Volume 97, Number 4, 2024

Pages 1479-1502

Koral V. Wheeler, Andrei Irimia, Meredith N. Braskie
Using Neuroimaging to Study Cerebral Amyloid Angiopathy and Its Relationship to Alzheimer’s Disease
Abstract: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β aggregation in the media and adventitia of the leptomeningeal and cortical blood vessels. CAA is one of the strongest vascular contributors to Alzheimer’s disease (AD). It frequently co-occurs in AD patients, but the relationship between CAA and AD is incompletely understood. CAA may drive AD risk through damage to the neurovascular unit and accelerate parenchymal amyloid and tau deposition. Conversely, early AD may also drive CAA through cerebrovascular remodeling that impairs blood vessels from clearing amyloid-β. Sole reliance on autopsy examination to study CAA limits researchers’ ability to investigate CAA’s natural disease course and the effect of CAA on cognitive decline. Neuroimaging allows for in vivo assessment of brain function and structure and can be leveraged to investigate CAA staging and explore its associations with AD. In this review, we will discuss neuroimaging modalities that can be used to investigate markers associated with CAA that may impact AD vulnerability including hemorrhages and microbleeds, blood-brain barrier permeability disruption, reduced cerebral blood flow, amyloid and tau accumulation, white matter tract disruption, reduced cerebrovascular reactivity, and lowered brain glucose metabolism. We present possible areas for research inquiry to advance biomarker discovery and improve diagnostics.

Pages 1503-1517

Guoliang Wei, Xuelong Tian, Hong Yang, Yinpei Luo, Guisong Liu, Shuqing Sun, Xing Wang, Huizhong Wen
Adjunct Methods for Alzheimer’s Disease Detection: A Review of Auditory Evoked Potentials
Abstract: The auditory afferent pathway as a clinical marker of Alzheimer’s disease (AD) has sparked interest in investigating the relationship between age-related hearing loss (ARHL) and AD. Given the earlier onset of ARHL compared to cognitive impairment caused by AD, there is a growing emphasis on early diagnosis and intervention to postpone or prevent the progression from ARHL to AD. In this context, auditory evoked potentials (AEPs) have emerged as a widely used objective auditory electrophysiological technique for both the clinical diagnosis and animal experimentation in ARHL due to their non-invasive and repeatable nature. This review focuses on the application of AEPs in AD detection and the auditory nerve system corresponding to different latencies of AEPs. Our objective was to establish AEPs as a systematic and non-invasive adjunct method for enhancing the diagnostic accuracy of AD. The success of AEPs in the early detection and prediction of AD in research settings underscores the need for further clinical application and study.

Pages 1519-1531

Xiaoyan Cui, Junqiao Wang, Bei Wu, Qianhua Zhao, Xueting Tang, Jing Wang
Interventions for Persons with Young-Onset Dementia and Their Families: A Scoping Review
Abstract: Background: Dementia occurring before age 65 is known as young-onset dementia (YOD), with Alzheimer’s disease being the most common type. YOD poses unique challenges for persons and families, impacting their working-age years and family responsibilities. Person-centered interventions and services are essential to improve their quality of life and social engagement. Objective: This study aims to synthesize non-pharmacological interventions for persons with YOD and their families to inform future targeted interventions. Methods: We conducted a systematic literature search across four databases: PubMed, PsycINFO, Scopus, and CINAHL. The included articles were carefully screened, categorized, and synthesized by following Arksey and O’Malley’s five stages framework. Results: We included 20 studies reported in 24 papers, with 11 studies (14 papers) on persons with YOD and nine studies (10 papers) on families. Quantitative intervention results vary, but qualitative interviews show positive feedback. Stakeholders provided positive evaluations, stating these interventions provided a sense of normalcy, facilitated communication among families, enhanced the independence of persons with YOD, and improved the families’ caregiving self-efficacy, thereby reducing care burden and psychological distress. The heterogeneity among the studies posed integration challenges. Conclusions: Interventions for YOD can improve the quality of life for both persons with YOD and their families. More extensive intervention studies are urgently needed, especially in developing countries, with a focus on family-centered and life course perspectives. In future intervention research design, a more extensive incorporation of stakeholder involvement is essential for successful implementation. Moreover, the integration of new technologies shows promise as a potential avenue for intervention advancement.

Pages 1535-1543

Veeda Michelle M. Anlacan*, Pamela Danielle T. Lanuza*, Anna Anjelica R. Sanchez, Roland Dominic G. Jamora *These authors contributed equally to this work.
Current Status and Challenges in Dementia Care in the Philippines: A Scoping Review
Abstract: Background: Dementia prevalence is increasing in low- and middle-income countries such as the Philippines. Objective: This study aimed to give an overview of dementia care in the Philippines and to identify gaps in terms of local epidemiology, research, financial coverage, diagnostics, pharmacotherapy, manpower, and caregiver support. Methods: This scoping review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines extension for scoping reviews. Six international and two local databases, and government and non-government websites were searched. Data published in the English or Filipino language on dementia epidemiology, research, diagnostics, management, manpower, and training were extracted from the earliest indexed record until June 2022. Results: The prevalence of dementia in the Philippines is high and research output on all aspects of dementia is low. Cost is a major barrier as health care coverage is limited, with reliance mainly on out-of-pocket payments, leading to challenges in the proper diagnosis and treatment of dementia. There is a low specialist-to-population ratio, with shortages beyond manpower and training. Conclusions: Gaps in dementia care include limited published local data, high healthcare costs, inadequate health financing, and limited manpower.

Pages 1545-1570

Haiqing Chang*, Erya Chen*, Tao Zhu, Jin Liu, Chan Chen (Handling Associate Editor: Ruth Peters) * These authors contributed equally to this work.
Communication Regarding the Myocardial Ischemia/Reperfusion and Cognitive Impairment: A Narrative Literature Review
Abstract: Coronary artery disease is a prevalent ischemic disease that results in insufficient blood supply to the heart muscle due to narrowing or occlusion of the coronary arteries. Various reperfusion strategies, including pharmacological thrombolysis and percutaneous coronary intervention, have been developed to enhance blood flow restoration. However, these interventions can lead to myocardial ischemia/reperfusion injury (MI/RI), which can cause unpredictable complications. Recent research has highlighted a compelling association between MI/RI and cognitive function, revealing pathophysiological mechanisms that may explain altered brain cognition. Manifestations in the brain following MI/RI exhibit pathological features resembling those observed in Alzheimer’s disease (AD), implying a potential link between MI/RI and the development of AD. The pro-inflammatory state following MI/RI may induce neuroinflammation via systemic inflammation, while impaired cardiac function can result in cerebral under-perfusion. This review delves into the role of extracellular vesicles in transporting deleterious substances from the heart to the brain during conditions of MI/RI, potentially contributing to impaired cognition. Addressing the cognitive consequence of MI/RI, the review also emphasizes potential neuroprotective interventions and pharmacological treatments within the MI/RI model. In conclusion, the review underscores the significant impact of MI/RI on cognitive function, summarizes potential mechanisms of cardio-cerebral communication in the context of MI/RI, and offers ideas and insights for the prevention and treatment of cognitive dysfunction following MI/RI.

Pages 1571-1580

Melissa J. Armstrong, Lisa L. Barnes (Handling Associate Editor: Carla Abdelnour)
Under-Diagnosis of Dementia with Lewy Bodies in Individuals Racialized as Black: Hypotheses Regarding Potential Contributors
Abstract: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias after Alzheimer’s disease (AD) dementia. DLB is under-diagnosed across populations but may be particularly missed in older Black adults. The object of this review was to examine key features of DLB and potential associations with race in order to hypothesize why DLB may be under-diagnosed in Black adults in the U.S. In terms of dementia, symptoms associated with high rates of co-pathology (e.g., AD, vascular disease) in older Black adults may obscure the clinical picture that might suggest Lewy body pathology. Research also suggests that clinicians may be predisposed to give AD dementia diagnoses to Black adults, potentially missing contributions of Lewy body pathology. Hallucinations in Black adults may be misattributed to AD or primary psychiatric disease rather than Lewy body pathology. Research on the prevalence of REM sleep behavior in diverse populations is lacking, but REM sleep behavior disorder could be under-diagnosed in Black adults due to sleep patterns or reporting by caregivers who are not bed partners. Recognition of parkinsonism could be reduced in Black adults due to clinician biases, cultural effects on self-report, and potentially underlying differences in the frequency of parkinsonism. These considerations are superimposed on structural and systemic contributions to health (e.g., socioeconomic status, education, structural racism) and individual-level social exposures (e.g., social interactions, discrimination). Improving DLB recognition in Black adults will require research to investigate reasons for diagnostic disparities and education to increase identification of core symptoms in this population.

Pages 1581-1588

Caleb E. Finch, Stanley M. Burstein
Dementia in the Ancient Greco-Roman World Was Minimally Mentioned
Abstract: Background: The possibility that Alzheimer’s disease and related dementias (ADRD) is a modern disease arises from the minimal mention of advanced cognitive decline by ancient Greeks and Romans, who were mainly concerned with the physical frailties of older ages. Objective: Because standard medical histories of elderly health lacked mention of cognitive decline, we examined texts by Greek and Roman authors that mentioned memory loss and dementia. Methods: Primary texts of Greco-Roman authors, 8th century BCE into the 3rd century CE, that mentioned cognitive decline were identified and critically evaluated. Secondary sources were excluded. Results: No ancient account of cognitive loss is equivalent to modern clinical data. The term dementia was occasionally used in antiquity, but not invariably linked to old age. Ancient Greeks and Romans expected intellectual competence beyond age 60. While some memory loss was acknowledged, we found only four accounts of severe cognitive loss that might represent ADRD. The possibility of modest ADRD prevalence in ancient Greece and Rome is consistent with its low prevalence in the Tsimane of Bolivia. These contemporary Amerindians live under conditions of high mortality from frequent infections and minimal cardiovascular disease with physically demanding lives. Tsimane after age 60 had increased mild cognitive impairment; the few cases of dementia were not clinically consistent with AD. Conclusions: The modern ‘epidemic level’ of advanced dementias was not described among ancient Greco-Roman elderly. The possible emergence of advanced ADRD in the Roman era may be associated with environmental factors of air pollution and increased exposure to lead. Further historical analysis may formulate critical hypotheses about the modernity of high ADRD prevalence.

Pages 1589-1620
Systematic Review

Jianhong Li*, Minguang Yang*, Renli Wei, Yue Cao, Xu Fan, Shenghang Zhang *These authors contributed equally to this work.
The Predictive Ability of Blood Neurofilament Light Chain in Predicting Cognitive Decline in the Alzheimer’s Disease Continuum: A Systematic Review and Meta-Analysis
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease with insidious onset. Identifying candidate predictors to forecast AD dementia risk before disease onset is crucial for early diagnosis and treatment. Objective: We aimed to assess the predictive ability of blood neurofilament light (NfL) chain in anticipating cognitive decline in the AD continuum. Methods: We systematically searched PubMed, Web of Science, and Embase from inception until April 7, 2023. Longitudinal observational studies examining the association between baseline blood NfL and cognitive decline or clinical disease conversion were included based on inclusion/exclusion criteria. The final effect size was represented by adjusted hazard ratios (HR) or standardized beta (s.β) coefficients with a 95% confidence interval (CI). Results: A total of 2,862 articles were identified, and 26 studies were included in this meta-analysis. The results indicated that baseline blood NfL could predict cognitive decline, with MMSE [s.β=-0.17, 95%CI (-0.26, -0.07)]; PACC [s.β=-0.09, 95%CI (-0.16, -0.03)]; ADAS-cog [s.β=0.21, 95%CI (0.13, 0.29)]; CDR-SOB [s.β=0.27, 95%CI (0.03, 0.50)]; Global cognitive composite [s.β=-0.05, 95%CI (-0.08, -0.01)]; Memory subdomain [s.β=-0.06, 95%CI (-0.09, -0.03)]; Language subdomain [s.β=-0.07, 95%CI (-0.10, -0.05)]; Executive function subdomain [s.β=-0.02, 95%CI (-0.03, -0.01)]; Visuospatial subdomain [s.β=-0.06, 95%CI (-0.08, -0.04)]. Additionally, baseline blood NfL could predict disease progression (conversion from CU/SCD/MCI to MCI/AD) in the AD continuum [Adjust HR=1.32, 95%CI (1.12, 1.56)]. Conclusions: Baseline blood NfL demonstrated predictive capabilities for global cognition and its memory, language, executive function, visuospatial subdomains decline in the AD continuum. Moreover, it exhibited the potential to predict disease progression in non-AD dementia participants.

Pages 1621-1627
Short Communication

Allison Caban-Holt, Michael L. Cuccaro, Shawnta L. Lloyd, Takiyah D. Starks, Larry D. Adams, Tayla Ford, Jonathan L. Haines, Gary Beecham, Christiane Reitz, Jeffery M. Vance, Margaret A. Pericak-Vance, Goldie Byrd
Attitudes and Perceptions about Brain Donation Among African Americans: Implications for Recruitment into Alzheimer’s Disease Research
Abstract: The objective of this study was to investigate attitudes toward brain donation and perceptions of medical research that influence brain donation among African Americans. Cross-sectional surveys were administered to African American community members (n=227). Findings indicate that only 27% of respondents were willing to donate their brain. As medical mistrust was not found to be a significant barrier to research participation, there may be opportunity to increase brain donation by providing information about Alzheimer’s disease and brain donation to potential donors and their families so that informed decisions about participating in research can be made.

Pages 1629-1639
Short Communication

Ana C. Valencia-Olvera, Deebika Balu, Annabelle Moore, Maitri Shah, Rebecca Ainis, Bingtao Xiang, Yaseen Saleh, Dongming Cai, Mary Jo LaDu, Leon M Tai
APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-β42 Levels in Non-Hyperlipidemic Mice
Abstract: APOE2 lowers Alzheimer’s disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-β peptide (Aβ) (EFAD) to evaluate the effect of APOE2 dosage on Aβ pathology. We found that heterozygous mice do not exhibit hyperlipidemia. Hippocampal but not cortical levels of soluble Aβ42 followed the order E2/2FAD>E2/3FAD<E3/3FAD and E2/2FAD>E2/4FAD<E4/4FAD without an effect on insoluble Aβ42. These findings offer initial insights on the impact of APOE2 on Aβ pathology.

Pages 1641-1643

Luigi Ferini-Strambi
Which Are the Most Reliable Sleep Parameters that Predict Cognitive Decline and Alzheimer’s Disease?Abstract: Sleep disorders can represent an independent risk factor for cognitive decline and Alzheimer’s disease (AD). It remains to be clarified if specific sleep parameters could be considered biomarkers of AD-related neurodegeneration. Several studies solely investigated the results of cross-sectional research, without providing conclusive evidence. Few longitudinal studies showed some inconsistencies in macrostructural and microstructural sleep findings. Methodological heterogeneity among studies can explain the discrepancies in the results. Moreover, the polysomnographic findings are usually related to only one-night recording. The combination of actigraphic recordings with sleep EEG monitoring for some consecutive days should be considered in future research.

Pages 1645-1660
Liyuan Jiao*, Ziye Jing*, Wenjie Zhang, Xuesen Su, Hualei Yan, Shouyuan Tian (Handling Associate Editor: Rekha Khandia) *These authors contributed equally to this work.
Codon Pattern and Context Analysis in Genes Triggering Alzheimer’s Disease and Latent Tau Protein Aggregation Post-Anesthesia Exhibited Unique Molecular Patterns Associated with Functional Aspects
Abstract: Background: Previous reports have demonstrated post-operative dementia and Alzheimer's disease (AD), and increased amyloid-β levels and tau hyperphosphorylation have been observed in animal models post-anesthesia. Objective: After surgical interventions, loss in memory has been observed that has been found linked with genes modulated after anesthesia. Present study aimed to study molecular pattern present in genes modulated post anesthesia and involved in characters progressing towards AD. Methods: In the present study, 17 transcript variants belonging to eight genes, which have been found to modulate post-anesthesia and contribute to AD progression, were envisaged for their compositional features, molecular patterns, and codon and codon context-associated studies. Results: The sequences' composition was G/C rich, influencing dinucleotide preference, codon preference, codon usage, and codon context. The G/C nucleotides being highly occurring nucleotides, CpGdinucleotides were also preferred; however, CpG was highly disfavored at p3-1 at the codon junction. The nucleotide composition of Cytosine exhibited a unique feature, and unlike other nucleotides, it did not correlate with codon bias. Contrarily, it correlated with the sequence lengths. The sequences were leucine-rich, and multiple leucine repeats were present, exhibiting the functional role of neuroprotection from neuroinflammation post-anesthesia. Conclusions: The analysis pave the way to elucidate unique molecular patterns in genes modulated during anesthetic treatment and might help ameliorate the ill effects of anesthetics in the future.

Pages 1661-1672
Lihua Chen, Meiwei Zhang, Weihua Yu, Juan Yu, Qiushi Cui, Chenxi Chen, Junjin Liu, Lihong Huang, Jiarui Liu, Wuhan Yu, Wenjie Li, Wenbo Zhang, Mengyu Yan, Jiani Wu, Xiaoqin Wang, Jiaqi Song, Fuxing Zhong, Xintong Liu, Xianglin Wang, Chengxing Li, Yuantao Tan, Jiangshan Sun, Wenyuan Li, Yang Lü
A Fully Automated Mini-Mental State Examination Assessment Model Using Computer Algorithms for Cognitive Screening
Abstract: Background: Rapidly growing healthcare demand associated with global population aging has spurred the development of new digital tools for the assessment of cognitive performance in older adults. Objective: To develop a fully automated Mini-Mental State Examination (MMSE) assessment model and validate the model’s rating consistency. Methods: The Automated Assessment Model for MMSE (AAM-MMSE) was an about 10-min computerized cognitive screening tool containing the same questions as the traditional paper-based Chinese MMSE. The validity of the AAM-MMSE was assessed in term of the consistency between the AAM-MMSE rating and physician rating. Results: A total of 427 participants were recruited for this study. The average age of these participants was 60.6 years old (ranging from 19 to 104 years old). According to the intraclass correlation coefficient (ICC), the interrater reliability between physicians and the AAM-MMSE for the full MMSE scale AAM-MMSE was high [ICC (2,1)=0.952; with its 95%CI of (0.883,0.974)]. According to the weighted kappa coefficients results the interrater agreement level for audio-related items showed high, but for items “Reading and obey”, “Three-stage command”, and “Writing complete sentence” were slight to fair. The AAM-MMSE rating accuracy was 87%. A Bland-Altman plot showed that the bias between the two total scores was 1.48 points with the upper and lower limits of agreement equal to 6.23 points and -3.26 points. Conclusions: Our work offers a promising fully automated MMSE assessment system for cognitive screening with pretty good accuracy.

Pages 1673-1683
Yuka Okinaka, Yoshiyuki Shinagawa, Carsten Claussen, Sheraz Gul, Ikuko Matsui, Yutaka Matsui, Akihiko Taguchi
RNA Analysis of Circulating Leukocytes in Patients with Alzheimer’s Disease
Abstract: Background: One of the key symptoms of Alzheimer’s disease (AD) is the impairment of short-term memory. Hippocampal neurogenesis is essential for short-term memory and is known to decrease in patients with AD. Impaired short-term memory and impaired neurogenesis are observed in aged mice alongside changes in RNA expression of gap junction and metabolism-related genes in circulating leukocytes. Moreover, after penetrating the blood-brain barrier via the SDF1/CXCR4 axis, circulating leukocytes directly interact with hippocampal neuronal stem cells via gap junctions. Objective: Evaluation of RNA expression profiles in circulating leukocytes in patients with AD. Methods: Patients with AD (MMSE≦23, n=10) and age-matched controls (MMSE≧28, n=10) were enrolled into this study. RNA expression profiles of gap junction and metabolism-related genes in circulating leukocytes were compared between the groups (jRCT: 1050210166). Results: The ratios of gap junction and metabolism-related genes were significantly different between patients with AD and age-matched controls. However, due to large inter-individual variations, there were no statistically significant differences in the level of single RNA expression between these groups. Conclusions: Our findings suggest a potential connection between the presence of circulating leukocytes and the process of hippocampal neurogenesis in individuals with AD. Analyzing RNA in circulating leukocytes holds promise as a means to offer novel insights into the pathology of AD, distinct from conventional markers.

Pages 1685-1687

Pasquale Mone, Antonio De Luca, Urna Kansakar, Gaetano Santulli
Leukocytes and Endothelial Cells Participate in the Pathogenesis of Alzheimer’s Disease: Identifying New Biomarkers Mirroring Metabolic Alterations
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder marked by amyloid-β accumulation, tau dysfunction, and neuroinflammation, involving endothelial cells and leukocytes. The breakdown of the blood-brain barrier allows immune cell infiltration, intensifying inflammation. A decreased ratio of Connexin-37 (Cx37, also known as GJA4: Gap Junction Protein Alpha 4) and Prolyl Hydroxylase Domain-Containing Protein 3 (PHD3, also known as EGLN3: Egl-9 Family Hypoxia Inducible Factor 3), Cx37/PHD3, consistently observed in different AD-related models, may represent a novel potential biomarker of AD, albeit the exact mechanisms underlying this phenomenon, most likely based on gap junction-mediated cellular interaction that modulate the cellular metabolite status, remain to be fully elucidated.

Pages 1689-1702
Alexander Ivan B. Posis, Aladdin H. Shadyab, Humberto Parada Jr., John E. Alcaraz, William S. Kremen, Linda K. McEvoy
Multimorbidity, Social Engagement, and Age-Related Cognitive Decline in Older Adults from the Rancho Bernardo Study of Healthy Aging
Abstract: Background: Multimorbidity is associated with increased rate of cognitive decline with age. It is unknown whether social engagement, which is associated with reduced risk of dementia, modifies associations between multimorbidity and cognitive decline. Objective: To examine the associations of multimorbidity with longitudinal cognitive test performance among community-dwelling older adults, and to determine whether associations differed by levels of social engagement. Methods: We used data from the Rancho Bernardo Study of Healthy Aging, a community-based prospective cohort study. Starting in 1992-1996, participants completed a battery of cognitive function tests at up to 6 study visits over 23.7 (mean=7.2) years. Multimorbidity was defined as ≥2 of 14 chronic diseases. Social engagement was assessed using items based on the Berkman-Syme Social Network Index. Multivariable linear mixed-effects models were used to test associations of multimorbidity and cognitive performance trajectories. Effect measure modification by social engagement was evaluated. Results: Among 1,381 participants (mean age=74.5 years; 60.8% women; 98.8% non-Hispanic White), 37.1% had multimorbidity and 35.1% had low social engagement. Multimorbidity was associated with faster declines in Mini-Mental State Examination (MMSE; β=-0.20; 95%CI -0.35, -0.04), Trail-Making Test Part B (β=10.02; 95%CI 5.77, 14.27), and Category Fluency (β=-0.42; 95%CI -0.72, -0.13) after adjustment for socio-demographic and health-related characteristics. Multimorbidity was associated with faster declines in MMSE among those with low compared to medium and high social engagement (p-interaction<0.01). Conclusions: Multimorbidity was associated with faster declines in cognition among community-dwelling older adults. Higher social engagement may mitigate multimorbidity-associated cognitive decline.

Pages 1703-1726
Suzanne M. de la Monte, Ming Tong
Agent Orange Herbicidal Toxin-Initiation of Alzheimer-Type Neurodegeneration
Abstract: Background: Agent Orange (AO) is a Vietnam War-era herbicide that contains a 1:1 ratio of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Emerging evidence suggests that AO exposures cause toxic and degenerative pathologies that may increase the risk for Alzheimer’s disease (AD). Objective: This study investigates the effects of the two main AO constituents on key molecular and biochemical indices of AD-type neurodegeneration. Methods: Long Evans rat frontal lobe slice cultures treated with 250 µg/ml of 2,4-D, 2,4,5-T, or both (D+T) were evaluated for cytotoxicity, oxidative injury, mitochondrial function, and AD biomarker expression. Results: Treatment with the AO constituents caused histopathological changes corresponding to neuronal, white matter, and endothelial cell degeneration, and molecular/biochemical abnormalities indicative of cytotoxic injury, lipid peroxidation, DNA damage, and increased immunoreactivity to activated Caspase 3, glial fibrillary acidic protein, ubiquitin, tau, paired-helical filament phosphorylated tau, AβPP, Aβ, and choline acetyltransferase. Nearly all indices of cellular injury and degeneration were more pronounced in the D+T compared with 2,4-D or 2,4,5-T treated cultures. Conclusions: Exposures to AO herbicidal chemicals damage frontal lobe brain tissue with molecular and biochemical abnormalities that mimic pathologies associated with early-stage AD-type neurodegeneration. Additional research is needed to evaluate the long-term effects of AO exposures in relation to aging and progressive neurodegeneration in Vietnam War Veterans.

Pages 1727-1735
Yi Jin Leow, See Ann Soo, Dilip Kumar, Fatin Zahra Binte Zailan, Gurveen Kaur Sandhu, Ashwati Vipin, Faith Phemie Hui En Lee, Smriti Ghildiyal, Shan Yao Liew, Chao Dang, Pricilia Tanoto, Isabelle Yu Zhen Tan, Wayne Freeman Weien Chong, Adnan Azam Mohammed, Kok Pin Ng, Nagaendran Kandiah
Mild Behavioral Impairment and Cerebrovascular Profiles Are Associated with Early Cognitive Impairment in a Community-Based Southeast Asian Cohort
Abstract: Background: Mild behavioral impairment (MBI) is one of the earliest observable changes when a person experiences cognitive decline and could be an early manifestation of underlying Alzheimer’s disease neuropathology. Limited attention has been given to investigating the clinical applicability of behavioral biomarkers for detection of prodromal dementia. Objective: This study compared the prevalence of self-reported MBI and vascular risk factors in Southeast Asian adults to identify early indicators of cognitive impairment and dementia. Methods: This cohort study utilized baseline data from the Biomarkers and Cognition Study, Singapore (BIOCIS). 607 participants were recruited and classified into three groups: cognitively normal (CN), subjective cognitive decline (SCD), and mild cognitive impairment (MCI). Group comparisons of cognitive-behavioral, neuroimaging, and blood biomarkers data were applied using univariate analyses. Multivariate logistic regression analyses were conducted to investigate the association between cerebrovascular disease, vascular profiles, and cognitive impairment. Results: SCD had significantly higher depression scores and poorer quality of life (QOL) compared to CN. MCI had significantly higher depression scores; total MBI symptoms, MBI-interest, MBI-mood, and MBI-beliefs; poorer sleep quality; and poorer QOL compared to CN. Higher Staals scores, glucose levels, and systolic blood pressure were significantly associated with MCI classification. Fasting glucose levels were significantly correlated with depression, anxiety, MBI-social, and poorer sleep quality. Conclusions: The results reflect current research that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. Self-reported questionnaires may aid in early diagnoses of prodromal dementia. Behavioral changes and diabetes could be potential targets for preventative healthcare for dementia.

Pages 1737-1749
Shengnan Zhang, Hongrui Ai, Jia Wang, Tiaotiao Liu, Xuyuan Zheng, Xin Tian, Wenwen Bai
Reduced Prefrontal-Thalamic Theta Flow During Working Memory Retrieval in APP/PS1 Mice
Abstract: Background: Working memory deficits in Alzheimer's disease (AD) are linked to impairments in the retrieval of stored memory information. However, research on the mechanism of impaired working memory retrieval in Alzheimer's disease is still lacking. Objective: The medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval. The purpose of this study is to investigate the functional interactions and information transmission between mPFC and MD in the AD model. Methods: We recorded local field potentials from mPFC and MD while the mice (APP/PS1 transgenic model and control) performed a T-maze spatial working memory task. The temporal dynamics of oscillatory activity and bidirectional information flow between mPFC and MD were assessed during the task phases. Results: We mainly found a significant decrease in theta flow from mPFC to MD in APP/PS1 mice during retrieval. Conclusions: Our results indicate an important role of the mPFC-MD input for retrieval and the disrupted information transfer from mPFC to MD may be the underlying mechanism of working memory deficits in APP/PS1 mice.

Pages 1751-1763
Pei Y. Ng, Cheng Zhang, Hu Li, Darren J. Baker
Senescence Targeting Methods Impact Alzheimer’s Disease Features in 3xTg Mice
Abstract: Background: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Objective: To investigate the effects of senescent cell clearance in the 3xTg mouse model. Methods: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC). Results: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease. Conclusions: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.

Pages 1765-1776
Anna-Leena Heikkinen, Teemu I. Paajanen, Tuomo Hänninen, Veera Tikkanen, Christer Hublin, Anne M. Koivisto, Anne M. Remes, Johanna Krüger
Neuropsychological Profiles, Etiologies, and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study
Abstract: Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of elderly patients, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting. Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset). Methods: The patients’ (n=210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n=55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n=35) or non-neurodegenerative (MCI-o, n=106) etiologies, and subjective cognitive decline (n=14). Results: The most prevalent diagnoses were Alzheimer’s disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p=0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p<0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p<0.05). Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.

Pages 1777-1792
Renée-Pier Filiou, Simona Maria Brambati, Maxime Lussier, Nathalie Bier
Speech Acts as a Window to the Difficulties in Instrumental Activities of Daily Living: A Qualitative Descriptive Study in Mild Neurocognitive Disorder and Healthy Aging
Abstract: Background: Executive functions (EF) are central to instrumental activities of daily living (IADL). A novel approach to the assessment of the impact of EF difficulties on IADL may be through the speech acts produced when performing IADL-inspired tasks in a laboratory-apartment. Speech acts may act as a window to the difficulties encountered during task performance. Objective: We aim to 1) qualitatively describe the speech acts produced by participants with mild neurocognitive disorder (mild NCD) and healthy controls (HC) as they performed 4 IADL-inspired tasks in a laboratory-apartment, and to then 2) compare their use in both groups. Methods: The participants’ performance was videotaped, and speech acts produced were transcribed. Qualitative description of all speech acts was performed, followed by a deductive-inductive pattern coding of data. Statistical analyses were performed to further compare their use by mild NCD participants and HC. Results: Twenty-two participants took part in the study (n mild NCD=11; n HC=11). Meta-categories of data emerged from pattern coding: strategies, barriers, reactions, and consequences. Mild NCD participants used significantly more strategies and barriers than did HC. They were more defensive of their performance, and more reactive to their difficulties than HC. Mild NCD participants’ verification of having completed all tasks was less efficient than controls. Conclusions: An assessment of speech acts produced during the performance of IADL-inspired tasks in a laboratory-apartment may allow to detect changes in the use of language which may reflect EF difficulties linked to cognitive decline.

Pages 1793-1806
Janna L. Harris, Xiaowan Wang, Sarah K. Christian, Lesya Novikova, Anuradha Kalani, Dongwei Hui, Sadie Ferren, Scott Barbay, Judit Perez Ortiz, Randolph J. Nudo, William M. Brooks, Heather M. Wilkins, Prabhakar Chalise, Mary Lou Michaelis, Elias K. Michaelis, Russell H. Swerdlow
Traumatic Brain Injury Alters the Trajectory of Age-Related Mitochondrial Change
Abstract: Background: Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer’s disease (AD). Objective: To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association. Methods: We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice. In the non-transgenics, we assessed behavior (1-5 days, 1 month, and 15 months), lesion size (1 and 15 months), respiratory chain enzymes (1 and 15 months), and mitochondrial DNA copy number (mtDNAcn) (1 and 15 months) after CCI/sham. In the transgenics we quantified post-injury mtDNAcn and tangle burden. Results: In the non-transgenics CCI caused acute behavioral deficits that improved or resolved by 1-month post-injury. Protein-normalized complex I and cytochrome oxidase activities were not significantly altered at 1 or 15 months, although complex I activity in the CCI ipsilesional cortex declined during that period. Hippocampal mtDNAcn was not altered by injury at 1 month, increased with age, and rose to the greatest extent in the CCI contralesional hippocampus. In the injured then aged transgenics, the ipsilesional hippocampus contained less mtDNA and fewer tangles than the contralesional hippocampus; mtDNAcn and tangle counts did not correlate. Conclusions: As mice age their brains increase mtDNAcn as part of a compensatory response that preserves mitochondrial function, and TBI enhances this response. TBI may, therefore, increase the amount of compensation required to preserve late-life mitochondrial function. If TBI does modify AD risk, altering the trajectory or biology of aging-related mitochondrial changes could mediate the effect.

Pages 1807-1827
Yulin Dai*, Yu-Chun Hsu*, Brisa S. Fernandes, Kai Zhang, Xiaoyang Li, Nitesh Enduru, Andi Liu, Astrid M Manuel, Xiaoqian Jiang, Zhongming Zhao, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Disentangling Accelerated Cognitive Decline from the Normal Aging Process and Unraveling Its Genetic Components: A Neuroimaging-Based Deep Learning Approach
Abstract: Background: The progressive cognitive decline, an integral component of Alzheimer’s disease (AD), unfolds in tandem with the natural aging process. Neuroimaging features have demonstrated the capacity to distinguish cognitive decline changes stemming from typical brain aging and AD between different chronological points. Objective: To disentangle the normal aging effect from the AD-related accelerated cognitive decline and unravel its genetic components using a neuroimaging-based deep learning approach. Methods: We developed a deep-learning framework based on a dual-loss Siamese ResNet network to extract fine-grained information from the longitudinal structural magnetic resonance imaging (MRI) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. We then conducted genome-wide association studies (GWAS) and post-GWAS analyses to reveal the genetic basis of AD-related accelerated cognitive decline. Results: We used our model to process data from 1,313 individuals, training it on 414 cognitively normal people and predicting cognitive assessment for all participants. In our analysis of accelerated cognitive decline GWAS, we identified two genome-wide significant loci: APOE locus (chromosome 19 p13.32) and rs144614292 (chromosome 11 p15.1). Variant rs144614292 (G>T) has not been reported in previous AD GWA studies. It is within the intronic region of NELL1, which is expressed in neurons and plays a role in controlling cell growth and differentiation. The cell-type-specific enrichment analysis and functional enrichment of GWAS signals highlighted the microglia and immune-response pathways. Conclusions: Our deep learning model effectively extracted relevant neuroimaging features and predicted individual cognitive decline. We reported a novel variant (rs144614292) within the NELL1 gene.

Pages 1829-1840
Robin Jeanna Vermeulen, Bram Roudijk, Tim Martin Govers, Maroeska Mariet Rovers, Marcel Gerardus Maria Olde Rikkert, Ben Franciscus Martinus Wijnen
Prognostic Information on Progression to Dementia: Quantification of the Impact on Quality of Life
Abstract: Background: The increasing interest in early identification of people at risk of developing dementia, has led to the development of numerous models aimed at estimating the likelihood of progression from mild cognitive impairment (MCI) to dementia. It is important to study both the need for and possible outcomes related with such prediction models, including the impact of risk predictions on perceived quality of life (QoL). Objective: This study aimed to quantify the impact that receiving a risk prediction on progression from MCI to dementia has on QoL. Methods: A Discrete Choice Experiment (DCE) and Time Trade Off (TTO) study were performed. Participants completed choice tasks related to dementia prognosis while imagining having MCI. We collected DCE data by an online survey, and TTO data via videoconferencing interviews. DCE data were analyzed using a mixed multinomial logit model and were anchored to a health state utility scale using mean observed TTO valuations. Results: 296 people participated in the DCE and 42 in the TTO. Moderate and high predicted dementia risks were associated with decrements in utility (-0.05 and -0.18 respectively), compared to no prognostic information. Low predicted risk was associated with an increase in utility (0.06), as well as the availability of medication or lifestyle interventions (0.05 and 0.13 respectively). Conclusions: This study shows a significant impact of dementia risk predictions on QoL and highlights the importance of caution when sharing information about expected MCI disease courses.

Pages 1841-1850
Erika Vestin, Gustaf Boström, Jan Olsson, Fredrik Elgh, Lars Lind, Lena Kilander, Hugo Lövheim, Bodil Weidung
Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study
Abstract: Background: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer’s disease (AD). Objective: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to anti-herpesvirus treatment and potential APOE ε4 carriership interaction. Methods: This study was conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001–2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied. Results: Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ε4 or anti-CMV IgG. Similar results were obtained for HSV-1. Conclusions: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.

Pages 1851-1860
Isabel J. Sible, Daniel A. Nation
Blood Pressure Variability and Plasma Alzheimer’s Disease Biomarkers in the SPRINT Trial
Abstract: Background: Recent observational studies suggest higher blood pressure (BP) variability (BPV) is associated with Alzheimer’s disease (AD) biomarkers amyloid-beta (Aβ) and tau. Less is known about relationships in interventional cohorts with strictly controlled mean BP levels. Objective: Investigate the longitudinal relationship between BPV and change in plasma AD biomarkers under standard versus intensive BP treatment. Methods: In this post hoc analysis of the SPRINT trial, 457 participants (n = 206 in standard group, n = 251 in intensive group) underwent repeated BP measurement between baseline and 12-months follow-up, and venipuncture at baseline and median (IQR) 3.5 (3.0 – 4.0) years later to determine plasma AD biomarkers total tau and Aβ1-42:Aβ1-40 ratio. BPV was calculated as tertiles of variability independent of mean. Linear mixed models investigated the effect of BPV x time on AD biomarker levels. Results: Higher BPV was associated with increased levels of total tau in the standard group (β [95% CI] 1st versus 3rd tertiles of BPV: 0.21 [0.02, 0.41], p = 0.035), but not in the intensive group (β [95% CI] 1st versus 3rd tertiles of BPV: -0.02 [-0.19, 0.16], p = 0.843). BPV was not associated with Aβ1-42:Aβ1-40 ratio in either group. Mean BP was not associated with biomarkers. Conclusions: Higher BPV was associated with increased plasma total tau under standard BP treatment. Findings add new evidence to prior observational work linking BPV to AD pathophysiology and suggest that, despite strict control of mean BP, BPV remains a risk for pathophysiological change underlying risk for AD.

Pages 1861-1875
Xiaoyu Zhang, Mohammad Haeri, Russell H. Swerdlow, Ning Wang
Loss of Adaptive DNA Breaks in Alzheimer’s Disease Brains
Abstract: Background: DNA breaks accumulate in Alzheimer’s disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. Conclusions: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

Pages 1877-1887
Yinlian Han, Mu Yang, Min Tian, Yang Yang, Wen Liu, Yiming Liu
The Relationship Between Fermented Dairy Consumption with Cognitive Function Among Older US Adults: Data from the NHANES 2011-2014
Abstract: Background: The aging global population has led to an increased burden of cognitive impairment in older adults. Objective: This study examined the relationship between fermented dairy intake and cognitive function in this population. Methods: Yogurt, cheese, and fermented dairy consumption were assessed through two 24-hour dietary recall interviews, categorized into low, medium, and high intake groups. Multivariate linear regression was employed to examine the relationship between fermented dairy intake and cognitive tests, including the Alzheimer’s Disease Word Learning Immediate Recall Test (CERAD-IRT), CERAD Delayed Recall Test (CERAD-DRT), Animal Fluency Test (AFT), Digit Symbol Substitution Test (DSST), and global cognitive z-scores, adjusting for potential confounding factors. Results: The study comprised 2,462 participants (average age 69.34±6.75 years, 52.07% female). Among yogurt consumers, global cognition and AFT z-scores are notably higher than non-consumers. Conversely, individuals who consume cheese display significantly lower CERAD-DRT z-scores. Compared to participants not intake fermented dairy, consumers of fermented dairy show significantly higher AFT and DSST z-scores and lower CERAD-DRT z-scores. Moreover, when categorizing individuals based on their intake of fermented dairy, those with low and medium consumption show significantly higher AFT and DSST z-scores, as well as significantly lower CERAD-DRT z-scores compared to non-consumers. Conclusions: Our study suggests that moderate consumption of fermented dairy products is associated with better executive function and verbal fluency in the elderly.

Pages 1889-1900
Lucas Gephine, Candice M. Roux, Thomas Freret, Michel Boulouard, Marianne Leger
Vulnerability of Spatial Pattern Separation in 5xFAD Alzheimer’s Disease Mouse Model
Abstract: Background: Alzheimer's disease (AD) is the most common cause of dementia and remains incurable. This age-related neurodegenerative disease is characterized by an early decline in episodic and spatial memory associated with progressive disruption of the hippocampal functioning. Recent clinical evidence suggests that impairment of the spatial pattern separation (SPS) function, which enables the encoding and storage of episodic spatial information, may be an indicator of the early stages of AD. Objective: The aim of our study was to characterize SPS performance at a prodromal stage in 5xFAD transgenic mouse model of AD. Methods: Behavioral performance of male wild-type (WT) and 5xFAD mice (n=14 per group) was assessed from the age of 4 months in two validated paradigms of SPS function either based on spontaneous exploration of objects or on the use of a touchscreen system. Results: Compared with age-matched WT littermates, a mild deficit in SPS function was observed in the object recognition task in 5xFAD mice, whereas both groups showed similar performance in the touchscreen-based task. These results were observed in the absence of changes in locomotor activity or anxiety-like behavior that could have interfered with the tasks assessing SPS function. Conclusions: Our results indicate an early vulnerability of the SPS function in 5xFAD mice in the paradigm based on spontaneous exploration of objects. Our work opens up the possibility of examining the early neurobiological processes involved in the decline of episodic memory and may help to propose new therapeutic strategies in the context of AD.

Pages 1901-1911
Renee C. Groechel, Albert C. Liu, Silvia Koton, Anna M. Kucharska-Newton, Pamela L. Lutsey, Thomas H. Mosley Jr., Priya Palta, A. Richey Sharrett, Keenan A. Walker, Dean F. Wong, Rebecca F. Gottesman (Handling Associate Editor: Mariagnese Barbera)
Associations Between Mid-Life Psychosocial Measures and Estimated Late Life Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study
Abstract: Background: Psychosocial factors are modifiable risk factors for Alzheimer’s disease (AD). One mechanism linking psychosocial factors to AD risk may be through biological measures of brain amyloid; however, this association has not been widely studied. Objective: To determine if mid-life measures of social support and social isolation in the Atherosclerosis Risk in Communities (ARIC) Study cohort are associated with late life brain amyloid burden, measured using florbetapir positron emission tomography (PET). Methods: Measures of social support and social isolation were assessed in ARIC participants (visit 2: 1990-1992). Brain amyloid was evaluated with florbetapir PET standardized uptake value ratios (SUVRs; visit 5: 2012-2014). Results: Among 316 participants without dementia, participants with intermediate (odds ratio (OR), 0.47; 95% CI, 0.25 – 0.88), or low social support (OR, 0.43; 95% CI, 0.22 – 0.83) in mid-life were less likely to have elevated amyloid SUVR, relative to participants with high social support. Participants with moderate risk for social isolation in mid-life (OR, 0.32; 95% CI, 0.14 – 0.74) were less likely to have elevated amyloid burden than participants at low risk for social isolation. These associations were not significantly modified by sex or race. Conclusions: Lower social support and moderate risk of social isolation in mid-life were associated with lower odds of elevated amyloid SUVR in late life, compared to participants with greater mid-life psychosocial measures. Future longitudinal studies evaluating mid-life psychosocial factors, in relation to brain amyloid as well as other health outcomes, will strengthen our understanding of the role of these factors throughout the lifetime.

Pages 1913-1922
Da Li*, Yan Sun*, Lin Ding, Yan Fu, Jie Zhou, Jin-Tai Yu, Lan Tan, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Associations of Growth-Associated Protein 43 with Cerebral Microbleeds: A Longitudinal Study
Abstract: Background: Cerebral microbleeds (CMB) play an important role in neurodegenerative pathology. Objective: The present study aims to test whether cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) level is linked to CMBs in elderly people. Methods: A total of 750 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had measurements of GAP-43 and CMBs were included in the study. According to the presence and extent of CMBs, participants were stratified into different groups. Regression analyses were used to assess cross-sectional and longitudinal associations between GAP-43 and CMBs. Results: Participants with CMB were slightly older and had higher concentrations of CSF GAP43. In multivariable adjusted analyses for age, gender, APOE ε4 status, and cognitive diagnoses, higher CSF GAP-43 concentrations were modestly associated with CMB presence (OR = 1.169, 95% CI = 1.001-1.365) and number (β = 0.020, SE = 0.009, p = 0.027). Similarly, higher CSF GAP43 concentrations were accrual of CMB lesions, associated with higher CMB progression (OR = 1.231, 95% CI = 1.044-1.448) and number (β = 0.017, SE =0.005, p = 0.001) in the follow up scan. In stratified analyses, slightly stronger associations were noted in male participants, those 65 years and older, carriers of APOE ε4 alleles, and with more advanced cognitive disorders. Conclusions: CSF GAP-43 was cross-sectionally associated with the presence and extent of CMBs. GAP-43 might be used as a biomarker to track the dynamic changes of CMBs in elderly persons.

Pages 1923-1930
MariaVelia Giulietti, Paolo Fabbietti, Roberta Spatuzzi, Anna Vespa
Effects of Mindfulness Based Interventions in Adults and Older Adults Caregivers of Patients with Early Stage Alzheimer’s Disease: A Randomized Pilot Study
Abstract: Background: Many studies have highlighted the effect of training with mindfulness-based interventions (MBIs) on the psycho-physical rebalancing of patients suffering from various pathologies, and their families. Objective: In this study, the effect of a training with mindfulness-based stress reduction (MBSR) on quality of life and emotion regulation (depression) was verified in caregivers (CGs) of patients affected by Alzheimer’s disease at early stage (AD-P). Methods: In this randomized controlled study, 22 CGs (age ≥ 60 years) were treated with MBIs, in particular MBSR, and 22 CGs had no treatment. Tests (T0-T1 six months) included: SF 36-Quality of Life (QoL); Caregiver Burden Inventory (CBI); FACIT-Spiritual-Well-Being; Beck Depression Inventory (BDI); Everyday Cognition scales; and Mini-Mental State Examination (for AD-P). Results: Significant differences emerged between T0 and T1 for CGs with MBSR in the following dimensions: Depression-BDI (p>0.001), Burden CBI-Total (0.001), CBI-Time dependent burden (p<0.001), CBI-Developmental burden (p<0.001), CBI-Physical burden (p<0.001); and pain (p=0.002) all decreased; while CBI-Social burden (p=0.004), QoL-Health Role Limitation (p<0.000), QoL-Role-Limitation-Emotional-Problem (p<0.000), QoL-Energy-fatigue (p<0.000), QoL-Emotional Well-Being (p<0.001), QoL-Social Well Being (p=0.010), and QoL-General Health (p=0.004) increased. The control group of untreated CG showed a significant worsening in the dimensions of Physical functioning (p=0.036) and pain (p=0.047). Conclusions: AD-CGs treated with MBI reduced their burden and depression and experienced an improvement in all the dimensions of quality of life.

Pages 1931-1937
Annette M. Bachand, Linda D. Dell
Can Incorrect Analysis of Time-Dependent Exposure Explain Associations between PM2.5 Exposure and Risk of Dementia?
Abstract: Background: Epidemiological studies have reported positive associations between long-term exposure to particulate matter of 2.5 microns or less in diameter (PM2.5) and risk of Alzheimer’s disease and other clinical dementia. Many of these studies have analyzed data using Cox Proportional Hazards (PH) regression, which estimates a hazard ratio (HR) for the treatment (in this case, exposure) effect on the time-to-event outcome while adjusting for influential covariates. PM 2.5 levels vary over time. As air quality standards for PM 2.5 have become more stringent over time, average outdoor PM 2.5 levels have decreased substantially. Objective: Investigate whether a Cox PH analysis that does not properly account for exposure that varies over time could produce an HR of similar magnitude to the HRs reported in recent epidemiological studies of PM2.5 and dementia risk. Methods: Simulation analysis. Results: We found that the resulting bias can affect statistical analyses that consider exposure levels at event times only, especially if PM2.5 levels decreased consistently over time. Furthermore, the direction of such bias is away from the null and of a magnitude that is consistent with the reported estimates of dementia risk in several epidemiological studies of PM2.5 exposure (HR≈1.2 to 2.0). Conclusions: This bias can be avoided by correctly assigning exposure to study subjects throughout the entire follow-up period. We recommend that investigators provide a detailed description of how time-dependent exposure variables were accounted for in their Cox PH analyses when they report their results.

Pages 1939-1950
Jiseung Kang, Mincheol Park, Tae Kim
Vitamin D Reduces GABA-Positive Astrocytes in the 5xFAD Mouse Model of Alzheimer’s Disease
Abstract: Background: Vitamin D has neuroprotective and immunomodulating functions that may impact glial cell function in the brain. Previously, we reported molecular and behavioral changes caused by deficiency and supplementation of vitamin D in an Alzheimer’s disease (AD) mouse model. Recent studies have highlighted reactive astrocytes as a new therapeutic target for AD treatment. However, the mechanisms underlying the therapeutic effects of vitamin D on the glial cells of AD remain unclear. Objective: To investigate the potential association between vitamin D deficiency/supplementation and the pathological progression of AD, including amyloid-β (Aβ) pathology and reactive astrogliosis. Methods: Transgenic hemizygous 5XFAD male mice were subjected to different dietary interventions and intraperitoneal vitamin D injections to examine the effects of vitamin D deficiency and supplementation on AD. Brain tissue was then analyzed using immunohistochemistry for Aβ plaques, microglia, and astrocytes, with quantifications performed via ImageJ software. Results: Our results demonstrated that vitamin D deficiency exacerbated Aβ plaque formation and increased GABA-positive reactive astrocytes in AD model mice, while vitamin D supplementation ameliorated these effects, leading to a reduction in Aβ plaques and GABA-positive astrocytes. Conclusions: Our findings highlight the significant impact of vitamin D status on Aβ pathology and reactive astrogliosis, underscoring its potential role in the prevention and treatment of AD. This study provides the first in vivo evidence of the association between vitamin D and reactive astrogliosis in AD model mice, indicating the potential for targeting vitamin D levels as a novel therapeutic approach for AD.

Pages 1951-1960
Teruyuki Matsuoka, Zahinoor Ismail, Ayu Imai, Keisuke Shibata, Kaeko Nakamura, Yukihide Nishimura, Ellen Rubinstein, Hiroyuki Uchida, Masaru Mimura, Jin Narumoto (Handling Associate Editor: Carlo Abbate)
Relationship Between Loneliness and Mild Behavioral Impairment: Validation of the Japanese Version of the MBI Checklist and a Cross-Sectional Study
Abstract: Background: Mild behavioral impairment (MBI) and loneliness are associated with cognitive decline and an increased risk of dementia. Objective: Our aim was to examine the validity of the Japanese version of the MBI checklist (MBI-C) and investigate the relationship between loneliness and MBI. Methods: The participants in this cross-sectional study included 5 cognitively normal persons and 75 persons with mild cognitive impairment. MBI-C and the revised University of California at Los Angeles loneliness scale (LS) were used to assess MBI and loneliness, respectively. Diagnostic performance of MBI-C was examined using receiver operating characteristic analysis. The relationship between MBI-C and LS was examined using multiple linear regression in 67 subjects who were assessed with both scales, with MBI-C total or domain score as the dependent variable and LS as the independent variable, adjusted for age, gender, living situation, presence of visual and hearing impairment, and Mini-Mental State Examination score. Results: Per the Youden index, in this mostly MCI sample, the optimal MBI-C cut-off score was 5.5 with sensitivity 0.917 and specificity 0.949. In multiple linear regression analysis, LS score was detected as a significant predictor of MBI-C total scores, and MBI-C decreased motivation, affective dysregulation, and abnormal thought and perception scores. Conclusions: The caregiver-rated Japanese MBI-C has excellent diagnostic performance. Loneliness is associated with a greater MBI burden, especially in the decreased motivation, affective dysregulation, and abnormal thought and perception domains. Interventions for loneliness in older people may have the potential to improve MBI.

Pages 1961-1970
Thanos Chatzikostopoulos, Moses Gialaouzidis, Anna Koutoupa, Magda Tsolaki
The Effects of Pomegranate Seed Oil on Mild Cognitive Impairment
Abstract Background: In recent years, there has been a growing interest, supported by many experimental and clinical studies, about the benefits of pomegranate in preventing various pathologic conditions, including brain neurodegeneration. The pomegranate seed oil (PSO) contains high levels of fatty acids that have antioxidant and anti-inflammatory properties. Objective: Due to the lack of clinical trials, the aim of the present study was to investigate the effects of PSO on cognition of people with mild cognitive impairment (MCI). Methods: Eighty people with the diagnosis of MCI were randomized forty to take 5 drops of PSO and follow the Mediterranean Diet (MeDi) and forty just followed MeDi. All were examined with an extensive neuropsychological assessment before and after one year of treatment. Results: The results showed that the participants who took the PSO had statistically significantly better global cognition (p=0.004), verbal episodic memory (p=0.009), and processing and executive functions (p<0.001) in contrast with the participants who did not take it. Conclusions: In conclusion, the PSO can be beneficial for people with MCI as it is helpful for some important cognitive domains. As PSO is a natural product that does not burden the human body, it can be used by people with MCI and be a significant and promising part of holistic approaches for the prevention of dementia.