Volume 97, Number 3, 2024

Pages 977-1005

Josue Valentin-Escalera, Manon Leclerc, Frédéric Calon (Handling Associate Editor: Francesco Panza)
High-Fat Diets in Animal Models of Alzheimer’s Disease: How Can Eating Too Much Fat Increase Alzheimer’s Disease Risk?
Abstract: High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as >35% of fat/weight and western diets containing >1% cholesterol or >15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance has been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD.

Pages 1007-1031

Ernest Amponsah Asiamah, Baofeng Feng, Ruiyun Guo, Xu Yaxing, Xiaofeng Du, Xin Liu, Jinyu Zhang, Huixian Cui, Jun Ma
The Contributions of the Endolysosomal Compartment and Autophagy to APOE ε4 Allele-Mediated Increase in Alzheimer’s Disease Risk
Abstract: Apolipoprotein E4 (APOE4), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer’s disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4-mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aβ accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4-mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals.

Pages 1033-1050

Yuru Han*, Congying Huang*, Yuhui Pan, Xuefeng Gu *These authors contributed equally to this work.
Single Cell Sequencing Technology and Its Application in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) involves degeneration of cells in the brain. Due to insidious onset and slow progression, AD is often not diagnosed until it gets progressed to a more severe stage. The diagnosis and treatment of AD has been a challenge. In recent years, high-throughput sequencing technologies have exhibited advantages in exploring the pathogenesis of diseases. However, the types of cells of the central nervous system are complex and traditional bulk sequencing cannot reflect their heterogeneity. Single-cell sequencing technology enables study at the individual cell level and has an irreplaceable advantage in the study of complex diseases. In recent years, this field has expanded rapidly and several types of single-cell sequencing technologies have emerged, including transcriptomics, epigenomics, genomics and proteomics. This review article provides an overview of these single-cell sequencing technologies and their application in AD.

Pages 1051-1068

Pengyang Du, Xiaomin Zhang, Xia Lian, Christian Hölscher, Guofang Xue
O-GlcNAcylation and Its Roles in Neurodegenerative Diseases
Abstract: As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation’s roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulate characteristic pathological protein toxicity and affect disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.

Pages 1069-1081

Jonathan Stone, John Mitrofanis, Daniel M. Johnstone, Stephen R. Robinson
The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer’s Disease
Abstract: This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent of the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer's disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid-β (Aβ), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of Aβ (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and Aβ; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, Aβ expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.

Pages 1083-1090
Ethics Review

Julie M. Robillard, Mario Masellis, Susanna E. Martin, Ara S. Khachaturian, Roger A. Dixon
The Return of Biomarker Results in Research: Balancing Complexity, Precision, and Ethical Responsibility
Abstract: Recent research aimed at the discovery, integration, and communication of health outcome measures (or “biomarkers”) in Alzheimer’s disease has raised challenging questions related to whether, how and when results from these investigations should be disclosed to research participants. Reflecting the apparent heterogeneity of many neurodegenerative diseases, biomarker or other risk factor results are often probabilistic, interactive, multi-modal, and selective. Such characteristics make it very complex to summarize and communicate to clinicians, researchers, and research participants. Whereas the format and content of academic literature is well-managed by the peer-review process, reporting individualized results to participants involves complex, sensitive, and ethical considerations. This paper describes three key factors to consider in decisions about the return of results to research participants: complexity, precision, and responsibility. The paper also presents six practical recommendations for implementing meaningful and ethical communication with research participants.

Pages 1091-1096
Short Communication

Laura Fort-Aznar, Laura Molina-Porcel, Oscar Ramos-Campoy, Diana Esteller, Laura Naranjo, Albert Lladó, Mircea Balasa, Raquel Ruiz-García, Anna Antonell, Raquel Sánchez-Valle
Misfolded α-Synuclein in Autosomal Dominant Alzheimer’s Disease
Abstract: We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer’s disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD.

Pages 1097-1100

Silvia Ottaviani, Fiammetta Monacelli
Rethinking Dementia Risk Prediction: A Critical Evaluation of a Multimodal Machine Learning Predictive Model
Abstract: A recent study by Ding et al. explores the integration of artificial intelligence (AI) in predicting dementia risk over a 10-year period using a multimodal approach. While revealing the potential of machine learning models in identifying high-risk individuals through neuropsychological testing, MRI imaging, and clinical risk factors, the imperative of dynamic frailty assessment emerges for accurate late-life dementia prediction. The commentary highlights challenges associated with AI models, including dimensionality and data standardization, emphasizing the critical need for a dynamic, comprehensive approach to reflect the evolving nature of dementia and improve predictive accuracy.

Pages 1101-1104

Maria Clara Selles, Mauricio Martins Oliveira
The Oxytocin Puzzle: Unlocking Alzheimer's Disease
Abstract: Alzheimer’s disease is a multi-factorial disease that disrupts many aspects of human behavior. In this comment, we highlight the work by Koulousakis et al. published in a recent issue of the Journal of Alzheimer’s Disease. In this study, the authors tested the therapeutic potential of the neuropeptide oxytocin in a pre-clinical model of Alzheimer’s disease and found positive behavioral outcomes on memory assessments. We discuss these findings in the context of oxytocin research in the field of Alzheimer’s disease and the literature regarding oxytocin-based therapeutics, including administration protocols and potential underlying cellular and molecular mechanisms.

Pages 1105-1109

Susanna E. Martin, Mallorie T. Tam, Julie M. Robillard
Technology in Dementia Education: An Ethical Imperative in a Digitized World
Abstract: Technology can support the delivery of care and improve the lives of people living with dementia. However, despite a substantial body of evidence demonstrating the benefits and opportunities afforded by technology, gaps remain in how technology and technology ethics are addressed in dementia care education. Here we discuss disparities in current educational programming and highlight the ethical challenges arising from underdeveloped knowledge exchange about dementia care technology. We put forward that for technology to be ethically deployed and maximized to improve outcomes, it must be embedded into dementia education programs and made widely accessible to the caregiver community.

Pages 1111-1123
Pankaj Gurjar, Azmat Ali Khan, Amer M. Alanazi, Vasil'ev Vasilii Gennad'evich, George Zouganelis, Athanasios Alexiou (Handling Associate Editor: Rekha Khandia)
Molecular Dissection of Herpes Simplex Virus Type 1 to Elucidate Molecular Mechanisms Behind Latency and Comparison of Its Codon Usage Patterns with Genes Modulated During Alzheimer’s Disease as a Part of Host-Pathogen Interaction
Abstract: Background: Herpes simplex virus type 1 (HSV-1) is associated with Alzheimer's disease, which goes into a cycle of latency and reactivation. The present study was envisaged to understand the reasons for latency and specific molecular patterns present in the HSV-1. Objective: The objective is the molecular dissection of Herpes simplex virus type 1 to elucidate molecular mechanisms behind latency and compare its codon usage patterns with genes modulated during Alzheimer’s disease as a part of host-pathogen interaction. Methods: In the present study, we tried to investigate the potential reasons for the latency of HSV-1 virus bioinformatically by determining the CpG patterns. Also, we investigated the codon usage pattern, the presence of rare codons, codon context, and protein properties. Results: The top 222 codon pairs graded based on their frequency in the HSV-1 genome revealed that with only one exception (CUG-UUU), all other codon pairs have codons ending with G/C. Considering it an extension of host-pathogen interaction, we compared HSV-1 codon usage with that of codon usage of genes modulated during Alzheimer's disease, and we found that CGT and TTT are only two codons that exhibited similar codon usage patterns and other codons showed statistically highly significant different codon preferences. Dinucleotide CpG tends to mutate to TpG, suggesting the presence of mutational forces and the imperative role of CpG methylation in HSV-1 latency. Conclusions: Upon comparison of codon usage between HSV-1 and Alzheimer's disease genes, no similarities in codon usage were found as a part of host-pathogen interaction. CpG methylation plays an imperative role in latency HSV-1.

Pages 1125-1137
Chunchao Zhang*, Xiaolin Lei*, Wenhao Ma, Jinyi Long, Shun Long, Xiang Chen, Jun Luo, Qian Tao *These authors contributed equally to this work.
Diagnosis Framework for Probable Alzheimer’s Disease and Mild Cognitive Impairment Based on Multi-Dimensional Emotion Features
Abstract: Background: Emotion and cognition are intercorrelated. Impaired emotion is common in populations with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), showing promises as an early detection approach. Objective: We aim to develop a novel automatic classification tool based on emotion features and machine learning. Methods Older adults aged 60 years or over were recruited among residents in the long-term care facilities and the community. Participants included healthy control participants with normal cognition (HC, n=26), patients with MCI (n=23), and patients with probable AD (n=30). Participants watched emotional film clips while multi-dimensional emotion data were collected, including mental features of Self-Assessment Manikin (SAM), physiological features of electrodermal activity (EDA), and facial expressions. Emotional features of EDA and facial expression were abstracted by using continuous decomposition analysis and EomNet, respectively. Bidirectional long short-term memory (Bi-LSTM) was used to train classification model. Hybrid fusion was used, including early feature fusion and late decision fusion. Data from 79 participants were utilized into deep machine learning analysis and hybrid fusion method. Results: By combining multiple emotion features, the model’s performance of AUC value was highest in classification between HC and probable AD (AUC=0.92), intermediate between MCI and probable AD (AUC=0.88), and lowest between HC and MCI (AUC=0.82). Conclusions: Our method demonstrated an excellent predictive power to differentiate HC/MCI/AD by fusion of multiple emotion features. The proposed model provides a cost-effective and automated method that can assist in detecting probable AD and MCI from normal aging.

Pages 1139-1159
Makoto Kurano, Yuko Saito, Yutaka Yatomi
Comprehensive Analysis of Metabolites in Postmortem Brains of Patients with Alzheimer’s Disease
Abstract: Background: Disturbed metabolism has been proposed as being involved in the pathogenesis of Alzheimer’s disease (AD), and more evidence from human AD brains is required. Objective: In this study, we attempted to identify or confirm modulations in the levels of metabolites associated with AD in postmortem AD brains. Methods: We performed metabolomics analyses using a gas chromatography mass spectrometry system in postmortem brains of patients with confirmed AD, patients with CERAD score B, and control subjects. Results: Impaired phosphorylation of glucose and elevation of several tricarboxylic acid (TCA) metabolites, except citrate, were observed and the degree of impaired phosphorylation and elevation in the levels of the TCA cycle metabolites were negatively and positively correlated, respectively, with the clinical phenotypes of AD. The levels of uronic acid pathway metabolites were modulated in AD and correlated positively with the amyloid- content. The associations of nucleic acid synthesis and amino acid metabolites with AD depended on the kinds of metabolites; in particular, the contents of ribose 5-phosphate, serine and glycine were negatively correlated, while those of ureidosuccinic acid and indole-3-acetic acid were positively modulated in AD. Comprehensive statistical analyses suggested that alterations in the inositol pathway were most closely associated with AD. Conclusions: The present study revealed many novel associations between metabolites and AD, suggesting that some of these might serve as novel potential therapeutic targets for AD.

Pages 1161-1171
Brenda L. Plassman, Cassie B. Ford, Valerie A. Smith, Nicole DePasquale, James R. Burke, Laura Korthauer, Brian R. Ott, Emmanuelle Belanger, Megan E. Shepherd-Banigan, Elyse Couch, Eric Jutkowitz, Emily C. O’Brien, Corinna Sorenson, Terrie T. Wetle, Courtney H. Van Houtven (Handling Associate Editor: Kelsey Thomas)
Elevated Amyloid-β PET Scan and Cognitive and Functional Decline in Mild Cognitive Impairment and Dementia of Uncertain Etiology
Abstract: Background: Elevated amyloid-β (Aβ) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer’s disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aβ on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. Objective: We aimed to investigate whether elevated Aβ on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology. Methods: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aβ on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. Results: Individuals with either MCI or dementia and elevated Aβ (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aβ on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aβ were also reported to have greater functional decline compared to those without elevated Aβ, even though the latter group showed significant care partner-reported functional decline over time. Conclusions: Elevated Aβ on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD.

Pages 1173-1187
Montserrat Alegret, Fernando García-Gutiérrez, Nathalia Muñoz, Ana Espinosa, Gemma Ortega, Núria Lleonart, Isabel Rodríguez, Maitee Rosende-Roca, Vanesa Pytel, Yahveth Cantero-Fortiz, Dorene M. Rentz, Marta Marquié, Sergi Valero, Agustín Ruiz, Christopher Butler, Mercè Boada
FACEmemory®, an Innovative Online Platform for Episodic Memory Pre-Screening: Findings from the First 3,000 Participants
Abstract: Background: The FACEmemory® online platform comprises a complex memory test and sociodemographic, medical, and family questions. This is the first study of a completely self-administered memory test with voice recognition, pre-tested in a memory clinic, sensitive to Alzheimer’s disease, using information and communication technologies, and offered freely worldwide. Objective: To investigate the demographic and clinical variables associated with the total FACEmemory score, and to identify distinct patterns of memory performance on FACEmemory. Methods: Data from the first 3,000 subjects who completed the FACEmemory test were analyzed. Descriptive analyses were applied to demographic, FACEmemory, and medical and family variables; t-test and chi-square analyses were used to compare participants with preserved versus impaired performance on FACEmemory (cut-off=32); multiple linear regression was used to identify variables that modulate FACEmemory performance; and machine learning techniques were applied to identify different memory patterns. Results: Participants had a mean age of 50.57 years and 13.65 years of schooling; 64.07% were women, and 82.10% reported memory complaints with worries. The group with impaired FACEmemory performance (20.40%) was older, had less schooling, and had a higher prevalence of hypertension, diabetes, dyslipidemia, and family history of neurodegenerative disease than the group with preserved performance. Age, schooling, sex, country, and completion of the medical and family history questionnaire were associated with the FACEmemory score. Finally, machine learning techniques identified four patterns of FACEmemory performance: normal, dysexecutive, storage, and completely impaired. Conclusions: FACEmemory is a promising tool for assessing memory in people with subjective memory complaints and for raising awareness about cognitive decline in the community.

Pages 1189-1209
Yun-Ting Tseng, Yu-Ling Chang, Yen-Shiang Chiu
Assessment of Language Function in Older Mandarin-Speaking Adults with Mild Cognitive Impairment using Multifaceted Language Tests
Abstract: Background: Individuals with amnestic mild cognitive impairment (aMCI), especially for those with multidomain cognitive deficits, should be clinically examined for determining risk of developing Alzheimer’s disease. English-speakers with aMCI exhibit language impairments mostly at the lexical–semantic level. Given that the language processing of Mandarin Chinese is different from that of alphabetic languages, whether previous findings for English-speakers with aMCI can be generalized to Mandarin Chinese speakers with aMCI remains unclear. Objective: This study examined the multifaceted language functions of Mandarin Chinese speakers with aMCI and compared them with those without cognitive impairment by using a newly developed language test battery. Methods: Twenty-three individuals with aMCI and 29 individuals without cognitive impairment were recruited. The new language test battery comprises five language domains (oral production, auditory and reading comprehension, reading aloud, repetition, and writing). Results: Compared with the controls, the individuals with aMCI exhibited poorer performance in the oral production and auditory and reading comprehension domains, especially on tests involving effortful lexical and semantic processing. Moreover, the aMCI group made more semantic naming errors compared with their counterparts and tended to experience difficulty in processing items belonging to the categories of living objects. Conclusions: The pattern identified in the present study is similar to that of English-speaking individuals with aMCI across multiple language domains. Incorporating language tests involving lexical and semantic processing into clinical practice is essential and can help identify early language dysfunction in Mandarin Chinese speakers with aMCI.

Pages 1211-1221
Yin-He Chai, Yi-Peng Han, Jin-Yan Zhang, Jian-Bo Zhou
Diabetic Retinopathy and Brain Structure, Cognition Function, and Dementia: A Bidirectional Mendelian Randomization Study
Abstract: Background: Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer’s disease. Diabetic retinopathy (DR) has been identified as a risk factor for dementia in patients with diabetes. Objective: This study aimed to investigate the causal relationships between DR and brain structure, cognitive function, and dementia. Methods: We performed bidirectional two-sample Mendelian randomization for DR, brain structure, cognitive function, and dementia using the inverse-variance weighted method. Results: Inverse-variance weighted analysis showed the association of DR with vascular dementia (OR = 1.68, 95% CI: 1.01–2.82), and dementia was significantly associated with the increased risk of non-proliferative DR (NPDR) (OR = 1.76, 95% CI: 1.04–2.98). Furthermore, better cognitive performance was significantly associated with a reduced risk of NPDR (OR = 0.85, 95% CI: 0.74–0.98). No association was observed between DR and brain structure. Conclusions: These findings suggest that the association of DR with vascular dementia. The reciprocal effect of cognitive performance and dementia on NPDR risk highlights the potential benefits of dementia prevention for reducing the burden of DR.

Pages 1223-1233
Christopher C. Karayiannis, Velandai Srikanth, Richard Beare, Hemal Mehta, Mark Gillies, Thanh G. Phan, Zheng Yang Xu, Christine Chen, Chris Moran
Type 2 Diabetes and Biomarkers of Brain Structure, Perfusion, Metabolism, and Function in Late Mid-Life: A Multimodal Discordant Twin Study
Abstract: Background: Type 2 diabetes (T2D) is associated with an increased risk of dementia and early features may become evident even in mid-life. Characterizing these early features comprehensively requires multiple measurement modalities and careful selection of participants with and without T2D. Objective: We conducted a cross-sectional multimodal imaging study of T2D-discordant twins in late mid-life to provide insights into underlying mechanisms. Methods: Measurements included computerized cognitive battery, brain MRI (including arterial spin labelling, diffusion tensor, resting state functional), fluorodeoxyglucose (FDG)-PET, and retinal optical coherence tomography. Results: There were 23 pairs, mean age 63.7 (±6.1) years. In global analyses, T2D was associated with poorer attention (β=-0.45, p<0.001) and with reduced FDG uptake (β=-5.04, p=0.02), but not with cortical thickness (p=0.71), total brain volume (p=0.51), fractional anisotropy (p=0.15), mean diffusivity (p=0.34), or resting state activity (p=0.4). Higher FDG uptake was associated with better attention (β=3.19, p=0.01) but not with other cognitive domains. In regional analyses, T2D was associated with lower accumbens volume (β=-44, p=0.0004) which was in turn associated with poorer attention. Conclusions: T2D-related brain dysfunction in mid-life manifests as attentional loss accompanied by evidence of subtle neurodegeneration and global reduction in cerebral metabolism, in the absence of overt cerebrovascular disease.

Pages 1235-1247
Katarzyna Zawiślak-Fornagiel, Daniel Ledwoń, Monika Bugdol, Anna Grażyńska, Maciej Ślot, Justyna Tabaka-Pradela, Izabela Bieniek, Joanna Siuda
Quantitative EEG Spectral and Connectivity Analysis for Cognitive Decline in Amnestic Mild Cognitive Impairment
Abstract: Background: Mild cognitive impairment (MCI) is considered to be the borderline of cognitive changes associated with aging and very early dementia. Cognitive functions in MCI can improve, remain stable or progress to clinically probable AD. Quantitative electroencephalography (qEEG) can become a useful tool for using the analytical techniques to quantify EEG patterns indicating cognitive impairment. Objective: The aim of our study was to assess spectral and connectivity analysis of the EEG resting state activity in amnestic MCI (aMCI) patients in comparison with healthy control group (CogN). Methods: 30 aMCI patients and 23 CogN group, matched by age and education, underwent equal neuropsychological assessment and EEG recording, according to the same protocol. Results: qEEG spectral analysis revealed decrease of global relative beta band power and increase of global relative theta and delta power in aMCI patients. Whereas, decreased coherence in centroparietal right area considered to be an early qEEG biomarker of functional disconnection of the brain network in aMCI patients. In conclusion, the demonstrated changes in qEEG, especially, the coherence patterns are specific biomarkers of cognitive impairment in aMCI. Conclusions: Therefore, qEEG measurements appears to be a useful tool that complements neuropsychological diagnostics, assessing the risk of progression and provides a basis for possible interventions designed to improve cognitive functions or even inhibit the progression of the disease.

Pages 1249-1260
Andrea Panzavolta, Chiara Cerami, Alessandra Marcone, Michele Zamboni, Sandro Iannaccone, Alessandra Dodich (Handling Associate Editor: Jordi Matias-Guiu)
Diagnostic Performance of Socio-Emotional Informant-Based Questionnaires for the Clinical Detection of the Behavioral Variant of Frontotemporal Dementia
Abstract: Background: Although social cognitive dysfunction is a major feature of the behavioral variant of frontotemporal dementia (bvFTD), quantitative measurement of social behavior changes is poorly available in clinical settings. Objective: The aim of the study is to evaluate diagnostic accuracy of social-emotional questionnaires in distinguishing bvFTD from healthy control (HC) subjects and Alzheimer’s disease (AD) patients. Methods: We enrolled 29 bvFTD, 24 AD, and 18 HC subjects matched for age, sex, and education. Two informant-based measures of socio-emotional sensitivity and empathy (i.e., revised Self-Monitoring Scale (rSMS) and Interpersonal Reactivity Index (IRI)) were administered. One-way ANOVA was performed to compare groups, whereas Receiver Operating Characteristics (ROC) curve analysis tested questionnaire ability in distinguishing groups. A short version of IRI (sIRI) was obtained by excluding the non-contributing subscale (i.e., personal distress). Results: Compared to HC and AD, bvFTD showed significantly lower scores in rSMS and IRI scores, except for IRI personal distress subscale. The sIRI showed an excellent performance in early diagnosis (bvFTD versus HC = AUC 0.95). Both sIRI and rSMS showed good performance in distinguishing bvFTD from AD (AUC 0.83). Conclusions: ROC analyses support the usefulness of informant social questionnaires in memory clinics and their potential value in screening procedures for research eligibility in forthcoming trials. In the timely diagnosis of bvFTD patients, IRI and rSMS may supply crucial information for the early detection of signs and symptoms affecting social-emotional skills, which might otherwise be underrecognized.

Pages 1261-1274
Hadley Stevens Smith, Jill O. Robinson, Ariel Levchenko, Stacey Pereira, Belen Pascual, Kathleen Bradbury, Victoria Arbones, Jamie Fong, Joshua M. Shulman, Amy L. McGuire, Joseph Masdeu
Research Participants’ Perspectives on Precision Diagnostics for Alzheimer’s Disease
Abstract: Background: Understanding research participants’ responses to learning Alzheimer’s disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. Objective: We assessed participants’ perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. Methods: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses to close-ended survey items by PET result using Fisher’s exact test and qualitatively coded open-ended responses. Results: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n=25) reported feelings of relief (Fisher’s exact p<0.001) and happiness (p<0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). Conclusions: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high.

Pages 1275-1288
Jianguo Zhou*, Mingli Zhao*, Zhou Yang, Liping Chen, Xiaoli Liu for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Exploring the Value of MRI Measurement of Hippocampal Volume for Predicting the Occurrence and Progression of Alzheimer's Disease Based on Artificial Intelligence Deep Learning Technology and Evidence-Based Medicine Meta-Analysis
Abstract: Background: Alzheimer’s disease (AD), a major dementia cause, lacks effective treatment. MRI-based hippocampal volume measurement using artificial intelligence offers new insights into early diagnosis and intervention in AD progression. Objective: This study, involving 483 AD patients, 756 patients with mild cognitive impairment (MCI), and 968 normal controls (NC), investigated the predictive capability of MRI-based hippocampus volume measurements for AD risk using artificial intelligence and evidence-based medicine. Methods: Utilizing data from ADNI and OASIS-brains databases, three convolutional neural networks (InceptionResNetv2, Densenet169, and SEResNet50) were employed for automated AD classification based on structural MRI imaging. A multitask deep learning model and a densely connected 3D convolutional network were utilized. Additionally, a systematic meta-analysis explored the value of MRI-based hippocampal volume measurement in predicting AD occurrence and progression, drawing on 23 eligible articles from PubMed and Embase databases. Results: InceptionResNetv2 outperformed other networks, achieving 99.75% accuracy and 100% AUC for AD-NC classification and 99.16% accuracy and 100% AUC for MCI-NC classification. Notably, at a 512x512 size, InceptionResNetv2 demonstrated a classification accuracy of 94.29% and an AUC of 98% for AD-NC and 97.31% accuracy and 98% AUC for MCI-NC. Conclusions: The study concludes that MRI-based hippocampal volume changes effectively predict AD onset and progression, facilitating early intervention and prevention.

Pages 1289-1298
Liu-Yun Wu, Joyce R. Chong, Jenny P.C. Chong, Saima Hilal, Narayanaswamy Venketasubramanian, Boon Yeow Tan, Arthur Mark Richards, Christopher P. Chen, Mitchell K.P. Lai
Serum Placental Growth Factor as a Marker of Cerebrovascular Disease Burden in Alzheimer’s Disease
Abstract: Background: Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer’s disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. Objective: This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. Methods: 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Results: Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Conclusions: Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF’s clinical utility.

Pages 1299-1312
Amir Saeed*, Talal Alharazi*, Khalid Alshaghdali, Raja Rezgui, Ibtihag Elnaem, Bunder Albdullah T. Alreshidi, Munazzah Tasleem, Mohd Saeed (Handling Associate Editor: Rekha Khandia) *These authors contributed equally to this work.
Targeting GluR3 in Depression and Alzheimer’s Disease: Novel Compounds and Therapeutic Prospects
Abstract: Background: The present study investigates the interrelated pathophysiology of depression and Alzheimer's disease (AD), with the objective of elucidating common underlying mechanisms. Objective: Our objective is to identify previously undiscovered biogenic compounds from the NuBBE database that specifically interact with GluR3. This study examines the bidirectional association between depression and AD, specifically focusing on the role of depression as a risk factor in the onset and progression of the disease. Methods: In this study, we utilize pharmacokinetics, homology modeling, and molecular docking-based virtual screening techniques to examine the GluR3 AMPA receptor subunit. Results: The compounds, namely ZINC000002558953, ZINC000001228056, ZINC000000187911, ZINC000003954487, and ZINC000002040988, exhibited favorable pharmacokinetic profiles and drug-like characteristics, displaying high binding affinities to the GluR3 binding pocket. Conclusions: These findings suggest that targeting GluR3 could hold promise for the development of therapies for depression and AD. Further validation through in vitro, in vivo, and clinical studies is necessary to explore the potential of these compounds as lead candidates for potent and selective GluR3 inhibitors. The shared molecular mechanisms between depression and AD provide an opportunity for novel treatment approaches that address both conditions simultaneously.

Pages 1313-1322
Li Shang, Liling Dong, Xinying Huang, Shanshan Chu, Wei Jin, Jialu Bao, Tianyi Wang, Chenhui Mao, Jing Gao
Comorbidity of Dementia: A Cross-Sectional Study of PUMCH Dementia Cohort
Abstract: Background: Comorbidities reduce quality of life for people with dementia and caregivers. Some comorbidities share a genetic basis with dementia. Objective: The objective of this study is to assess comorbidity in patients with different dementia subtypes in order to better understand the pathogenesis of dementias. Methods: A total of 298 patients with dementia were included. We collected some common comorbidities. We analyzed the differences in comorbidities among patients with dementia according to clinical diagnosis, age of onset (early-onset: <65 and late-onset: ≥65 years old) and apolipoprotein (APOE) genotypes by using the univariate and multivariate approaches. Results: Among 298 participants, there were 183 Alzheimer's disease (AD), 40 vascular dementia (VaD), 37 frontotemporal dementia (FTLD), 20 Lewy body dementia (LBD), and 18 other types of dementia. Based on age of onset, 156 cases had early-onset dementia and 142 cases had late-onset dementia. The most common comorbidities observed in all dementia patients were hyperlipidemia (68.1%), hypertension (39.9%), insomnia (21.1%), diabetes mellitus (19.5%), and hearing impairment (18.1%). The prevalence of hypertension and cerebrovascular disease was found to be higher in patients with VaD compared to those with AD (p=0.002, p<0.001, respectively) and FTLD (p=0.028, p=0.004, respectively). Additionally, patients with late-onset dementia had a higher burden of comorbidities compared to those with early-onset dementia. It was observed that APOE ε4/ε4 carriers were less likely to have insomnia (p=0.031). Conclusions: Comorbidities are prevalent in patients with dementia, with hyperlipidemia, hypertension, insomnia, diabetes, and hearing impairment being the most commonly observed. Comorbidity differences existed among different dementia subtypes.

Pages 1323-1339
Mourad Belkhelfa, Samy Bekrar, Lina Rezaig, Narimene Beder, Faiza Touri, Khaled, Yamina Yousfi, Hedia Nabi, Assia Slimani, Nabila Attal, Ayed Belarbi, Madjid Bessaha, Chafia Touil-Boukoffa
Neuroinflammatory Responses Occur in Brain Lesions During Alzheimer’s Disease: Postmortem Case Report
Abstract: Background: Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder. It is characterized by a gradual decrease in cognitive function and is considered a disorder in which the intensifying neuronal loss. The autopsy is considered the gold standard for the diagnosis of AD and non-AD dementia. Objective: Our study aims to clarify the involvement of neuroinflammation processes in brain lesions of AD. Methods: The defunct was admitted to the forensic medicine department of Issad Hassani Hospital (Algeria). In order to recover the brain, an autopsy was performed within 24 hours of death and then immediately fixed in formaldehyde to maintain structural brain integrity for histological and immunohistochemical analysis. Results: Our findings indicate the presence of tissue lesions in the specific brain regions: right middle frontal gyrus, right cingulate gyrus, right putamen and globus pallidus, right caudate nucleus, right hippocampus, inferior parietal lobule, left parahippocampal gyrus, and left hippocampus. Notably, there is a predominant occurrence of lesions: granulovacuolar degeneration, Hirano bodies, cotton-wool, and neuritic plaques. The causes of neurodegenerative processes are probably related to TNF-α, IL-1β, and TGF-β production and iNOS expression by the NF-κB activation pathway in the R-HP, inducing necroptosis. Conclusions: The occurrence of neuroinflammatory responses is linked to tissue lesions in AD. The production of inflammatory cytokines is the basis of this process, which ultimately leads to the necroptosis, which is triggered by neuroinflammation amplification. The inhibition of neuroinflammation by targeting TNF-α/iNOS could stop tissue damage, this may be a promising therapeutic pathway.

Pages 1341-1351
Lidón Marin-Marin*, Julia Renau-Lagranja*, César Ávila, Victor Costumero (Handling Associate Editor: Shunichiro Shinagawa) *These authors contributed equally to this work.
Depression and Agitation Factors Are Related to Regional Brain Atrophy and Faster Longitudinal Cognitive Decline in Mild Cognitive Impairment
Abstract: Background: Neuropsychiatric symptoms (NPS) are a common aspect of Alzheimer’s disease (AD). Multiple studies have investigated its brain correlates, but it still remains unclear how they relate with brain atrophy in mild cognitive impairment (MCI). Objective: Our objective was to investigate brain volume in MCI patients as a function of NPS. Methods: We measured grey matter volume, neuropsychological status and NPS (Neuropsychiatric Inventory, NPI), in a sample of 81 MCI patients (43 females). Participants were divided in groups depending on presence (NPS+) or absence (NPS-) of NPS and on type of NPS. Results: We found lower volume of left temporal pole in patients with depression compared to NPS- (p=0.012), and in patients with agitation compared to NPS- in the right middle occipital gyrus (p=0.003). We also found a significant correlation between volume of left temporal pole and MMSE (r(78)=0.232, p=0.019). Finally, NPS+ presented lower cross-sectional cognitive level than NPS- (t(79)=1.79, p=0.038), and faster cognitive decline (t(48)=-1.74, p=0.044). Conclusions: Our results support the colocalization of structural damage as a possible mechanism underlying the relationship between MCI and depression and provide novel evidence regarding agitation. Moreover, our longitudinal evidence highlights the relevance of an adequate identification of NPS in MCI patients to identify those at risk of faster cognitive decline.

Pages 1353-1363
Megan Schwinne, Alvaro Alonso, Blaine R. Roberts, Sabrina Hickle, Inge M.W. Verberk, Emmanuel Epenge, Guy Gikelekele, Nathan Tsengele, Immaculee Kavugho, Samuel Mampunza, Kevin E. Yarasheski, Charlotte E. Teunissen, Anthony Stringer, Allan Levey, Jean Ikanga
The Association of Alzheimer’s Disease-Related Blood-Based Biomarkers with Cognitive Screening Test Performance in the Congolese Population in Kinshasa
Abstract: Background: Alzheimer’s disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-β42/40 (Aβ42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. Objective: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. Methods: In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer’s Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aβ42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Results: Lower plasma Aβ42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p<0.001). These relationships were observed in healthy controls (CSID p=0.01, AQ p=0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOE ε4 allele, did not alter these relationships. Conclusions: Understanding relationships between AD-related screening tests and blood biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.

Pages 1365-1379
Sarah J. Getz, Bonnie E. Levin, James E. Galvin
The Assessment of Situational Judgement Questionnaire: A Novel Instrument to Detect Susceptibility to Financial Scamming
Abstract:Background: Existing measures of scam susceptibility lack ecological validity and situational variability. Evidence suggests that all adults may be susceptible to scams, though a comprehensive fraud victimization theory remains to be explored. Objective: To identify cognitive and sociodemographic variables that differentiate individuals with high scam susceptibility from those less susceptible. This article describes the development and feasibility of the Assessment of Situational Judgment questionnaire (ASJ), a brief tool designed to detect scam susceptibility. Methods: The 17-item ASJ was developed using a combination of existing scams reported by the Florida Division of Consumer Services and legitimate scenarios. Participants were presented with scam and legitimate scenarios and queried regarding their willingness to engage. Response options were offered with instructions on a 7-point Likert scale (extremely unlikely to extremely likely). Pilot data from a development sample provided the foundation for the final version of the ASJ. Results: The final version of the ASJ was administered to 183 online participants. The Scam factor (8 items) explained 50.6% of the variance. The Legit factor (9 items) reported on a 7-point Likert scale explaining 10.6% of the variance. A Scam to Legit ratio provides a proxy for overall scam susceptibility. Cut-off scores of 24 on the Scam factor, 47 on the Legit factor, and 0.62 on the ratio optimize measures of scam susceptibility. Conclusions: The ASJ is a brief, ecologically valid measure of scam susceptibility. There is a need for a sensitive and specific tool to detect scam susceptibility in clinical, community, and financial settings.

Pages 1381-1392
Deng-Pan Wu*, Yan-Su Wei*, Yu-Xuan Du*, Ling-Ling Liu, Qiu-Qing Yan, Yuan-Dan Zhao, Chao Yu, Jin-Yuan Liu, Zhen-Guo Zhong, Jin-Lan Huang *These authors contributed equally to this project.
Ameliorative Role of Mitochondrial Therapy in Cognitive Function of Vascular Dementia Mice
Abstract: Background: Mitochondrial dysfunction plays a vital role in the progression of vascular dementia (VaD). We hypothesized that transfer of exogenous mitochondria might be a beneficial strategy for VaD treatment. Objective: The study was aimed to investigate the role of mitochondrial therapy in cognitive function of VaD. Methods: The activity and integrity of isolated mitochondria were detected using MitoTracker and Janus Green B staining assays. After VaD mice were intravenously injected with exogenous mitochondria, Morris water maze and passive avoidance tests were used to detect cognitive function of VaD mice. Haematoxylin and eosin, Nissl, TUNEL, and Golgi staining assays were utilized to measure neuronal and synaptic injury in the hippocampus of VaD mice. Detection kits were performed to detect mitochondrial membrane potential (ΔΨm), SOD activity and the levels of ATP, ROS, and MDA in the brains of VaD mice. Results: The results showed that isolated mitochondria were intact and active. Mitochondrial therapy could ameliorate cognitive performance of VaD mice. Additionally, mitochondrial administration could attenuate hippocampal neuronal and synaptic injury, improve mitochondrial ΔΨm, ATP level and SOD activity, and reduce ROS and MDA levels in the brains of VaD mice. Conclusions: The study reports profitable effect of mitochondrial therapy against cognitive impairment of VaD, making mitochondrial treatment become a promising therapeutic strategy for VaD.

Pages 1393-1405
Yi-Chou Hou, Ti-I Chueh, Kuo-Cheng Lu, Yi-Chien Liu, Tso-Hsiao Chen, Shing-Hwa Liu, Ruei-Ming Chen
The Ratio of Plasma Amyloid-β 1-42 over Serum Albumin Can Be a Novel Biomarker Signature for Diagnosing End-Stage Renal Disease-Associated Cognitive Impairment
Abstract: Background: Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can significantly predict ESRD-associated cognitive decline. Objective: This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI. Methods: In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of ≥60 mL/min and a Mini-Mental State Examination (MMSE) score of >27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-β (Aβ)1-42, serum indoxyl sulfate, and hematologic and biochemical parameters were measured. Results: Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aβ1-42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aβ1-42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aβ1-42 over albumin was 0.785 and significant (p < 0.05). Conclusions: This cohort study has shown that the ratio of plasma Aβ1-42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline.

Pages 1407-1419
Isabelle K. Gorham, Danielle Marie Reid, Jie Sun, Zhengyang Zhou, Robert C. Barber, Nicole R. Phillips (Handling Associate Editor: Irundika Dias)
Blood-Based mtDNA Quantification Indicates Population-Specific Differences Associated with Alzheimer’s Disease-Related Risk
Abstract: Background: Age is known to be the biggest risk factor for Alzheimer’s disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors. Objective: This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood. Methods: Examining blood from both non-Hispanic white (NHW) and MA participants (N=527, MA n=284, NHW n=243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction. Results: In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOE ε2/ε3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort. Conclusions: This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk.

Pages 1421-1433
Hajime Takase*, Gen Hamanaka*, Tomonori Hoshino*, Ryo Ohtomo, Shuzhen Guo, Emiri T. Mandeville, Eng H. Lo1, Ken Arai *These authors equally contributed to this work.
Transcriptomic Profiling Reveals Neuroinflammation in the Corpus Callosum of a Transgenic Mouse Model of Alzheimer's Disease
Abstract: Background: Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. Objective: This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. Methods: We conducted behavioral tests for spatial learning and memory in 5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. Results: Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1, Per2, and Cry1 is also observed. Conclusions: This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies.

Pages 1435-1448
Sayaka Okahashi*, Taiji Noguchi*, Masumi Ishihara, Aiko Osawa, Fumie Kinoshita, Ikue Ueda, Masaki Kamiya, Takeshi Nakagawa, Izumi Kondo, Takashi Sakurai, Hidenori Arai, Tami Saito *These authors equally contributed to this work.
Dyadic Art Appreciation and Self-Expression Program (NCGG-ART) for People with Dementia or Mild Cognitive Impairment and Their Family Caregivers: A Feasibility Study
Abstract: Background: Non-pharmacological interventions effective for depressive mood and bilateral relationships among persons with cognitive impairment (PwCI) and their family caregivers (FCGs) have not been established.  Objective: To examine the feasibility of a newly developed group-based art appreciation and self-expression program (NCGG-ART) for dyads of PwCI and their FCGs. Methods: This pilot randomized control trial included 34 dyads of PwCI diagnosed with mild to moderate Alzheimer's disease or mild cognitive impairment, and their FCGs, from an outpatient rehabilitation service (Holistic Physio-Cognitive Rehabilitation [HPCR]). Participants were randomly divided equally into the HPCR (control group) or NCGG-ART and HPCR (intervention group) groups. Both included 1-hour weekly, 6-week programs. The primary outcome was depressive symptoms among FCGs assessed using the Patient Health Questionnaire-9 (PHQ-9). Feasibility outcomes included participant satisfaction and motivation. FCGs were interviewed about their experiences and feelings regarding the program, which were analyzed using content analysis. Results: Thirty-two dyads (intervention group:16; control group:16) completed the study period. High participation rates, satisfaction, and motivation were demonstrated throughout the intervention. Scores in the PHQ-9 among FCGs did not show positive effects: mean changes in the score were 1.3 for the intervention group and -0.8 for the control group (Cohen d:0.56). However, the qualitative analysis revealed favorable experiences and feelings of the FCGs, such as positive emotions, social interactions, and person-centered attitudes to and positive relationships with PwCI. Conclusions: This program demonstrated high feasibility with FCGs’ favorable responses to emotions and relationships with PwCI, ensuring future investigations with a confirmatory study design.

Pages 1449-1461
Freddie Márquez, Wassim Tarraf Ariana M. Stickel, Kevin A. González, Fernando D. Testai, Jianwen Cai, Linda C. Gallo, Gregory A. Talavera, Martha L. Daviglus, Sylvia Wassertheil-Smoller, Charles DeCarli, Neil Schneiderman, Hector M. González
Hypertension, Cognitive Decline, and Mild Cognitive Impairment Among Diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging Results (SOL-INCA)
Abstract: Background: Hypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos. Objective: To assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos. Methods: This population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008–2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016–2018), with a mean follow-up duration of 7 years (n=6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors. Results: Compared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β=-0.08; CI=[-0.16;-0.01]; p<0.05), and processing speed (β=-0.11; CI=[-0.20;-0.02]; p<0.05). Incident hypertension was not associated with significant change in cognitive performance. Both incident (OR=1.70; CI=[1.16;2.50]; p<0.01) and persistent hypertension (OR=2.13; CI=[1.57;2.88]; p<0.001) were associated with significantly higher odds ratios of having MCI. Conclusions: These findings indicate that persistent hypertension is associated with clinical impairment and domain-specific cognitive decline in middle-aged and older Hispanics/Latinos. It underscores the importance of monitoring blood pressure in routine healthcare visits beginning at midlife in this population to reduce the burden of cognitive decline.

Pages 1463-1475
Victor L. Villemagne*, Vincent Doré*, Lee Chong, Michael Kassiou, Rachel Mulligan, Azadeh Feizpour, Jack Taylor, Miriam Roesner, Tamara Miller, Christopher C. Rowe *These authors contributed equally to this work.
Brain 11β-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem™ Assessed by PET in Alzheimer’s Disease and Cognitively Normal Individuals
Abstract: Background: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer’s disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection. Objective: To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. Methods: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). Results: All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum. Conclusions: TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of ≤10 mg daily in future clinical studies.