed genes were mainly associated with inflammatory pathways. A key gene, Regulator of G-protein Signaling 1 (RGS1), was obtained by LASSO regression and PPI network. RGS1 was confirmed to mainly express in macrophages and microglia according to single-cell/nucleus analysis. The difference in expression of RGS1 in macrophages and microglia between disease groups and controls was statistically significant (p < 0.0001). The expression of RGS1 in the disease groups was upregulated with the differentiation of macrophages and microglia. RelA was a key transcription factor regulating RGS1. Conclusions: Macrophages and microglia are involved in the inflammatory response of MI and AD. RGS1 may be a key biomarker in this process.

Qiang He, Wenjing Wang, Hao Li, Yang Xiong, Chuanyuan Tao, Lu Ma, Chao You (Handling Associate Editor: Liyong Wu)
Genetic Insights into the Risk of Metabolic Syndrome and Its Components on Dementia: A Mendelian Randomization
Abstract: Background: The role of metabolic syndrome (MetS) on dementia is disputed. Objective: We conducted a Mendelian randomization to clarify whether the genetically predicted MetS and its components are casually associated with the risk of different dementia types. Methods: The genetic predictors of MetS and its five components (waist circumference, hypertension, fasting blood glucose, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) come from comprehensive public genome-wide association studies (GWAS). Different dementia types are collected from the GWAS in the European population. Inverse variance weighting is utilized as the main method, complemented by several sensitivity approaches to verify the robustness of the results. Results: Genetically predicted MetS and its five components are not causally associated with the increasing risk of dementia (all p>0.05). In addition, no significant association between MetS and its components and Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and dementia due to Parkinson’s disease (all p>0.05), except the association between HDL-C and dementia with Lewy bodies. HDL-C may play a protective role in dementia with Lewy bodies (OR: 0.81, 95%CI: 0.72-0.92, p=0.0010). Conclusions: From the perspective of genetic variants, our study provides novel evidence that MetS and its components are not associated with different dementia types.

Alina Lee, Di Shan, David Castle, Tarek K. Rajji, Clement Ma
Landscape of Phase II Trials in Alzheimer’s Disease
Abstract: Background: Drug development in Alzheimer’s disease (AD) over the past two decades has had high rates of failure. Novel trial designs, such as adaptive designs, have the potential to improve the efficiency of drug development in AD. Objective: To evaluate the design characteristics, temporal trends, and differences in design between sponsor types in phase II trials of investigational agents in AD. Methods: Phase I/II, II, and II/III trials for AD with drug or other biological interventions registered from December 1996 to December 2021 in ClinicalTrials.gov were included. Descriptive statistics were used to summarize trial characteristics. Linear, logistic, and multinomial regression models assessed temporal trends and differences between sponsor types in design characteristics. Results: Of N=474 trials identified, randomized parallel group design was the most common design (72%). Only 12 trials (2.5%) used an adaptive design; adaptive features included early stopping rules, model-based dose-finding, adaptive treatment arm selection, and response adaptive randomization. The use of non-randomized parallel-group and open-label single arm designs increased over time. No temporal trend in the use of adaptive design was identified. Trials sponsored by industry only were more likely to use a randomized parallel-group design and have a larger estimated sample size than trials with other sponsor types. Conclusions: Our systematic review showed that very few phase II trials in AD used an adaptive trial design. Innovation and implementation of novel trial designs in AD trials can accelerate the drug development process.

Liss Elin Larsson, Rui Wang, Tommy Cederholm, Fleur Wiggenraad, Marie Rydén, Göran Hagman, Mai-Lis Hellénius, Miia Kivipelto, Charlotta Thunborg (Handling Associate Editor: Miguel Borda)
Association of Sarcopenia and Its Defining Components with the Degree of Cognitive Impairment in a Memory Clinic Population
Abstract: Background: Sarcopenia and cognitive impairment are two leading causes of disabilities. Objective: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients. Methods: 368 patients were included (age 59.0 ±7.25 years, women: 58.7%), displaying three clinical phenotypes of cognitive impairments, i.e., subjective cognitive impairment (SCI, 57%), mild cognitive impairment (MCI, 26%), and Alzheimer’s disease (AD, 17%). Sarcopenia was defined according to diagnostic algorithm recommended by the European Working Group on Sarcopenia in Older People. Components of sarcopenia were grip strength, bioelectrical impedance analysis, and gait speed. They were further aggregated into a score (0-3 points) by counting the numbers of limited components. Multi-nominal logistic regression was applied. Results: Probable sarcopenia (i.e., reduced grip strength) was observed in 9.6% of the patients, and 3.5% were diagnosed with sarcopenia. Patients with faster gait speed showed less likelihood of MCI (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.06-0.90) and AD (OR: 0.12, 95% CI: 0.03-0.60). One or more limited sarcopenia components was associated with worse cognitive function. After adjusting for potential confounders, the association remained significant only for AD (OR 4.29, 95% CI 1.45-11.92). Conclusions: The results indicate a connection between the sarcopenia components and cognitive impairments. Limitations in the sarcopenia measures, especially slow walking speed, were related to poorer cognitive outcomes. More investigations are required to further verify the causal relationship between sarcopenia and cognitive outcomes.

Minh Tuan Hoang, Ingemar Kåreholt, Pär Schön, Lena von Koch, Hong Xu, Edwin C.K Tan, Kristina Johnell, Maria Eriksdotter, Sara Garcia-Ptacek
The Impact of Educational Attainment and Income on Long-Term Care for Persons with Alzheimer’s Disease and Other Dementias: A Swedish Nationwide Study
Abstract: Background: Long-term care improves independence and quality of life of persons with dementia (PWD). The influence of socioeconomic status on access to long-term care was understudied. Objective: To explore the socioeconomic disparity in long-term care for PWD. Methods: This registry-based study included 14,786 PWD, registered in the Swedish registry for cognitive and dementia disorders (2014-2016). Education and income, two traditional socioeconomic indicators, were the main exposure. Outcomes were any kind of long-term care, specific types of long-term care (home care, institutional care), and the monthly average hours of home care. The association between outcomes and socioeconomic status was examined with zero-inflated negative binomial regression and binary logistic regression. Results: PWD with compulsory education had lower likelihood of receiving any kind of long-term care (OR 0.80, 95% CI 0.68-0.93), or home care (OR 0.83, 95% CI 0.70-0.97), compared to individuals with university degrees. Their monthly average hours of home care were 0.70 times (95% CI 0.59-0.82) lower than those of persons with university degrees. There was no significant association between education and the receipt of institutional care. Stratifying on persons with Alzheimer’s disease showed significant association between lower education and any kind of long-term care, and between income and the hours of home care. Conclusions: Socioeconomic inequalities in long-term care existed in this study population. Lower-educated PWD were less likely to acquire general long-term care, home care and had lower hours of home care, compared to their higher-educated counterparts. Income was not significantly associated with the receipt of long-term care.

Jing Li, Jordan Weiss, Ashish Rajadhyaksha, Daisy Acosta, Amal Harrati, Ivonne Z. Jiménez Velázquez, Mao-Mei Liu, Jorge J. Llibre Guerra, Juan de Jesús Llibre Rodriguez, William H. Dow
Dementia Attributable Healthcare Utilizations in the Caribbean versus United States
Abstract: Background: Despite the high burden of Alzheimer’s disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region. Objective: This study examines healthcare utilization associated with Alzheimer’s disease and other dementias among older adults in the Caribbean as compared to the US. Methods: We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined changes in hospital nights and physician visits in response to incident and ongoing dementias. Results: Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean. Conclusions: The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean.