Volume 91, Number 4, IN PRESS

Systematic Review
Hamidul Huque, Ranmalee Eramudugolla, Benjamin Chidiac, Nicole Ee, Lauren Ehrenfeld, Fiona E. Matthews, Ruth Peters, Kaarin J. Anstey
Could Country-Level Factors Explain Sex Differences in Dementia Incidence and Prevalence? A Systematic Review and Meta-Analysis
Abstract: Background: Despite rising interest in sex differences in dementia, it is unclear whether sex differences in dementia incidence and prevalence are apparent globally. Objective: We examine sex differences in incidence and prevalence of Any dementia, Alzheimer’s disease (AD), and Vascular dementia, and evaluate whether country-level indicators of gender inequality accounted for differences. Methods: Systematic review with meta-analysis was used to obtain estimates of incidence and prevalence of Any dementia, AD, and VaD using random effects meta-analysis, and population-based studies with clinical or validated dementia measures. Meta-regression was used to evaluate how country-specific factors of life-expectancy, education, and gender differences in development, unemployment, and inequality indices influenced estimates. Results: We identified 205 eligible studies from 8,731 articles, representing 998,187 participants across 43 countries. There were no sex differences in incidence of Any dementia, AD, or VaD, except in the 90+ age-group (women higher). When examined by 5-year age bands, the only sex difference in prevalence of Any dementia was in the 85+, and there was no sex difference in VaD. AD was more prevalent in women at most ages. Globally, the overall prevalence of dementia in adults 65+ was higher for women (80.22/1000, 95% CI 62.83–97.61) than men (54.86/1000, 95% CI 43.55–66.17). Meta-regression revealed that sex differences in Any dementia prevalence, were associated with gender differences in life expectancy and in education. Conclusion: Globally, there are no sex differences in age-specific dementia incidence, but prevalence of AD is higher in women. Country-level factors like life expectancy and gender differences in education may explain variability in sex differences.

Systematic Review
Karra D. Harrington, Shradha Vasan, Jee eun Kang, Martin J. Sliwinski, Michelle H. Lim
Loneliness and Cognitive Function in Older Adults Without Dementia: A Systematic Review and Meta-Analysis
Abstract: Background: Loneliness has been highlighted as a risk factor for dementia. However, the nature of the relationship between loneliness and cognitive function prior to onset of dementia is unclear. Objective: The aim of this systematic review and meta-analysis was to examine the relationship between loneliness and cognitive function in samples screened for dementia at study commencement. Methods: Five electronic databases (PubMed, PsycNET, Web of Science, EBSCOhost, Scopus) were searched from inception to August 31, 2021. A narrative review and random-effects meta-analysis were conducted on studies meeting search criteria. PROSPERO registration number: CRD42020155539. Results: The sixteen studies that met inclusion criteria involved 30,267 individuals, with mean age ranging from 63.0 to 84.9 years. Studies varied in dementia screening criteria, measurement of loneliness and cognitive function, and statistical modeling approach. The narrative review indicated that loneliness was associated with poorer global cognition, episodic memory, working memory, visuospatial function, processing speed, and semantic verbal fluency. Results of the meta-analysis indicated that loneliness was negatively associated with global cognitive function (overall r = -0.08; 95% CI = -0.14, -0.02; n= 6). Due to lack of sufficient data and heterogeneity between studies, we were unable to explore associations with other cognitive domains or longitudinal associations. Conclusion: Loneliness is associated with subtle impairment across multiple cognitive domains in older adults who were screened for dementia. Better characterization of this relationship will provide important information about how loneliness contributes to the clinical and pathological sequalae of AD and be informative for risk reduction and early detection strategies.

Systematic Review
Michael Hén Forbord Fischer, Ivan Chrilles Zibrandtsen, Peter Høgh, Christian Sandøe Musaeus
Systematic Review of EEG Coherence in Alzheimer’s Disease
Abstract: Background: Magnitude-squared coherence (MSCOH) is an electroencephalography (EEG) measure of functional connectivity. MSCOH has been widely applied to investigate pathological changes in patients with Alzheimer’s disease (AD). However, significant heterogeneity exists between the studies using MSOCH. Objective: We systematically reviewed the literature on MSCOH changes in AD as compared to healthy controls to investigate the clinical utility of MSCOH as a marker of AD. Methods: We searched PubMed, Embase, and Scopus to identify studies reporting EEG MSCOH used in patients with AD. The identified studies were independently screened by two researchers and the data was extracted, which included cognitive scores, preprocessing steps, and changes in MSCOH across frequency bands. Results: A total of 35 studies investigating changes in MSCOH in patients with AD were included in the review. Alpha coherence was significantly decreased in patients with AD in 24 out of 34 studies. Differences in other frequency bands were less consistent. Some studies showed that MSCOH may serve as a diagnostic marker of AD. Conclusion: Reduced alpha MSCOH is present in patients with AD and MSCOH may serve as a diagnostic marker. However, studies validating MSCOH as a diagnostic marker are needed.

Commentary
Ruth F. Itzhaki
COVID-19 and Alzheimer’s Disease: What Is the Connection?
Abstract: Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS‐CoV‐2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of AD.

Commentary
Arnold R. Eiser, Tamas Fulop
Alzheimer’s Disease Is a Multi-Organ Disorder: It May Already Be Preventable
Abstract: In this commentary, we offer an overview of the several environmental and metabolic factors that have been identified as contributing to the development of Alzheimer’s disease (AD). Many of these factors involve extracranial organ systems including immune system dysfunction accompanied by neuroinflammation (inflammaging), gastrointestinal dysbiosis, insulin resistance, and hepatic dysfunction. A variety of microbial factors including mouth flora, viruses, and fungi appear to play a significant role. There is a role for the colonic microbiome becoming dysbiotic and producing toxic metabolites. Declining hepatic function contributes diminished neuronal precursors and reduces toxin elimination. Environmental toxins especially metals play an important role in impairing the blood-brain barrier and acting synergistically with biotoxins and other toxic chemicals. Prevention and treatment of AD appears to require measuring several of these biomarkers and implementing corrective actions regarding such toxicants and correcting metabolic dysfunction at early or preclinical stages of this disorder.

Atte Rahkonen, Heidi Taipale, Marjaana Koponen, Sirpa Hartikainen, Anna-Maija Tolppanen, Antti Tanskanen, Miia Tiihonen (Handling Associate Editor: Selvil Yasar)
The Cumulative Use of Muscle Relaxants and the Risk of Alzheimer’s Disease: A Nationwide Case-Control Study
Abstract: Background: Use of pharmacological treatments is one possible modifiable risk factor for cognitive disorders. Objective: To investigate if the use of muscle relaxants is associated with the risk of Alzheimer’s disease (AD). Methods: The study was performed in a nested case-control design. Altogether 70,718 community-dwelling residents of Finland who received AD diagnosis in 2005-2011 were included as cases (the MEDALZ study). Each case was matched with four controls without AD by age, sex, and region of residence (N=282,858). Data was extracted from Prescription register (1995-2012), Special Reimbursement register (1972-2012), and Hospital Discharge register (1972-2012). Drug use periods were modeled with PRE2DUP-method. Defined daily dose (DDD) was used to quantify the use. Analyses were conducted for any muscle relaxant use, and drug specific analyses were done for orphenadrine and tizanidine. A five-year lag window prior to the diagnosis was used, and results analyzed with conditional logistic regression. Results: The use of any muscle relaxant was associated with the risk of AD, aOR (95% CI) 1.04 (1.02-1.07). Stronger associations were observed with longer use (>366 days, aOR 1.12 (1.03-1.21)) than shorter use (1-365 days aOR, 1.04 (1.02-1.06)) compared to non-users. Dose-response was not observed. Tizanidine was not associated with AD, whereas cumulative exposure of orphenadrine (≥101 DDDs) was associated with the risk of AD, aOR 1.19 (1.07-1.32). Conclusion: Muscle relaxant use was associated with the risk of AD and higher exposure to orphenadrine showed increased risk. Further studies on higher doses and longer durations of use are warranted.

Emily Z. Huie, Anthony Escudero, Naomi Saito, Danielle Harvey, My-Le Nguyen, Katherine L. Lucot, Jayne LaGrande, Dan Mungas, Charles DeCarli, Melissa Lamar, Julie A. Schneider, Alifiya Kapasi, Robert A. Rissman, Andrew F. Teich, Brittany N. Dugger
TDP-43 Pathology in the Setting of Intermediate and High Alzheimer’s Disease Neuropathologic Changes: A Preliminary Evaluation Across Ethnoracial Groups
Abstract: Background: Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer’s disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White cohorts. Objective: We sought to evaluate the presence of TDP-43 pathology across ethnoracial groups utilizing the National Alzheimer’s Coordinating Center; a database containing data from over 29 institutions across the United States. Cases (N=1,135: Hispanics/Latinos=29, African Americans/Black Americans=51, Asians/Asian Americans=10, American Indians/Alaskan Natives=2, non-Hispanic White=1,043) with intermediate/high AD having data on TDP-43 pathology in the amygdala, hippocampus, entorhinal cortex, and neocortex. Methods: TDP-43 pathology frequency in each neuroanatomic region among ethnoracial groups were compared using generalized linear mixed effects models with center as a random effect adjusting for age at death, education, and gender. Results: Although groups were imbalanced, there was no significant difference across ethnoracial groups based on TDP-43 pathology (p=0.84). With respect to neuroanatomical regions evaluated, there were no significant differences across ethnoracial groups (p-values>0.06). There were also no significant differences for age at death and gender ratios across ethnoracial groups based on TDP-43 pathology. Although not statistically significant, TDP-43 pathology was present less often in Hispanic/Latinos (34%) when compared to non-Hispanic Whites (46%). Conclusion: While this is a preliminary evaluation, it highlights the need for diverse cohorts and on TDP-43 pathology research across ethnoracial groups. This is the first study to our knowledge having a focus on the neuroanatomical distribution of TDP-43 deposits in Hispanic/Latino decedents with AD.

Marisa Lima, Miguel Tábuas-Pereira, João Durães, Daniela Vieira, Pedro Faustino, Inês Baldeiras, Isabel Santana
Neuropsychological Assessment in the Distinction Between Biomarker Defined Frontal-Variant of Alzheimer’s Disease and Behavioral-Variant of Frontotemporal Dementia
Abstract: Background: Frontal-variant of Alzheimer’s disease (fvAD) was purposed for patients with AD pathology that, despite the typical amnestic presentation, show early and progressive deterioration of behavior and executive functions, closely resembling the behavioral-variant of frontotemporal dementia (bvFTD). This leads to a challenging differential diagnosis where neuropsychological evaluation and in vivo pathological evidence are essential. Objective: To evaluate the contribution of a comprehensive neuropsychological assessment (NP) battery in distinguishing between fvAD-dementia and bvFTD supported by cerebrospinal fluid (CSF) biomarkers. Methods: We included 40 patients with a baseline NP profile with prominent early executive and/or behavioral dysfunction, who meet both diagnosis of bvFTD and fvAD-dementia, according to international criteria. All patients underwent comprehensive NP assessment and CSF-AD biomarker evaluation. Neuropsychological domains as well as clinical and sociodemographic features, and APOE genotype were compared between groups. Results: 21 patients (52.5%) met the biological criteria for AD (decreased Aβ42 together with increased T-tau or P-tau in CSF) and were therefore classified as fvAD (mean age was 64.57, with 47.6% female). There were no differences between groups regarding age/age-at-onset, gender, or educational level. Regarding neuropsychological profile, performances in language and memory functions were equivalent in both groups. Significant differences were found in visuo-constructional abilities (p=0.004), Trail Making Test A (p<0.001), and Raven’s Colored Progressive Matrices (p=0.019), with fvAD patients showing worst performances. Conclusion: In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia and may be useful in clinical practice.

Che Liu*, Sang H. Lee, David A. Loewenstein, James E. Galvin, Bonnie E. Levin, Alexander McKinney, Noam Alperin* (Handling Associate Editor: Stephen Rao) *These authors contributed equality to this work.
Early Amnestic Mild Cognitive Impairment Is Associated with Reduced Total Cerebral Blood Flow with no Brain Tissue Loss
Abstract: Background: Lower cerebral blood flow (CBF) and brain atrophy are linked to Alzheimer's disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. Objective: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. Methods: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. Results: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ)=0.324 and stβ=0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ=0.327 and stβ=0.284) and in aMCI (stβ=0.627 and stβ=0.485). Conclusion: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss.

Neelam Sharma*, Rupkatha Banerjee*, Ronald L. Davis *These authors contributed equally to this work.
Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer’s Disease
Abstract: Background: Mitochondrial (MT) dysfunction is a hallmark of Alzheimer’s disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology. Objective: To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology. Methods: The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays. =Results: We disovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade. Conclusion: Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics.

Min Zhu*, Minglu Tang*, Yifeng Du *These authors contributed equally to this work.
Identification of TAC1 Associated with Alzheimer’s Disease Using a Robust Rank Aggregation Approach
Abstract: Background: Alzheimer’s disease (AD) brings heavy burden to society and family. There is an urgent need to find effective methods for disease diagnosis and treatment. The robust rank aggregation (RRA) approach that could aggregate the resulting gene lists has been widely utilized in genomic data analysis. Objective: To identify hub genes using RRA approach in AD. Methods: Seven microarray datasets in frontal cortex from GEO database were used to identify differential expressed genes (DEGs) in AD patients using RRA approach. STRING was performed to explore the protein-to-protein interaction (PPI). Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were utilized for enrichment analysis. Human Gene Connectome and Gene Set Enrichment Analysis were used for functional annotation. Finally, the expression levels of hub genes were validated in the cortex of 5xFAD mice by quantitative real-time polymerase chain reaction. Results: After RRA analysis, 473 DEGs (216 upregulated and 257 downregulated) were identified in AD samples. PPI showed that DEGs had a total of 416 nodes and 2750 edges. These genes were divided into 17 clusters, each of which contains at least three genes. After functional annotation and enrichment analysis, TAC1 is identified as the hub gene and may be related to synaptic function and inflammation. In addition, Tac1 was found downregulated in cortices of 5xFAD mice. Conclusion: In the current study, TAC1 is identified as a key gene in the frontal cortex of AD, providing insight into the possible pathogenesis and potential therapeutic targets for this disease.

Jian Wang, Neng-Wei Yu, Duo-Zi Wang, Lei Guo, Shu Yang, Bo Zheng, Fu-Qiang Guo, Jian-Hong Wang (Handling Associate Editor: Wang-Sheng Jin)
Helicobacter pylori Infection Is Associated with Long-Term Cognitive Decline in Older Adults: A Two-Year Follow-Up Study
Abstract: Background: Previous cross-sectional studies have identified a possible link between Helicobacter pylori (H. pylori) infection and dementia. However, the association of H. pylori infection with longitudinal cognitive decline has rarely been investigated. Objective: This cohort study aims to demonstrate the effects of H. pylori infection on longitudinal cognitive decline. Methods: This cohort study recruited 268 subjects with memory complaints. Among these subjects, 72 had a history of H. pylori infection, and the rest 196 subjects had no H. pylori infection. These subjects were followed up for 24 months and received cognitive assessment in fixed intervals of 12 months. Results: At baseline, H. pylori infected, and uninfected participants had no difference in MMSE scores. At 2 years of follow-up, H. pylori infected participants had lower MMSE scores than uninfected participants. H. pylori infection was associated with an increased risk of longitudinal cognitive decline, as defined by a decrease of MMSE of 3 points or more during follow-up, adjusting for age, sex, education, APOE ε4 genotype, hypertension, diabetes, hyperlipidemia, and smoking history (HR: 2.701; 95% CI: 1.392 to 5.242). H. pylori infection was associated with larger cognitive decline during follow-up, adjusting for the above covariates (standardized coefficient: 0.282, p<0.001). Furthermore, H. pylori infected subjects had significantly higher speed of cognitive decline than uninfected subjects during follow-up, adjusting for the above covariates. Conclusion: H. pylori infection increases the risk of longitudinal cognitive decline in older subjects with memory complaints. This study is helpful for further understanding the association between infection and dementia.

André Janse, Ondine van de Rest, Lisette C.P.G.M. de Groot, Renger F. Witkamp
The Association of Vitamin D Status with Mild Cognitive Impairment and Dementia Subtypes: A Cross-Sectional Analysis in Dutch Geriatric Outpatients
Abstract: Background: Vitamin D deficiency is associated with all-cause dementia and Alzheimer’s disease (AD). At the same time, this knowledge is limited specifically for vascular dementia (VaD), while data regarding other subtypes of dementia are even more limited. Objective: To investigate the association of 25-hydroxy vitamin D (25(OH)D) status with dementia subtypes in an outpatient geriatric population. Methods: In a cross-sectional design, we analyzed data from 1,758 patients of an outpatient memory clinic in The Netherlands. Cognitive disorders were diagnosed by a multidisciplinary team according to international clinical standards. At each first-visit 25(OH)D levels were measured. Data were analyzed using ANCOVA in four models with age, gender, BMI, education, alcohol, smoking, season, polypharmacy, calcium, eGFR, and glucose as co-variates. 25(OH)D was treated as a continuous square rooted (sqr) variable. Results: In the fully adjusted model, reduced 25(OH)D serum levels (sqr) were found in AD (estimated mean 7.77 ± 0.11 CI95% 7.55-7.99): and in VaD (estimated mean 7.60 ± 0.16 CI95% 7.28-7.92) patients compared to no-dementia (ND) patients (estimated mean 8.27 ± 0.09 CI95% 8.10-8.45) (ND-AD: p=0.006, CI95% 0.08-0.92.; ND-VaD p= 0.004 CI95% 0.13-1.22). We did not find differences in 25(OH)D levels of mild cognitive impairment (MCI) or other dementia patients compared to ND patients, nor differences in comparing dementia subtypes. Conclusion: We observed significantly lower 25(OH)D serum levels in both AD and VaD patients compared to no-dementia patients, but no significant differences between MCI and Lewy body and mixed dementia subtypes in this cross-sectional study of a geriatric outpatient clinic population.

Chelsea C. Hays Weeks, Zvinka Z. Zlatar, M.J. Meloy, David D. Shin, Liu, Thomas, Christina E. Wierenga (Handling Associate Editor: David Libon)
APOE Genotype Modifies the Association of Fusiform Gyrus Cerebral Metabolic Rate of Oxygen Consumption and Object Naming Performance
Abstract: Background: The apolipoprotein E (APOE) ε4 allele confers risk for age and Alzheimer’s disease related cognitive decline but the mechanistic link remains poorly understood. Blood oxygenation level dependent (BOLD) response in the fusiform gyrus (FG) during object naming appears greater among APOE ε4 carriers even in the face of equivalent cognitive performance, suggesting neural compensation. However, BOLD is susceptible to known age and APOE-related vascular changes that could confound its interpretation. Objective: To address this limitation, we used calibrated fMRI during an object naming task and a hypercapnic challenge to obtain a more direct measure of neural function – percent change cerebral metabolic rate of oxygen consumption (%ΔCMRO2). Methods: Participants were 45 older adults without dementia (28 ε4-, 17 ε4+) between the ages of 65 and 85. We examined APOE-related differences in %ΔCMRO2 in the FG during object naming and the extent to which APOE modified associations between FG %ΔCMRO2 and object naming accuracy. Exploratory analyses also tested the hypothesis that %ΔCMRO2 is less susceptible to vascular compromise than are measures of %ΔCBF and %ΔBOLD. Results: We observed a modifying role of APOE on associations between FG %ΔCMRO2 and cognition, with ε4 carriers (but not non-carriers) demonstrating a positive association between right FG %ΔCMRO2 and object naming accuracy. Conclusion: Results suggest that the relationship between neural function and cognition is altered among older adult APOE ε4 carriers prior to the onset of dementia, implicating CMRO2 response as a potential mechanism to support cognition in APOE-related AD risk.

Riccardo Sacripante, Nicola Girtler, Elisa Doglione, Flavio Nobili, Sergio Della Sala
Forgetting Rates of Prose Memory in Mild Cognitive Impairment
Abstract: Background: Some authors report steeper slopes of forgetting in early Alzheimer’s disease (AD), while others do not. Contrasting findings are thought to be due to methodological inconsistencies or variety of testing methods, yet they also emerge when people are assessed on the same testing procedure. Objective: We aimed to assess if forgetting slopes of people with mild cognitive impairment due to AD (MCI-AD) are different from age-matched healthy controls (HC) by using a prose paradigm. Methods: Twenty-nine people with MCI-AD and twenty-six HC listened to a short prose passage and were asked to freely recall it after delays of 1 h and 24 h. Results: Generalized linear mixed modelling revealed that, compared to HC, people with MCI-AD showed poorer encoding at immediate recall and steeper forgetting up to 1 h in prose memory as assessed by free recall and with repeated testing of the same material. Forgetting rates between groups did not differ from 1 h to 24 h. Conclusion: The differences observed in MCI-AD could be due to a post-encoding deficit. These findings could be accounted either by a differential benefit from retrieval practice, whereby people with MCI-AD benefit less than HC, or by a working memory deficit in people with MCI-AD, which fails to support their memory performance from immediate recall to 1 h.

Luciana Mascarenhas Fonseca, Naomi Sage Chaytor, Yunusa Olufadi, Dedra Buchwald, James E. Galvin, Maureen Schmitter-Edgecombe, Astrid Suchy-Dicey (Handling Associate Editor: Katherine Bangen)
Intraindividual Cognitive Variability and Magnetic Resonance Imaging in Aging American Indians: Data from the Strong Heart Study
Abstract: Background: American Indians have high prevalence of risk factors for Alzheimer’s disease and related dementias (ADRD) compared to the general population, yet dementia onset and frequency in this population are understudied. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, may be a novel, noninvasive biomarker of neurodegeneration and early dementia. Objective: To characterize the cross-sectional associations between IICV and hippocampal, total brain volume, and white matter disease measured by magnetic resonance imaging (MRI) among older American Indians. Methods: IICV measures for memory, executive function, and processing speed, and multidomain cognition were calculated for 746 American Indians (aged 64-95) who underwent MRI. Regression models were used to examine the associations of IICV score with hippocampal volume, total brain volume, and graded white matter disease, adjusting for age, sex, education, body mass index, intracranial volume, diabetes, stroke, hypertension, hypercholesterolemia, alcohol use, and smoking. Results: Higher memory IICV measure was associated with lower hippocampal volume (Beta= −0.076; 95%CI −0.499, −0.023; p=0.031). After adjustment for Bonferroni or IICV mean scores in the same tests, the associations were no longer significant. No IICV measures were associated with white matter disease or total brain volume. Conclusion: These findings suggest that the IICV measures used in this research cannot be robustly associated with cross-sectional neuroimaging features; nonetheless, the results encourage future studies investigating the associations between IICV and other brain regions, as well as its utility in the prediction of neurodegeneration and dementia in American Indians.

Lynn Chenoweth, Anna Williams, Jane McGuire, Patricia Reyes, Genevieve Maiden, Henry Brodaty, Zhixin Liu, Jacquelene Cook, Donna McCade, Cathleen Taylor-Rubin, Matilda Freeman, Claire Burley
Evaluating Implementation and Outcomes of a Person-Centered Care Model for People with Dementia in the Rehabilitation In-Patient Setting: Project Protocol
Abstract: Background: While Australian guidelines promote person-centered healthcare (PCC) for persons with dementia, healthcare systems, routines, rules, and workplace cultures can pose challenges in the provision of PCC. Objective: To present a knowledge translation protocol of the PCC model in a sub-acute rehabilitation hospital. Methods: The two-year pre/post/follow-up translation project will include (n=80) persons with dementia, (n=80) adult family/carers of patient participants, (n=60) healthcare staff (medical, nursing, allied health), and (n=8) PCC staff champions. Champions will complete six half-days’ training in PCC. Medical, nursing, and allied health staff will be provided with PCC learning manuals, complete six hours of online PCC education and attend six face-to-face PCC education sessions. Champions will provide ongoing support to staff in PCC practice. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework will be used to evaluate: i) outcomes for prospective patients provided with PCC, compared with a matched sample of retrospective patients (primary outcomes agitation incidence and severity); 2) champion and staff PCC knowledge, confidence, engagement, and practice quality; 3) person, family/carer, champion, and staff satisfaction with PCC; 4) PCC costs and benefits; and 5) organizational structures, systems and policies required to implement and maintain PCC in sub-acute healthcare. Results: We will identify if PCC benefits persons with dementia, staff, and healthcare services, and we will generate evidence on the educational and organizational resources required to embed PCC in practice. Conclusion: Project findings will inform tailored PCC education applications for dissemination in healthcare and produce evidence-based PCC practice guidelines to improve healthcare for persons with dementia.

Jessica Nicolazzo, Marina Cavuoto, Ella Rowsthorn, Lachlan Cribb, Lisa Bransby, Madeline Gibson, Prudence Wall, Dennis Velakoulis, Dhamidhu Eratne, Rachel Buckley, Nawaf Yassi, Stephanie Yiallourou, Amy Brodtmann, Garun S. Hamilton, Matthew T. Naughton, Yen Ying Lim, Matthew P. Pase (Handling Associate Editor: Ruth Peters)
Insomnia Symptoms and Biomarkers of Alzheimer’s Disease in the Community
Abstract: Background: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer’s disease remains equivocal. Objective: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a cognitively unimpaired middle-aged community sample. Methods: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia’s core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOE ε4 genotype. Results: Higher ISI score was associated with greater average levels of CSF Aβ42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p=0.002) and more awakenings (per 5: 123 pg/mL, 95% CI = 55-192, p<0.001). Difficulty initiating sleep was not associated with CSF Aβ42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels. Conclusion: Insomnia symptoms were associated with higher CSF Aβ42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.

Xingyao Tang*, Ying Wang*, Rafael Simó, Coen D.A. Stehouwer, Jian-Bo Zhou *These authors contributed equally to this work.
The Association Between Diabetes Duration and Domain-Specific Cognitive Impairment: A Population‑Based Study
Abstract: Background: Diabetes is a risk factor for cognitive impairment, and disease duration is associated with geriatric decline and functional disabilities. Objective: This study aimed to examine the association of diabetes duration with domain-specific cognitive impairment in elderly. Methods: A total of 3,142 participants from the National Health and Nutrition Examination Survey (NHANES) from the period between 2011 and 2014 were included. We assessed cognitive function using the Digit Symbol Substitution Test (DSST), the CERAD Word Learning (CERAD-WL) test, the CERAD Delayed Recall (CERAD-DR) test and animal fluency (AF) test. Results: After adjusting for age, sex, race/ethnicity, education level, and annual household income, we found that diabetes with a duration longer than 20 years were at 3.32-fold increased risk of DSST impairment (OR=3.32, 95%CI: 1.95 to 5.67), 1.72-fold increased risk of CERAD-WL impairment (OR=1.72, 95%CI: 1.13 to 2.62), and 1.76-fold increased risk of AF impairment (OR=1.76, 95%CI: 1.23 to 2.53), compared with those with no diabetes. Associations were generally stronger in women than in men. Participants with diabetes, who were diagnosed at 50-59 years old were at increased risk of DSST impairment, CERAD-WL impairment, CERAD-DR impairment, and AF impairment per 5 years longer duration of diabetes. Conclusion: Longer diabetes duration was associated with the increased risk of cognitive impairment, especially in processing speed and attention. The presence of chronic kidney disease was associated with the increased risk of DSST impairment.

Ataru Igarashi, Yukinori Sakata, Mie Azuma-Kasai, Harue Kamiyama, Mika Kawaguchi, Kiyoyuki Tomita, Mika Ishii, Manabu Ikeda
Linguistic and Psychometric Validation of the Cognition Bolt-On Version of the Japanese EQ-5D-5L for the Elderly
Abstract: Background: The need for a cognition bolt-on version of the EQ-5D, which would capture cognitive impairment by adding a dimension to the generic instrument assessing health status, has been increasing in Japan. Objective: To develop a cognition bolt-on version of the 5-level EQ-5D (EQ-5D-5L+C), we linguistically validated a cognition dimension and psychometrically validated the EQ-5D-5L+C. Methods: Following linguistic validation of the cognition dimension, psychometric validation of the EQ-5D-5L+C proxy version utilized anonymized data collected from nursing home residents between October 2021 to April 2022. The validity, reliability, and sensitivity to change were evaluated. Results: Data from 254 participants, including the finalized Japanese EQ-5D-5L+C proxy version, were analyzed for the psychometric validation. Mean (± standard deviation) age and Mini-Mental State Examination (MMSE) scores were 87.14±7.29 years and 15.76±8.46, respectively. The correlation was strongest between the cognition dimension and MMSE scores (rs=-0.640). Test-retest reliability was good in the cognition dimension in both baseline and two-time points (3 months: k=0.644; 6 months: k=0.656). Although a correlation between changes in the cognition dimension and those in the MMSE score from baseline was weak (3 months: rs=-0.191; 6 months: rs=-0.267), a correlation with changes in the MMSE score was higher when the cognition dimension was added compared to the EQ-5D alone (3 months: rs=-0.142 versus rs=-0.074). Conclusion: The Japanese EQ-5D-5L+C proxy version developed is a valid tool that captures health status including cognitive function, with a consideration for an over-time assessment. The benefits in adding the cognition dimension to the EQ-5D-5L to assess health state were suggested.

José María García-Alberca, Esther Gris, Paz de la Guía, Silvia Mendoza, María López de la Rica
Efficacy of Souvenaid® Combined with Acetylcholinesterase Inhibitors in the Treatment of Mild Alzheimer’s Disease
Abstract: Background: Souvenaid® is a medical food that contains nutrients that can help synapse synthesis in Alzheimer’s disease (AD). The potential effectiveness of combination therapy of Souvenaid with cholinesterase inhibitors (AChEI) is currently not well-known. Objective: To look into the effect of combination therapy with Souvenaid plus AChEI in people with mild AD in the real-world. Methods: We carried out a retrospective analysis in mild AD patients attending a memory clinic. Three groups were studied according to the treatment they received: Souvenaid alone (n=66), AChEI alone (n=84), and Souvenaid+AChEI (n=70). Treatment effects were evaluated at baseline, 6 and 12 months. Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test (TMT/A-B), Phonemic and Semantic Verbal Fluency Test (PVFT/SVFT); neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by the Bayer Activities Daily Living Scale (BAYER-S). A Mixed Model for Repeated Measures analysis was carried out to evaluate changes in outcome scores. Results: After 12 months Souvenaid+AChEI showed significant improvement in MMSE (p<0.001), RAVLT (p<0.0001), SVFT (p=0.002), PVFT (p=0.007), TMTA (p=0.039), TMTB (p=0.001), and NPI (p<0.0001) compared to AChEI alone. Conclusion: Souvenaid showed cognitive and behavioral benefits in mild AD patients. These effects increased when Souvenaid and AChEI were used in combination. This study can serve as a model for the design of prospective controlled trials that help to support the combined use of Souvenaid and antidementia drugs in AD.

Xin Wang, Xueyan Zhou, Jingyun Lee, Cristina M. Furdui, Tao Ma
In-Depth Proteomic Analysis of De Novo Proteome in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the most common dementia syndrome in the elderly characterized by synaptic failure and unique brain pathology. De novo protein synthesis is required for the maintenance of memory and synaptic plasticity. Mounting evidence links impaired neuronal protein synthesis capacity and overall protein synthesis deficits to AD pathogenesis. Meanwhile, identities of AD-associated dysregulation of “newly synthesized proteome” remain elusive. Objective: To investigate de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice. Methods: In this study, we combined the bioorthogonal noncanonical amino acid tagging (BONCAT) method with the unbiased large-scale proteomic analysis in acute living brain slices (we name it “BONSPEC”) to investigate de novo proteome alterations in the hippocampus of Tg19959 AD model mice. We further applied multiple bioinformatics methods to analyze in-depth the proteomics data. Results: In total, 1,742 proteins were detected across the 10 samples with the BONSPEC method. After exclusion of those only detected in less than half of the samples in both groups, 1,362 proteins were kept for further analysis. 37 proteins were differentially expressed (based on statistical analysis) between the WT and Tg19959 groups. Among them, 19 proteins were significantly decreased while 18 proteins were significantly increased in the hippocampi of Tg19959 mice compared to WT mice. The results suggest that proteins involved in synaptic function were enriched in de novo proteome of AD mice. Conclusion: Our study could provide insights into the future investigation into the molecular signaling mechanisms underlying AD and related dementias (ADRDs).

Lidón Marin-Marin, Anna Miró-Padilla, Víctor Costumero
Structural But Not Functional Connectivity Differences within Default Mode Network Indicate Conversion to Dementia
Abstract: Background: Malfunctioning of the default mode network (DMN) has been consistently related to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, evidence on differences in this network between MCI converters (MCI-c) and non-converters (MCI-nc), which could mark progression to AD, is still inconsistent. Objective: To multimodally investigate the DMN in the AD continuum. Methods: We measured gray matter (GM) volume, white matter (WM) integrity, and functional connectivity (FC) at rest in healthy elderly controls, MCI-c, MCI-nc, and AD patients, matched on sociodemographic variables. Results: Significant differences between AD patients and controls were found in the structure of most of the regions of the DMN. MCI-c only differed from MCI-nc in GM volume of the left parahippocampus and bilateral hippocampi and middle frontal gyri, as well as in WM integrity of the parahippocampal cingulum connecting the left hippocampus and precuneus. We found significant correlations between integrity in some of those regions and global neuropsychological status, as well as an excellent discrimination ability between converters and non-converters for the sum of GM volume of left parahippocampus, bilateral hippocampi, and middle frontal gyri, and WM integrity of left parahippocampal cingulum. However, we found no significant differences in FC. Conclusion: These results further support the relationship between abnormalities in the DMN and AD, and suggest that structural measures could be more accurate than resting-state estimates as markers of conversion from MCI to AD.

Rachel R. Corrigan, Luis Labrador*, John Grizzanti*, Megan Mey, Helen Piontkivska, Gemma Casadesus-Smith *These authors contributed equally to this work.
Neuroprotective Mechanisms of Amylin Receptor Activation, Not Antagonism, in the APP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Background: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer’s disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. Objective: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. Methods: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. Results: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. Conclusion: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD.

Yu Kyung Jun, Seung Woo Lee, Kwang Woo Kim, Jung Min Moon, Seong-Joon Koh, Hyun Jung Lee, Joo Sung Kim, Kyungdo Han*, Jong Pil Im* *These authors contributed equally to this work and share last authorship.
Positive Results from the Fecal Immunochemical Test Can Be Related to Dementia: A Nationwide Population-Based Study in South Korea
Abstract: Background: The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC. Objective: We investigated the association between positive results of FIT and the incidence of dementia using a nationwide database. Methods: FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service. Results: The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p<0.0001). FIT-positive participants had a higher risk of Alzheimer’s disease (AD) (p<0.0001) and vascular dementia (p=0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age <65 years) than older participants (p<0.0001 for all kinds of dementia; p=0.0002 for AD). Conclusion: FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies.

Mingming Yang, Rongrong Qi, Yuxiao Liu, Xin Shen, Yulou Zhao, Nana Jin, Ruozhen Wu, Fei Liu, Jianlan Gu
Casein Kinase 1δ Phosphorylates TDP-43 and Suppresses Its Function in Tau mRNA Processing
Abstract: Background: Neurofibrillary tangles aggregated from anomalous hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD). Trans-active response DNA-binding protein of 43 kDa (TDP-43) enhances the instability and exon (E) 10 inclusion of tau mRNA. Cytoplasmic inclusion of hyperphosphorylated TDP-43 in the neurons constitutes the third most prevalent proteinopathy of AD. Casein kinase 1δ (CK1δ) is elevated in AD brain and phosphorylates TDP-43 in vitro. Objective: To determine the roles of CK1δ in phosphorylation, aggregation, and function of TDP-43 in the processing of tau mRNA. Methods: The interaction and colocalization of TDP-43 and CK1δ were analyzed by co-immunoprecipitation and immunofluorescence staining. TDP-43 phosphorylation by CK1δ was determined in vitro and in cultured cells. RIPA-insoluble TDP-43 aggregates obtained by ultracentrifugation were analyzed by immunoblots. The instability and E10 splicing of tau mRNA were studied by using a reporter of green fluorescence protein tailed with 3’-untranslational region of tau mRNA and a mini-tau gene and analyzed by real-time quantitative PCR and reverse transcriptional PCR. Results: We found that CK1δ interacted and co-localized with TDP-43. TDP-43 was phosphorylated by CK1δ at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells, which was mutually enhanced. CK1δ overexpression promoted the aggregation of TDP-43 and suppressed its activity in enhancing the instability and E10 inclusion of tau mRNA. Conclusion: CK1δ phosphorylates TDP-43, promotes its aggregation, and inhibits its activity in promoting the instability of tau mRNA and inclusion of tau E10. Elevated CK1δ in AD brain may contribute to TDP-43 and tau pathologies directly or indirectly.

Ruihua Sun, Junkui Shang, Xi Yan, Jingran Zhao, Wan Wang, Wenjing Wang, Wei Li, Chenhao Gao, Fengyu Wang, Haohan Zhang, Yanliang Wang, Huixia Cao, Jiewen Zhang
VCAM1 Drives Vascular Inflammation Leading to Continuous Cortical Neuronal Loss Following Chronic Cerebral Hypoperfusion
Abstract: Background: Chronic cerebral hypoperfusion (CCH) is associated with neuronal loss and blood-brain barrier (BBB) impairment in vascular dementia (VaD). However, the relationship and the molecular mechanisms between BBB dysfunction and neuronal loss remain elusive. Objective: We explored the reasons for neuron loss following CCH. Methods: Using permanent bilateral common carotid artery occlusion (2VO) rat model, we observed the pathological changes of cortical neurons and BBB in the sham group as well as rats 3d, 7d, 14d, and 28d post 2VO. In order to further explore the factors influencing neuron loss following CCH with regard to cortical blood vessels, we extracted cortical brain microvessels at five time points for transcriptome sequencing. Finally, integrin receptor a4β1 (VLA-4) inhibitor was injected into the tail vein, and cortical neuron loss was detected again. Results: We found that cortical neuron loss following CCH is a continuous process, but damage to the BBB is acute and transient. Results of cortical microvessel transcriptome analysis showed that biological processes related to vascular inflammation mainly occurred in the chronic phase. Meanwhile, cell adhesion molecules, cytokine-cytokine receptor interaction were significantly changed at this phase. Among them, the adhesion molecule VCAM1 plays an important role. Using VLA-4 inhibitor to block VCAM1-VLA-4 interaction, cortical neuron damage was ameliorated at 14d post 2VO. Conclusion: Injury of the BBB may not be the main reason for persistent loss of cortical neurons following CCH. The continuous inflammatory response within blood vessels maybe an important factor in the continuous loss of cortical neurons following CCH.

Hamed Azami, Sebastian Moguilner, Hector Penagos, Rani A. Sarkis, Steven E. Arnold, Stephen N. Gomperts*, Alice D. Lam* *These authors contributed equally to this work.
EEG Entropy in REM Sleep as a Physiologic Biomarker in Early Clinical Stages of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is associated with EEG changes across the sleep-wake cycle. As the brain is a non-linear system, non-linear EEG features across behavioral states may provide an informative physiologic biomarker of AD. Multiscale fluctuation dispersion entropy (MFDE) provides a sensitive non-linear measure of EEG information content across a range of biologically relevant time-scales. Objective: To evaluate MFDE in awake and sleep EEGs as a potential biomarker for AD. Methods: We analyzed overnight scalp EEGs from 35 cognitively normal healthy controls, 23 participants with mild cognitive impairment (MCI), and 19 participants with mild dementia due to AD. We examined measures of entropy in wake and sleep states, including a slow-to-fast-activity ratio of entropy (SFAR-entropy). We compared SFAR-entropy to linear EEG measures including a slow-to-fast-activity ratio of power spectral density (SFAR-PSD) and relative alpha power, as well as to cognitive function. Results: SFAR-entropy differentiated dementia from MCI and controls. This effect was greatest in REM sleep, a state associated with high cholinergic activity. Differentiation was evident in the whole brain EEG and was most prominent in temporal and occipital regions. Five minutes of REM sleep was sufficient to distinguish dementia from MCI and controls. Higher SFAR-entropy during REM sleep was associated with worse performance on the Montreal Cognitive Assessment. Classifiers based on REM sleep SFAR-entropy distinguished dementia from MCI and controls with high accuracy, and outperformed classifiers based on SFAR-PSD and relative alpha power. Conclusion: SFAR-entropy measured in REM sleep robustly discriminates dementia in AD from MCI and healthy controls.