Volume 96, Number 4, 2023

Pages 1339-1352

Emily M. Briceño, Usha Dhakal, Uttam Sharma, Nabin Adhikari, Meeta S. Pradhan, Lochana Shrestha, Pankaj Jalan, Janak Rai, Kenneth M. Langa, Jinkook Lee, Dirgha Ghimire, Carlos F. Mendes de Leon
Neuropsychological Assessment of Older Adults in Nepal for Population-Based Dementia Ascertainment: Needs, Challenges, and Opportunities
Abstract: The population of Nepal is rapidly aging, as in other low and middle-income countries, and the number of individuals living with Alzheimer’s Disease and related dementias (ADRD) is expected to increase. However, information about the neuropsychological assessment of ADRD in Nepal is lacking. We first aimed to examine the needs, challenges, and opportunities associated with the neuropsychological assessment of older adults in Nepal for population-based ADRD ascertainment. Second, we introduce the Chitwan Valley Family Study-Study of Cognition and Aging in Nepal (CVFS-SCAN), which is poised to address these needs, and its collaboration with the Harmonized Cognitive Assessment Protocol (HCAP) international network. We reviewed the existing literature on the prevalence, risk factors, available neuropsychological assessment instruments, and sociocultural factors that may influence the neuropsychological assessment of older adults for ADRD ascertainment in Nepal. Our review revealed no existing population-based data on the prevalence of ADRD in Nepal. Very few studies have utilized formal cognitive assessment instruments for ADRD assessment, and there have been no comprehensive neuropsychological assessment instruments that have been validated for the assessment of ADRD in Nepal. We describe how the CVFS-SCAN study will address this need through careful adaptation of the HCAP instrument. We conclude that the development of culturally appropriate neuropsychological assessment instruments is urgently needed for the population-based assessment of ADRD in Nepal. The CVFS-SCAN is designed to address this need and will contribute to the growth of global and equitable neuropsychology and to the science of ADRD in low- and middle-income countries.

Pages 1353-1382

William B. Grant, Steven M. Blake
Diet’s Role in Modifying Risk of Alzheimer’s Disease: History and Present Understanding
Abstract: Diet is an important nonpharmacological risk-modifying factor for Alzheimer’s disease (AD). The approaches used here to assess diet’s role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15–20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries’ entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low–animal product diet with plenty of anti-inflammatory, low–glycemic load foods may be helpful.

Pages 1383-1398

Shuqi Tao*, Wenyuan Fan*, Jinmeng Liu*, Tong Wang, Haoning Zheng, Gaoxiu Qi, Yanchun Chen, Haoyun Zhang, Zhangyu Guo, Fenghua Zhou *These authors contributed equally to this work.
NLRP3 Inflammasome: An Emerging Therapeutic Target for Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is currently the most prevalent neurological disease, and no effective and practical treatments and therapies exist. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (NLRP3) inflammasome is vital in the human innate immune response. However, when the NLRP3 inflammasome is overactivated by persistent stimulation, several immune-related diseases, including AD, atherosclerosis, and obesity, result. This review will focus on the composition and activation mechanism of the NLRP3 inflammasome, the relevant mechanisms of involvement in the inflammatory response to AD, and AD treatment targeting NLRP3 inflammasome. This review aims to reveal the pathophysiological mechanism of AD from a new perspective and provide the possibility of more effective and novel strategies for preventing and treating AD.

Pages 1399-1409

Paloma Monllor, Praktush Kumar, Mari-Ángeles Lloret, Artemis Ftara, Jose-Luis Leon, Begoña Lopez, Ana Cervera-Ferri, Ana Lloret (Handling Associate Editor: Madeleine Hackney) *These authors contributed equally to this work.
Multifactorial Causation of Alzheimer’s Disease Due to COVID-19
Abstract: There are several implications of the surge in the incidence of pandemics and epidemics in the last decades. COVID-19 being the most remarkable one, showed the vulnerability of patients with neurodegenerative diseases like Alzheimer’s disease (AD). This review studies the pathological interlinks and triggering factors between the two illnesses and proposes a multifactorial pathway of AD causation due to COVID-19. The article first evaluates and describes all the postulated hypotheses which explain the etiology and possible pathogenesis of the disease in four domains: Inflammation and Neurobiochemical interactions, Oxidative Stress, Genetic Factors, and Social Pathology. We believe that a probable hypothesis of an underlying cause of AD after COVID-19 infection could be the interplay of all these factors.

Pages 1411-1426

Xiao Xue Zeng, Jie Bangzhe Zeng
Systems Medicine as a Strategy to Deal with Alzheimer’s Disease
Abstract: The traits of Alzheimer's disease (AD) include amyloid plaques made of Aβ1-40 and Aβ1-42, and neurofibrillary tangles by the hyperphosphorylation of tau protein. AD is a complex and disorder that is heterogenous in genetical, neuropathological, and clinical contexts. Current available therapeutics are unable to cure AD. Systems medicine is a strategy by viewing the body as a whole system, taking into account each individual’s unique health profile, provide treatment and associated nursing care clinically for the patient, aiming for precision. Since the onset of AD can lead towards cognitive impairment, it is vital to intervene and diagnose early and prevent further progressive loss of neurons. Moreover, as the individual’s brain functions are impaired due to neurodegeneration in AD, it is essential to reconstruct the neurons or brain cells to enable normal brain functions. Although there are different subtypes of AD due to varied pathological lesions, in the majority cases of AD, neurodegeneration and severe brain atrophy develop at the chronic stage. Novel approaches including RNA based gene therapy, stem cell based technology, bioprinting technology, synthetic biology for brain tissue reconstruction are researched in recent decades in the hope to decrease neuroinflammation and restore normal brain function in individuals of AD. Systems medicine include the prevention of disease, diagnosis and treatment by viewing the individual’s body as a whole system, along with systems medicine based nursing as a strategy against AD that should be researched further.

Pages 1427-1439
Systematic Review

Patricio Solis-Urra, María Rodriguez-Ayllon, Miriam Álvarez-Ortega, Cristina Molina-Hidalgo, Pablo Molina-Garcia, Cristina Arroyo-Ávila, Antonio García-Hermoso, Audrey M. Collins, Shivangi Jain, Juan Domingo Gispert, Teresa Liu-Ambrose, Francisco B. Ortega, Kirk I. Erickson, Irene Esteban-Cornejo
Physical Performance and Amyloid-β in Humans: A Systematic Review and Meta-Analysis of Observational Studies
Abstract: Background: Accumulation of amyloid-β (Aβ) plaques is one of the main features of Alzheimer’s disease (AD). Physical performance has been related to dementia risk and Aβ, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aβ. Yet, no evidence synthesis has been performed in humans. Objective: To investigate the association of physical performance with Aβ in humans, including Aβ accumulation on brain, and Aβ abnormalities measured in cerebrospinal fluid (CSF) and blood. Methods: A systematic review with multilevel meta-analysis was performed from inception to June 16th, 2022. Studies were eligible if they examined the association of physical performance with Aβ levels, including the measure of physical performance as a predictor and the measure of Aβ as an outcome in humans. Results: 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aβ in the brain (ES= 0.01; 95% CI -0.21 to 0.24; I2= 69.9%), in the CSF (ES= -0.28; 95% CI -0.98 to 0.41; I2= 91.0%) or in the blood (ES=-0.19; 95% CI -0.61 to 0.24; I2= 99.75%). Significant heterogeneity was found across the results, which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. Conclusions: The association between physical performance and Aβ is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aβ levels in humans.

Pages 1441-1451
Systematic Review

Maria Ly*, Gary Z. Yu*, Won Jong Chwa, Cyrus A. Raji *These authors contributed equally to this work.
Paving the Way for Alzheimer's Disease Prevention: A Systematic Review of Global Open-Access Neuroimaging Datasets in Healthy Individuals
Abstract: Background: Given the advent of large-scale neuroimaging data-driven endeavors for Alzheimer’s disease, there is a burgeoning need for well-characterized neuroimaging databases of healthy individuals. With the rise of initiatives around the globe for the rapid and unrestricted sharing of data resources, there is now an abundance of open-source neuroimaging datasets available to the research community. However, there is not yet a systematic review that fully details the demographic information and modalities actually available in all open access neuroimaging databases around the globe. Objective: This systematic review aims to provide compile a list of MR structural imaging databases encompassing healthy individuals across the lifespan. Methods: In this systematic review, we searched EMBASE and PubMed until May 2022 for open-access neuroimaging databases containing healthy control participants of any age, race, with normal development and cognition having at least one structural T1-weighted neuroimaging scan. Results: A total of 403 databases were included, for up to total of 48,268 participants with all available demographic information and imaging modalities detailed in Supplementary Table 1. There were significant trends noted when compiling normative databases for this systematic review, notably that 11.7% of databases included reported ethnicity in their participants, with underrepresentation of many socioeconomic groups globally. Conclusions: As efforts to improve primary prevention of AD may require a broader perspective including increased relevance of earlier stages in life, and strategies in addressing modifiable risk factors may be individualized to specific demographics, improving data characterization to be richer and more rigorous will greatly enhance these efforts.

Pages 1453-1476
Scoping Review

Stephanie M. Grasso, Camille A. Wagner Rodriguez, Núria Montagut Colomer, Sonia-Karin Marqués Kiderle, Raquel Sánchez-Valle, Miguel Ángel Santos Santos (Handling Associate Editor: Jordi Matias Guiu)
Bilingual Primary Progressive Aphasia: A Scoping Review of Assessment and Treatment Practices
Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by speech and/or language impairment with relatively spared cognition. Research investigating behavioral speech-language intervention and methods for cognitive-linguistic assessment in PPA has predominantly centered around monolingual speakers. This gap hinders the widespread adoption of evidence-based approaches and exacerbates the inequities faced by culturally and linguistically diverse populations living with PPA. Objective: This scoping review synthesizes the current evidence for assessment and treatment practices in bilingual PPA as well as the operationalization of bilingualism in PPA. Methods: Arksey & O’Malley’s scoping review methodology was utilized. Information was extracted from each study and entered into a data-charting template designed to capture information regarding operationalization of bilingualism in PPA and assessment and treatment practices. Results: Of the 16 identified studies, 14 reported the results of assessments conducted in both languages. Three studies reported positive naming treatment outcomes. Thirteen studies included English-speaking participants, revealing linguistic bias. Most studies reported age of acquisition, proficiency, and patterns of language use rather than providing an operational definition for bilingualism. Conclusions: Neither formal assessment measures nor clear guidelines for assessment of bilingual PPA currently exist; however, language-specific measures are emerging. Speech-language intervention in bilingual PPA has been relatively unexplored, representing a significant gap in the literature. In order to improve diagnostic and treatment options for bilingual PPA, targeted efforts to increase representation of bilinguals from various sociocultural contexts, as well as those who speak a variety of language pairs, is necessary.

Pages 1477-1488
Mu-Cyun Wang, Jeng-Min Chiou, Yen-Ching Chen, Jen-Hau Chen
Association Between Olfactory Dysfunction and Cognitive Impairment in Dementia-Free Older Adults: A Prospective Cohort Study in Taiwan
Abstract: Background: Previous studies assessing olfactory function and cognition have mostly been cross-sectional, and few have investigated the Asian geriatric population. Objective: To examine the relationships of olfaction with global or domain-specific cognitive function in Taiwanese community-dwelling older adults. Methods: This cohort study (2015-2019) is part of the Taiwan Initiative for Geriatric Epidemiological Research. The Taiwanese version of the Montreal Cognitive Assessment (MoCA-T) and a battery of neuropsychological tests were assessed at baseline and at a two-year follow-up. The cross-culture modified Sniffin' Sticks Identification Test (SSIT) was utilized to measure olfactory function. Generalized linear mixed models were used to examine the association of olfaction with cognitive performance over two years. Results: Data were collected from 376 participants (55.1% women), with a mean age of 75.6 years. A one-point decrease in the SSIT score (worsening of olfaction) was associated with worse global cognition (MoCA-T: β ̂=-0.13), memory (β ̂=-0.08 to -0.06), and verbal fluency (β ̂=-0.07). Compared with an SSIT score≥11 (normosmia), an SSIT score<8 (anosmia) was associated with worse global cognition (MoCA-T: β ̂=-0.99), memory (β ̂=-0.48 to -0.42), executive function (Trail Making Test A: β ̂=-0.36), attention (digit span backward: β ̂=-0.34), and verbal fluency (β ̂=-0.45). After stratified analyses, the associations remained in older adults ≥75 years, males, and non-carriers of apolipoprotein E ε4 in terms of global cognition, memory, and verbal fluency. Conclusions: Odor identification deficits were associated with poor global or domain-specific cognitive function in a four-year cohort of community-dwelling older adults. Cognitive assessments should be conducted in dementia-free elderly individuals with impaired odor identification.

Pages 1489-1504
Xiaoping Wang, Rui Huang, Bin Huang, Xiaojia Li
S1PR2 Regulates Autophagy Through the AKT/mTOR Pathway to Promote Pathological Damage in Alzheimer’s Disease
Abstract: Background: Alzheimer's disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases. Objective: This study aimed to explore the role and possible mechanism of S1PR2 in AD. Methods: S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aβ25-35 to construct an AD cell model, and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed. Results: The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aβ production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2. Conclusion: S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway.

Pages 1505-1514
Zhengshi Yang, Sarah J. Banks, Aaron R. Ritter, Jeffrey L. Cummings, Karthik Sreenivasan, Jefferson W. Kinney, Jessica K. Caldwell, Christina G. Wong, Justin B. Miller, Dietmar Cordes
Microglial Imaging in Alzheimer’s Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study
Abstract: Background: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer’s disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. Objective: The goal of this study was to study human GE180 from the perspective of the previous animal observations. Methods: With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. Results: Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. Conclusions: 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

Pages 1515-1528
Elin Axelsson Andrén, Petronella Kettunen, Maria Bjerke, Sindre Rolstad, Henrik Zetterberg, Kaj Blennow, Anders Wallin, Johan Svensson (Handling Associate Editor: Yi-Cheng Zhu)
Diagnostic Performance of Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid-β Protein Precursor β in the Subcortical Small Vessel Type of Dementia
Abstract: Background: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. Objective: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer’s disease (AD), and mixed dementia (combined AD and SSVD). Methods: This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96). The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated. Results: Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834 – 0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830 – 0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838 – 0.968). Conclusions: The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers.

Pages 1549-1546
Fan Zhang, Melissa Petersen, Leigh Johnson, James Hall, Sid E. O’Bryant, for the Health and Aging Brain Study (HABS-HD) Study Team
Comorbidities Incorporated to Improve Prediction for Prevalent Mild Cognitive Impairment and Alzheimer's Disease in the HABS-HD Study
Abstract: Background: Blood biomarkers have the potential to transform Alzheimer's disease (AD) diagnosis and monitoring, yet their integration with common medical comorbidities remains insufficiently explored. Objective: This study aims to enhance blood biomarkers' sensitivity, specificity, and predictive performance by incorporating comorbidities. We assess this integration's efficacy in diagnostic classification using machine learning, hypothesizing that it can identify a confident set of predictive features. Methods: We analyzed data from 1,705 participants in the Health and Aging Brain Study-Health Disparities, including 116 AD patients, 261 with mild cognitive impairment, and 1,328 cognitively normal controls. Blood samples were assayed using electrochemiluminescence and single molecule array technology, alongside comorbidity data gathered through clinical interviews and medical records. We visually explored blood biomarker and comorbidity characteristics, developed a Feature Importance and SVM-based Leave-One-Out Recursive Feature Elimination (FI-SVM-RFE-LOO) method to optimize feature selection, and compared four models: Biomarker Only, Comorbidity Only, Biomarker and Comorbidity, and Feature-Selected Biomarker and Comorbidity. Results: The combination model incorporating 17 blood biomarkers and 12 comorbidity variables outperformed single-modal models, with NPV12 at 92.78%, AUC at 67.59%, and Sensitivity at 65.70%. Feature selection led to 22 chosen features, resulting in the highest performance, with NPV12 at 93.76%, AUC at 69.22%, and Sensitivity at 70.69%. Additionally, interpretative machine learning highlighted factors contributing to improved prediction performance. Conclusions: In conclusion, combining feature-selected biomarkers and comorbidities enhances prediction performance, while feature selection optimizes their integration. These findings hold promise for understanding AD pathophysiology and advancing preventive treatments.

Pages 1547-1554
Júlia Carolina Lopes Boschetti, Karla Lírio Soares, Glaucimeire Rocha Carvalho, Abraão Carlos Verdin Filho, Alyne Mendonça Marques Ton, Thiago de Melo Costa Pereira, Rodrigo Scherer
CGAs-Rich Conilon Coffee Consumption Improves Cognition and Reduces Oxidative Stress in Elderly with Alzheimer’s Disease: A Pilot Study
Abstract: Background: The consumption of coffee has been associated with beneficial effects when it comes to Alzheimer’s disease (AD). However, to the best of our knowledge, there are no studies on Conilon coffee consumption in elderly people with AD. Objective: Evaluate the effects of Conilon coffee consumption in elderly with AD. Methods: The study was carried out with 9 participants who consumed a minimum of 2 cups (200 mL cup) of Conilon coffee per day for 90 days. Cognitive assessment was done before (T0) and after 90 days (T90). Blood analysis was conducted at T0 and T90, as well as the assessment of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive species (TBARS). The levels of chlorogenic acids and caffeine in the coffee beverage were quantified by liquid chromatography. Results: During the treatment, the participants consumed at least 550 mg and 540 mg of CGAs and caffeine, respectively. A significant improvement in cognition between T0 and T90 was observed as per MMSE, CTP, and clock drawing tests. Furthermore, there was a significant reduction in AOPP (37%) and TBARS (60%), indicating a reduction in oxidative stress. The consumption of the coffee did not significantly alter any blood parameter, which confirms the safety of the coffee treatment during the 90 days. Conclusions: Our study demonstrated for the first time that regular consumption of coffee with high amounts of CGAs and caffeine improves cognitive functions and reduces oxidative stress, without altering blood parameters that indicate possible signs of toxicity in classical target organs.

Pages 1555-1563
Jie-Qiong Li*, Xiao-Ling Zhong*, Jing-Hui Song, Song Chi, An-Mu Xie, Lan Tan, Jin-Tai Yu, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Associations Between TREML2 Gene Variants and Alzheimer’s Disease: Biomarkers, Neuroimage, and Cognition
Abstract: Background: Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. Objective: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). Methods: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ε4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. Results: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Conclusions: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

Pages 1565-1578
Ahmet Sarper Bozkurt, Şenay Görücü Yılmaz
Ferroptotic Potency of ISM1 Expression in the Drug-Induced Alzheimer’s Disease-Like Phenotype Under the Influence of Betulin
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by two main pathological mechanisms, mostly hyperphosphorylated tau and amyloid-β toxicity. Although many studies focus on these basic mechanisms, ferroptosis draws attention as an important pathway responsible for neurodegeneration in AD. There is no definitive treatment for AD but alternative phytochemicals to drugs come into prominence. Betulin is usually obtained from the birch tree. It is an abundant triterpene and has a high antioxidant capacity. Isthmin-1 (ISM1) is a secreted adipokine. Objective: In this study, we investigated the potential treatment of AD in the ferroptosis-ISM1-betulin triangle. Methods: For this, we created an AD model with okadaic acid (200 ng/kg)) in 36 Wistar albino male rats and treated with betulin (20 mg/kg/day, i.p). We evaluated ISM1 gene expression, iron accumulation, and total oxidative metabolism parameters (TAS, TOS, OSI) in hippocampal tissue. We analyzed cognitive recovery in AD with Morris Water Maze Test and general locomotor activity, explore, and anti-anxiolytic effect with Open Field Test. Results: We compared the obtained data with metabolic and genetic results. In conclusion, betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Conclusions: Betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Although this study suggests the corrective effect of betulin and ISM1 on cognitive gain and anxiety, it is the first study to show the total antioxidant capacity of betulin in AD.

Pages 1579-1592
Jing Tian, Eric Du, Kun Jia, Tienju Wang, Lan Guo, Jeffrey M. Zigman, Heng Du
Elevated Ghrelin Promotes Hippocampal Ghrelin Receptor Defects in Humanized Amyloid-β Knockin Mice During Aging
Abstract: Background: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer’s disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. Objective: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin (hAβ KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. Methods: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAβ KI mice as well as primary neuron cultures. Results: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. Conclusions: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings.

Pages 1593-1607
Wafa El Kadiri*, Manon Perrignon-Sommet*, Benoit Delpont, Mathilde Graber, Sophie Mohr, Thomas Mouillot, Hervé Devilliers, Sylvie Grall, Fabienne Lienard, Marjolaine Georges, Marie-Claude Brindisi, Laurent Brondel, Yannick Bejot, Corinne Leloup, Agnès Jacquin-Piques *These authors contributed equally to this work.
Changes in Taste Perception in Patients with Minor and Major Cognitive Impairment Linked to Alzheimer’s Disease Recorded by Gustatory Evoked Potentials
Abstract: Background: The need for early diagnosis biomarkers in Alzheimer’s disease (AD) is growing. Only few studies have reported gustatory dysfunctions in AD using subjective taste tests. Objective: The main purpose of the study was to explore gustatory functions using subjective taste tests and recordings of gustatory evoked potentials (GEPs) for sucrose solution in patients with minor or major cognitive impairment (CI) linked to AD, and to compare them with healthy controls. The secondary objective was to evaluate the relationships between GEPs and the results of cognitive assessments and fasting blood samples. Methods: A total of 45 subjects (15 healthy subjects, 15 minor CI patients, 15 major CI patients) were included to compare their gustatory functions and brain activity by recording GEPs in response to a sucrose stimulation. CI groups were combined in second analyses in order to keep a high power in the study. Correlations were made with cognitive scores and hormone levels (ghrelin, leptin, insulin, serotonin). Results: Increased P1 latencies and reduced N1 amplitudes were observed in minor or major patients compared to controls. GEPs were undetectable in 6 major and 4 minor CI patients. Thresholds for sucrose detection were significantly higher in the major CI group than in controls or the minor CI group. No correlation was found with hormone levels. Conclusions: The cortical processing of sensory taste information seems to be altered in patients with minor or major CI linked to AD. This disturbance was identifiable with subjective taste tests only later, at the major CI stage.

Pages 1609-1622
José María García-Alberca, María Dolores de la Rosa, Paloma Solo de Zaldívar, María Ledesma, Estela Oltra, Esther Gris, Olga Ocejo, Javier Torrecilla, Carmen Zafra, Ana Sánchez-Fernández, Tomás Mancilla, Mercedes López-Romero, Raquel Jerez, Nuria Santana, José Pablo Lara, Miguel Ángel Barbancho, Encarnación Blanco-Reina
Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer’s disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD. Objective: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia. Methods: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n=40) that received three times a week one session per day of 20 minutes in the NSC and a control group (n=37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis. Results: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score -18.87±5.56 versus -1.74±0.67, p=0.004), agitation (mean change score -2.32±2.02 versus -0.78±1.44, p=0.003) and irritability (mean change score -3.35±2.93 versus -1.42±1.31, p=0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score -9.67±7.67 versus -7.66±6.08, p=0.003). Conclusions: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia.

Pages 1623-1638
Takeshi Kawarabayashi, Takumi Nakamura, Kazuya Miyashita, Tatsuya Segawa, Isamu Fukamachi, Takashi Sugawara, Hironori Oka, Kunihiko Ishizawa, Masakuni Amari, Hiroo Kasahara, Kouki Makioka, Yoshio Ikeda, Masamitsu Takatama, Mikio Shoji
Clinical Evaluation of Cerebrospinal Fluid p217tau and Neurofilament Light Chain Levels in Patients with Alzheimer’s Disease or Other Neurological Diseases
Abstract: Background: The cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 217 (p217tau) or 181 (p181tau), and neurofilament light chain (NfL) are definite biomarkers of tauopathy and neurodegeneration in Alzheimer’s disease (AD). Objective: To validate their utility in excluding other neurological diseases and age-related changes in clinical settings. Methods: We developed monoclonal antibodies against p217tau and NfL, established novel ELISAs, and analyzed 170 CSF samples from patients with AD or other neurological diseases. Results: In AD, p217tau is a more specific and abundant CSF component than p181tau. However, CSF NfL levels increase age-dependently and to a greater extent in central and peripheral nervous diseases than in AD. Conclusions: CSF p217tau correlates better with AD neurodegeneration than other tau-related biomarkers and the major phosphorylated tau species. The clinical usage of NfL as a neurodegeneration biomarker in AD requires exclusion of various central and peripheral neurological diseases.

Pages 1639-1649
Dongbing Lai, Michael Zhang, Rudong Li, Chi Zhang, Pengyue Zhang, Yunlong Liu, Sujuan Gao, Tatiana Foroud
Identifying Genes Associated with Alzheimer’s Disease Using Gene-Based Polygenic Risk Score
Abstract: Background: Except APOE, Alzheimer’s disease (AD) associated genes identified in recent large-scale genome-wide association studies (GWAS) had small effects and explained a small portion of heritability. Many AD-associated genes have even smaller effects thereby sub-threshold p-values in large-scale GWAS and remain to be identified. For some AD-associated genes, drug targeting them may have limited efficacies due to their small effect sizes. Objective: The purpose of this study is to identify AD-associated genes with sub-threshold p-values and prioritize drugs targeting AD-associated genes that have large efficacies. Methods: We developed a gene-based polygenic risk score (PRS) to identify AD genes. It was calculated using SNPs located within genes and having the same directions of effects in different study cohorts to exclude cohort-specific findings and false positives. Gene co-expression modules and protein-protein interaction networks were used to identify AD-associated genes that interact with multiple other genes, as drugs targeting them have large efficacies via co-regulation or interactions. Results: Gene-based PRS identified 389 genes with 164 of them not previously reported as AD-associated. These 389 genes explained 56.12%-97.46% SNP heritability; and they were enriched in brain tissues and 164 biological processes, most of which are related to AD and other neurodegenerative diseases. We prioritized 688 drugs targeting 64 genes that were in the same co-expression modules and/or PPI networks. Conclusions: Gene-based PRS is a cost-effective way to identify AD-associated genes without substantially increasing the sample size. Co-expression modules and PPI networks can be used to identify drugs having large efficacies.

Pages 1651-1661
Yan-Bing Liu, Xue-Jie Wang, Lan Tan, Chen-Chen Tan, Wei Xu, for the Alzheimer’s Disease Neuroimaging Initiative
PICALM Variation Moderates the Relationships of APOE ε4 with Alzheimer’s Disease Cerebrospinal Biomarkers and Memory Function Among Non-Demented Population
Abstract: Background: APOE ε4 and PICALM are established genes associated with risk of late-onset Alzheimer’s disease (AD). Previous study indicated interaction of PICALM with APOE ε4 in AD patients. Objective: To explore whether PICALM variation could moderate the influences of APOE ε4 on AD pathology biomarkers and cognition in pre-dementia stage. Methods: A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ε4 carriers) were genotyped for PICALM rs3851179 and APOE ε4 at baseline and were followed for influences on changes of cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis. Results: The interaction term of rs3851179 × APOE ε4 accounted for a significant amount of variance in baseline general cognition (p = 0.039) and memory function (p = 0.002). The relationships of APOE ε4 with trajectory of CSF Aβ42 (p = 0.007), CSF P-tau181 (p = 0.003), CSF T-tau (p = 0.001), and memory function (p = 0.017) were also moderated by rs3851179 variation. Conclusions: APOE ε4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ε4 in pre-dementia stage.

Pages 1663-1683
Morgan J. Robinson, Sean Newbury, Kartar Singh, Zoya Leonenko, Michael A. Beazely (Handling Associate Editor: Rakez Kayed)
The Interplay Between Cholesterol and Amyloid-β on HT22 Cell Viability, Morphology, and Receptor Tyrosine Kinase Signaling
Abstract: Background: There is a lack of understanding in the molecular and cellular mechanisms of Alzheimer’s disease that has hindered progress on therapeutic development. The focus has been on targeting toxic amyloid-β (Aβ) pathology, but these therapeutics have generally failed in clinical trials. Aβ is an aggregation-prone protein that has been shown to disrupt cell membrane structure in molecular biophysics studies and interfere with membrane receptor signaling in cell and animal studies. Whether the lipid membrane or specific receptors are the primary target of attack has not been determined. Objective: This work elucidates some of the interplay between membrane cholesterol and Aβ42 on HT22 neuronal cell viability, morphology, and platelet-derived growth factor (PDGF) signaling pathways. Methods: The effects of cholesterol depletion by methyl-β-cyclodextrin followed by treatment with Aβ and/or PDGF-AA were assessed by MTT cell viability assays, western blot, optical and AFM microscopy. Results: Cell viability studies show that cholesterol depletion was mildly protective against Aβ toxicity. Together cholesterol reduction and Aβ42 treatment compounded the disruption of the PDGFα receptor activation. Phase contrast optical microscopy and live cell atomic force microscopy imaging revealed that cytotoxic levels of Aβ42 caused morphological changes including cell membrane damage, cytoskeletal disruption, and impaired cell adhesion; cell damage was ameliorated by cellular cholesterol depletion. Conclusions: Cholesterol depletion impacted the effects of Aβ42 on HT22 cell viability, morphology, and receptor tyrosine kinase signaling.

Pages 1685-1693
Juan C. Meléndez, Encarnación Satorres, Alfonso Pitarque, Joaquin Escudero, Iraida Delhom, Ana-Belén Navarro-Prados
Transcranial Direct Current Stimulation Intervention in Alzheimer’s Disease and Its Follow-Up
Abstract: Background: Alzheimer’s disease (AD) stands as the prevailing type of dementia, marked by gradual memory loss and cognitive decline. Transcranial direct current stimulation (tDCS) is a non-invasive method used to regulate cortical brain function and has been explored as a potential treatment for cognitive impairment. Objective: This study aimed to compare the effects of daily home-based active or sham tDCS on cognitive function in patients with early-stage AD and its follow-up after one month. Methods: The study involved a randomized, blinded, and controlled-placebo design, with 18 participants enrolled. The primary outcome measures were general cognitive function, immediate, and delayed recall, and executive function. Participants included in the study were randomly assigned to the anodal and sham tDCS groups. Participants were assessed before and after the intervention and one month after the end of treatment. The home-based intervention was applied for 5 consecutive days, daily. Results: The results showed a significant interaction between the active and sham groups; in particular, improvements in MMSE scores, immediate memory and delayed recall were observed at one-month follow-up in the active group. Conclusions: The positive effects of tDCS on cognitive function in AD patients observed suggest that tDCS may induce long-term neuroplastic changes, leading to sustained improvements in cognitive abilities.

Pages 1695-1709
Elisa Giunti, Roberto Collu, Sarah Daley, Henry Querfurth, Peter Morin, Richard Killick, Rachel D. Melamed, Weiming Xia (Handling Associate Editor: Huali Wang)
Reduction of Phosphorylated Tau in Alzheimer’s Disease Induced Pluripotent Stem Cell-Derived Neuro-Spheroids by Rho-Associated Coiled-Coil Kinase Inhibitor Fasudil
Abstract: Background: Alzheimer’s disease (AD) is the most predominant form of dementia. Rho-associated coiled coil kinase (ROCK) inhibitor, fasudil, is one of the candidate drugs against the AD progression. Objective: We aimed to investigate possible changes of AD associated markers in three-dimensional neuro-spheroids (3D neuro-spheroids) generated from induced pluripotent stem cells derived from AD patients or healthy control subjects (HC) and to determine the impact of pharmacological intervention with the ROCK inhibitor fasudil. Methods: We treated 3D neuro-spheroids with fasudil and tested the possible effect on AD markers by ELISA, transcriptomic and proteomic analyses. Results: Transcriptomic analysis revealed a reduction in the expression of AKT serine/threonine-protein kinase 1 (AKT1) in AD neuro-spheroids, compared to HC. This decrease was reverted in the presence of fasudil. Proteomic analysis showed up- and downregulation of proteins related to AKT pathway in fasudil-treated neuro-spheroids. We found an evident increase of phosphorylated tau at four different residues (pTau181, 202, 231, and 396) in AD compared to HC-derived neuro-spheroids. This was accompanied by a decrease of secreted clusterin (clu) and an increase of intracellular clu levels in AD patient-derived neuro-spheroids. Increases of phosphorylated tau in AD patient-derived neuro-spheroids were suppressed in the presence of fasudil. Conclusions: Fasudil modulates clu protein levels and enhances AKT1 that results in the suppression of AD associated tau phosphorylation.

Pages 1711-1720
Pingjian Ding, Mark Gurney, George Perry, Rong Xu (Handling Editor: Daniela Galimberti)
Association of COVID-19 with Risk and Progression of Alzheimer’s Disease: Non-Overlapping Two-Sample Mendelian Randomization Analysis of 2.6 Million Subjects
Abstract: Background: Epidemiological studies showed that COVID-19 increases risk of Alzheimer’s disease (AD). However, it remains unknown if there is a potential genetic predispositional effect. Objective: To examine potential effects of genetic susceptibility of COVID-19 on the risk and progression of AD, we performed a non-overlapping 2-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies (GWAS). Methods: Two-sample Mendelian randomization (MR) analysis of over 2.6 million subjects was used to examine whether genetic susceptibility of COVID-19 is not associated with the risk of AD, cortical amyloid burden, hippocampal volume, or AD progression score. Additionally, a validation analysis was performed on a combined sample size of 536,190 participants. Results: We show that the AD risk was not associated with genetic susceptibility of COVID-19 risk (OR=0.98, 95% CI 0.81-1.19) and COVID-19 severity (COVID-19 hospitalization: OR=0.98, 95% CI 0.9-1.07, and critical COVID-19: OR=0.98, 95% CI 0.92-1.03). Genetic predisposition to COVID-19 is not associated with AD progression as measured by hippocampal volume, cortical amyloid beta load, and AD progression score. These findings were replicated in a set of 536,190 participants. Consistent results were obtained across models based on different GWAS summary statistics, MR estimators and COVID-19 definitions. Conclusions: Our findings indicated that the genetic susceptibility of COVID-19 is not associated with the risk and progression of AD.

Pages 1721-1722

Xinghao Zhang, Pengfei Wu, Yue Zhao
COVID-19 in Relation to Alzheimer’s Disease: Mendelian Randomization Analyses Add to Multiple Lines of Evidence
Abstract: The potential link between COVID-19 and Alzheimer's disease (AD) has been an intriguing topic in the global pandemic. Whether the susceptibility and severity of COVID-19 affects the onset and progression of AD is of great concern. Clinical studies suggested an increased risk of AD occurrence or cognitive deficit after COVID-19. Basic research found that severe COVID-19 induced changes resembling AD. Evidence synthesis should always take into account diverse study designs, both traditional and novel. The recent study by Ding et al. aimed to investigate the association of COVID-19 with AD using a non-overlapping two-sample Mendelian randomization analysis.

Pages 1723-1737
John E. Lewis, H. Reginald McDaniel, Judi M. Woolger, Sher Ali Khan
The Characterization of the Th1/Th2 Ratio in Moderate-Severe Alzheimer’s Disease Patients and Its Response to an Aloe Polymannose-Based Dietary Supplement
Abstract: Background: Alzheimer’s disease (AD) is a leading killer of Americans, imparting a tremendous societal toll. Relationships between immune function and inflammation with cognition are well-established in AD, but the Th1/Th2 ratio of immune function is unknown. Describing the Th1/Th2 ratio and its relationship with cognition may shed light on the disease’s clinical context. How the Th1/Th2 ratio responds to dietary supplementation is another unknown question in this population. Objective: The objectives of the study were to: 1) characterize the Th1/Th2 ratio according to IL-2/IL-10, IFN-γ/IL-10, IL-2/IL-4, IFN-γ/IL-4, IL-2/TNF-α, and IFN-γ/TNF-α in subjects with moderate-to-severe AD and in comparison to healthy adults; 2) investigate the effect of an aloe polymannose multinutrient complex (APMC) dietary supplement on the Th1/Th2 ratios over 12 months; and 3) compare the changes in the Th1/Th2 ratios with the changes in cognition from baseline to 12 months. Methods: Subjects consumed 2.5 g of the APMC four times per day for 12 months, and they were assessed on cognition and cytokines at baseline and 12 months. Results: The Th1/Th2 ratios in AD patients were significantly higher than the healthy controls, and five of the six ratios decreased from baseline to 12 months follow-up (other than IL-2/TNF-α). Several significant relationships were noted between the changes in Th1/Th2 ratios with cognitive assessments. Conclusions: Our results showed an overall rebalancing of the Th1/Th2 ratio in response to APMC, these changes were related to improved cognition in subjects with moderate-to-severe AD, and the APMC supplement was safely tolerated.

Pages 1739-1746
Yuan Gao*, Xiaocui Duan*, Wanlin Li, Xiaoyu Zhang, Xiaohui Xian, Yuan Zhu, Hualong Wang, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Lingqiang Zhu) *These authors contributed equally to this work.
Elevated Homocysteine Levels and Hypertension Relate to Cognitive Impairment via Increased White Matter Hyperintensity Volume
Abstract: Background: Recent studies have identified a relationship between elevated homocysteine levels and hypertension (HTN) with Alzheimer's disease (AD), but its pathogenesis remains unclear. Objective: To evaluate elevated homocysteine levels and HTN as risk factors for cognitive impairment (CI) and determine their relationship with white matter hyperintensity volume. Methods: A total of 521 subjects were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and divided into two groups according to the diagnostic criteria of the ADNI database. The CI group included 370 subjects, consisting of 122 with AD and 248 with mild CI, while the cognitively normal (CN) group contained 151 subjects. The history of HTN, homocysteine levels, white matter hyperintensity (WMH) volume and Mini-Mental State Examination (MMSE) scores were analyzed. Results: The study found that patients with CI had higher homocysteine levels than those with CN. Additionally, WMH volume was significantly correlated with homocysteine levels in CI patients, and MMSE scores decreased as WMH volume increased. Further analysis revealed that CI patients with HTN had significantly higher homocysteine levels than those without HTN. Furthermore, the correlation between WMH volume and homocysteine levels was significant only in CI patients with HTN and not in those without HTN. In CN patients, there was no correlation between WMH volume and homocysteine levels in either the HTN or non-HTN groups, and no difference was observed in homocysteine levels. Conclusions: It is indicated that elevated homocysteine levels in conjunction with HTN are associated with the increased volume of WMHs and cognitive impairment.

Pages 1747-1758
Janet K. Sluggett, Tracy Air, Monica Cations, Gillian E. Caughey, Catherine E. Lang, Stephanie A. Ward, Susannah Ahern, Xiaoping Lin, Kasey Wallis, Maria Crotty, Maria C. Inacio
Clinical Quality Indicators for Monitoring Hospitalizations Among Older People with Dementia Accessing Aged Care Services
Abstract: Background: There is a need for clinical quality indicators (CQIs) that can be applied to dementia quality registries to monitor care outcomes for people with Alzheimer’s disease and other forms of dementia. Objective: To develop tertiary and primary care-based dementia CQIs for application to clinical registries for individuals with dementia accessing aged care services and determine 1) annual trends in CQI incidence between 2011-2012 and 2015-2016, 2) associated factors, and 3) geographic and facility variation in CQI incidence. Methods: This retrospective repeated cross-sectional study included non-Indigenous individuals aged 65-105 years who lived with dementia between July 2008-June 2016, were assessed for government-funded aged care services, and resided in New South Wales or Victoria (n=180,675). Poisson or negative binomial regression models estimated trends in annual CQI incidence and associated factors. Funnel plots examined CQI variation. Results: Between 2011-2012 and 2015-2016, CQI incidence increased for falls (11.0% to 13.9%, adjusted incidence rate ratio (aIRR) 1.05 (95%CI 1.01-1.06)) and delirium (4.7% to 6.7%, aIRR 1.09 (95%CI 1.07-1.10)), decreased for unplanned hospitalizations (28.7% to 27.9%, aIRR 0.99 (95%CI 0.98-0.99)) and remained steady for fracture (6.2% to 6.5%, aIRR 1.01 (95%CI 0.99-1.01)) and pressure injuries (0.5% to 0.4%, aIRR 0.99 (95%CI 0.96-1.02)). Being male, older, having more comorbidities and living in a major city were associated with higher CQI incidence. Considerable geographical and facility variation was observed for unplanned hospitalizations and delirium CQIs. Conclusions: The CQI results highlighted considerable morbidity. The CQIs tested should be considered for application in clinical quality registries to monitor dementia care quality.

Pages 1759-1765
Katerina A. Tetzloff, Joseph R. Duffy, Heather M. Clark, Nha Trang Thu Pham, Mary M. Machulda, Hugo Botha, Clifford R. Jack Jr., Dennis W. Dickson, Val J. Lowe, Keith A. Josephs, Jennifer L. Whitwell, Rene L. Utianski
Amyloid and Tau PET Positivity in Progressive Agrammatic Aphasia and Apraxia of Speech
Abstract: Background: The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer’s disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. Objective: This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Methods: Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. Results: The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Conclusions: Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers.

Pages 1767-1780
Meghan I. Short*, Alison E. Fohner*, Håvard K. Skjellegrind, Alexa Beiser, Mitzi M. Gonzales, Claudia L. Satizabal, Thomas R. Austin, W.T. Longstreth, Jr., Joshua C. Bis, Oscar Lopez, Kristian Hveem, Geir Selbæk, Martin G. Larson, Qiong Yang, Hugo J. Aparicio, Emer R. McGrath, Robert E. Gerszten, Charles S. DeCarli, Bruce M. Psaty, Ramachandran S. Vasan**, Habil Zare**; Sudha Seshadri** *These authors contributed equally to this work. **These senior authors contributed equally to this work.
Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging
Abstract: Background: Alzheimer’s disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. Objective: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. Methods: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n=1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n=2,117, mean 6-year follow-up). Results: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2:p=0.014; M4:p=4.2×10–5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. Conclusions: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

Pages 1781-1799
Joshua P. White, Adrian Schembri, Carmen Prenn-Gologranc, Matej Ondrus, Stanislav Katina, Petr Novak, Yen Ying Lim, Chris Edgar, Paul Maruff
Sensitivity of Individual and Composite Test Scores from the Cogstate Brief Battery to Mild Cognitive Impairment and Dementia Due to Alzheimer’s Disease
Abstract: Background: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer’s disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. Objective: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Methods: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Results: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ~ 0.79-0.88), and CDR > 0.5 (AUCs ~ 0.89-0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. Conclusions: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity.

Pages 1801-1812
Jieun Yoon, Kazunori Sasaki, Korin Tateoka, Tetsuaki Arai, Hiroko Isoda, Tomohiro Okura
Evaluation of Cognitive and Physical Function Among Older Adults by Their Physical Activity: A Cross-Sectional Kasama Study, Japan
Abstract: Background: The amyloid-β1-42 (Aβ42) level is a biomarker that is widely used to evaluate individual cognitive dysfunction early in neurodegenerative diseases, as well as differentiate between normal cognitive function, mild cognitive impairment, Alzheimer’s disease, and vascular cognitive impairment. Objective: Our cross-sectional study evaluated the association between daily exercise and physical and cognitive function and Aβ42 levels among a subsample of 325 older adults from the Kasama Study. Methods: Participants (age: 74.5 [range 65–90] years) were classified into three exercise groups: the dual-task (DEG, n=128), single-task (SEG, n=122), and non-exercise (NEG, n=75) groups. The main outcomes were the plasma Aβ42 levels and the scores of the five cognitive (5-COG) tests and five cognition-related physical function (5-PHYS) tests. Results: The Aβ42 levels and 5-COG and 5-PHYS scores were higher in the SEG and DEG than in the NEG. The Aβ42 levels were higher in the DEG than in the NEG (p=0.008). Conclusions: Physical activities such as regular exercise may benefit older adults, improving their cognitive and physical function.

Pages 1813-1825
Bing Zhao, Ya-Nan Ou, Xuan-Yue Zhang, Yan Fu, Lan Tan, Alzheimer’s Disease Neuroimaging Initiative
Differential Associations of APOE ε2 and APOE ε4 Genotypes with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in Individuals Without Dementia
Abstract: Background: The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. Objective: To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. Methods: A total of 989 non-demented ADNI participants were included. The associations of APOE ε2 and APOE ε4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aβ mediated the associations between APOE genotypes and tau. Results: APOE ε2 carriers only showed higher Aβ levels (β [95% CI]=0.07 [0.01, 0.13], p=0.026). Conversely, APOE ε4 carriers exhibited lower Aβ concentration (β [95% CI]=-0.27 [-0.31, -0.24], p<0.001), higher t-Tau (β [95% CI]=0.25 [0.08, 0.18], p<0.001) and higher p-Tau (β [95% CI]=0.31 [0.25, 0.37], p<0.001). Subgroup analysis showed that APOE ε2 was significantly positively associated with Aβ only in females (β [95%CI]=0.12 [0.04, 0.21], p=0.005) and older people (β [95%CI]=0.06 [0.001, 0.12], p=0.048). But the effects of APOE ε4 were independent of gender and age. Besides, the associations of APOE ε4 with t-Tau and p-Tau were both mediated by baseline Aβ. Conclusions: Our data suggested that APOE ε2 could promote Aβ clearance, while the process could be modified by sex and age. However, APOE ε4 might cause the accumulation of Aβ and tau pathology independent of sex and age.

Pages 1827-1836
Maria Vittoria Spampinato, Jenny Ulber, Habiba Fayyaz, Allison Sullivan, Heather R. Collins, for the Alzheimer’s Disease Neuroimaging Initiative
Neuropsychiatric Symptoms and In Vivo Alzheimer’s Biomarkers in Mild Cognitive Impairment
Abstract: Background: Neuropsychiatric symptoms (NPS) carry an increased risk of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). There is a need to understand how to integrate NPS into the paradigm outlined in the 2018 NIA-AA Research Framework. Objective: To evaluate a prediction model of MCI-AD progression using a collection of variables, including NPS, cognitive testing, apolipoprotein E4 status (APOE4), imaging and laboratory AD biomarkers. Methods: Of 300 elderly subjects, 219 had stable MCI and 81 MCI-AD progression over a 5-year follow-up. NPS were measured using the Neuropsychiatric Inventory (NPI). A multivariate Cox Proportional Hazards Regression Analysis assessed the effects of APOE4, baseline NPI, baseline CSF amyloid-β, phosphorylated and total tau, baseline AD-signature MRI biomarker, baseline memory and executive function on MCI-AD progression. Results: 27% progressed to dementia (median follow-up = 43 months). NPS were found in stable MCI (62.6%) and MCI-AD converters (70.3%). The Cox model exhibited a good fit (p < 0.001), and NPS (HR = 1.033, p = 0.027), phosphorylated tau (HR = 1.011, p = 0.025), total tau (HR = 1.005, p = 0.024), AD-signature MRI biomarker (HR = 0.111, p = 0.002), executive function (HR = 0.727, p = 0.045), and memory performance (HR = 0.387, p < 0.001) were significantly associated with dementia. Conclusions: NPS may inform dementia risk assessment in conjunction with cognitive testing and imaging and laboratory AD biomarkers. NPS is independently associated with the risk of MCI-dementia progression, over and beyond the contributions of CSF biomarkers.