Volume 85, Number 3, 2022

Pages 943-955

Shirley Tran, Sanjaya Kuruppu, Niwanthi W. Rajapakse
Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia?
Abstract: Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer’s disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1–7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.

Pages 957-973

Mhd Ammar Kouki, Anna Barlach Pritchard, Jane Elizabeth Alder, StJohn Crean
Do Periodontal Pathogens or Associated Virulence Factors Have a Deleterious Effect on the Blood-Brain Barrier, Contributing to Alzheimer’s Disease?
Abstract: The central nervous system (CNS) is protected by a highly selective barrier, the blood-brain barrier (BBB), that regulates the exchange and homeostasis of bloodborne molecules, excluding xenobiotics. This barrier forms the first line of defense by prohibiting pathogens from crossing to the CNS. Aging and chronic exposure of the BBB to pathogens renders it permeable, and this may give rise to pathology in the CNS such as Alzheimer’s disease (AD). Researchers have linked pathogens associated with periodontitis to neuroinflammation and AD-like pathology in vivo and in vitro. Although the presence of periodontitis-associated bacteria has been linked to AD in several clinical studies as DNA and virulence factors were confirmed in brain samples of human AD subjects, the mechanism by which the bacteria traverse to the brain and potentially influences neuropathology is unknown. In this review, we present current knowledge about the association between periodontitis and AD, the mechanism whereby periodontal pathogens might provoke neuroinflammation and how periodontal pathogens could affect the BBB. We suggest future studies, with emphasis on the use of human in vitro models of cells associated with the BBB to unravel the pathway of entry for these bacteria to the CNS and to reveal the molecular and cellular pathways involved in initiating the AD-like pathology. In conclusion, evidence demonstrate that bacteria associated with periodontitis and their virulence factors are capable of inflecting damage to the BBB and have a role in giving rise to pathology similar to that found in AD.

Pages 975-992

Debora Cutuli, Eugenia Landolfo, Laura Petrosini, Francesca Gelfo
Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer’s Disease, and Other Neurodegenerative Disorders
Abstract: Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer’s disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.

Pages 993-999
Short Communication

Lilah M. Besser, James E. Galvin (Handling Associate Editor: Lori Newkirk)
Rural Versus Non-Rural Residence and Psychosocial Outcomes Among Caregivers of Patients with Dementia and Related Disorders
Abstract: We used data on 718 dementia caregivers and multivariable linear regression to test associations between residential locale and psychosocial outcomes (grief, wellbeing, burden, quality of life [QOL], self-efficacy/mastery, and social networks). Rural residence (versus urban or suburban) was not associated with the psychosocial outcomes. However, for rural caregivers, greater self-efficacy/mastery was associated with lower grief (versus urban/suburban) and burden (versus suburban), and greater social network quality was associated with lower burden (versus suburban) and higher QOL (versus urban). Interventions targeting self-efficacy/mastery and social networks may be particularly effective at improving rural caregivers’ mental health and QOL.

Pages 1001-1008
Short Communication

Tai June Yoo
Anti-Inflammatory Gene Therapy Improves Spatial Memory Performance in a Mouse Model of Alzheimer’s Disease
Abstract: The immune system plays a critical role in neurodegenerative processes involved in Alzheimer’s disease (AD). In this study, a gene-based immunotherapeutic method examined the effects of anti-inflammatory cellular immune response elements (CIREs) in the amyloid-β protein precursor (AβPP) mouse model. Bi-monthly intramuscular administration, beginning at either 4 or 6 months, and examined at 7.5 through 16 months, with plasmids encoding Interleukin (IL)-10, IL-4, TGF-β polynucleotides, or a combination thereof, into AβPP mice improved spatial memory performance. This work demonstrates an efficient gene therapy strategy to downregulate neuroinflammation, and possibly prevent or delay cognitive decline in AD.

Pages 1009-1020
Luca Sacchi, Tiziana Carandini, Giorgio Giulio Fumagalli, Anna Margherita Pietroboni, Valeria Elisa Contarino, Silvia Siggillino, Marina Arcaro, Chiara Fenoglio, Felicia Zito, Giorgio Marotta, Massimo Castellani, Fabio Triulzi, Daniela Galimberti, Elio Scarpini, Andrea Arighi (Handling Associate Editor: Marco Bozzali)
Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer’s Disease Spectrum: Who Really Deserves an A+?
Abstract: Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. Methods: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ42 within a 365-days interval. Thresholds used for dichotomization were: Aβ42<640 pg/mL (Aβ42+); pTau>61 pg/mL (pTau+); and Aβ42/40<0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho=0.93-0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho=0.56, p=0.0063) and Aβ42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho=-0.56, p=0.0058; rho=-0.52, p=0.0117 respectively). No correlations between CSF-Aβ42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2=0.55-0.59, p<0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ42 or using Aβ42/40, instead of Aβ42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ42/40 and secondarily pTau rather than Aβ42 levels.

Pages 1021-1029
Carla R. Schubert, Adam J. Paulsen, A. Alex Pinto, Natascha Merten, Karen J. Cruickshanks (Handling Associate Editor: Michelle Mielke)
Effect of Long-Term Storage on the Reliability of Blood Biomarkers for Alzheimer’s Disease and Neurodegeneration
Abstract: Background: Stored blood samples from longitudinal cohort studies may be useful for studying biomarkers of preclinical Alzheimer’s disease. Objective: This study aimed to determine the reliability of amyloid-β40 and amyloid-β42 (Aβ40, Aβ42), total tau (TTau), and neurofilament light (NfL) concentrations measured in blood samples stored long-term at -80°C. Methods: Aβ40, Aβ42, TTau, and NfL were measured in serum and plasma samples from two longitudinal cohort studies. Serum samples had been stored at -80°C for 5 (n=24), 14 (n=24), and 20 years (N=78) and plasma samples had been stored for 16 years (N=78). Biomarker concentrations were measured in duplicate using a single molecule array assay (Simoa; Quanterix, Billerica, MA). Replicate samples for each sample type and storage length were included. Results: The concentrations of Aβ40, Aβ42, TTau, and NfL were within expected ranges. Some serum TTau concentrations were below the limit of detection. The average intra-assay coefficients of variation (CV) for duplicate measures were 2-7% for all assays except for serum TTau, which were higher (CVs 13% and 17%). Mean differences in original replicate pair Aβ40, Aβ42, and NfL concentrations were slightly greater in samples stored for longer versus shorter time periods. Conclusion: Aβ40, Aβ42, TTau, and NfL can be measured in serum and plasma samples that have been stored up to 20 years at -80°C. Long-term storage may be associated with small increases in the variability of concentrations in samples stored 14 or more years.

Pages 1031-1044
Andrew L. Zhou*, Nidhi Sharda*, Vidur V. Sarma*, Kristen M. Ahlschwede, Geoffry L. Curran, Xiaojia Tang, Joseph F. Poduslo, Krishna R. Kalari, Val J. Lowe, Karunya K. Kandimalla *These authors contributed equally to this work.
Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin
Abstract: Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ40, 125I-Aβ42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

Pages 1045-1052
Emanuela Rotondo, Daniela Galimberti, Matteo Mercurio, Giulia Giardinieri, Sara Forti, Roberto Vimercati, Vittoria Borracci, Giorgio G. Fumagalli, Anna M. Pietroboni, Tiziana Carandini, Alessandro Nobili, Elio Scarpini, Andrea Arighi
Caregiver Tele-Assistance for Reduction of Emotional Distress During the COVID-19 Pandemic. Psychological Support to Caregivers of People with Dementia: The Italian Experience
Abstract: Background: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers. Objective: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown. Methods: 50 caregivers were divided into two groups: “Caregiver-focused group” (Cg) and “Patient-focused group” (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life. Results: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (p>0.05), whereas they worsened significantly in Pg (p<0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (p=0.015), while they remained unchanged in Pg (p=0.483). Conclusion: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support.

Pages 1053-1061
Xiaoru Sun*, Hui Zhang*, Dongdong Yao, Yaru Xu, Qi Jing, Silu Cao, Li Tian, Cheng Li *These authors contributed equally to this work.
Integrated Bioinformatics Analysis Identifies Hub Genes Associated with Viral Infection and Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease, the etiology of which is unclear. Previous studies have suggested that some viruses are neurotropic and associated with AD. Objective: By using bioinformatics analysis, we investigated the potential association between viral infection and AD. Methods: A total of 5,066 differentially expressed genes (DEGs) in the temporal cortex between AD and control samples were identified. These DEGs were then examined via weighted gene co-expression network analysis (WGCNA) and clustered into modules of genes with similar expression patterns. Of identified modules, module turquoise had the highest correlation with AD. The module turquoise was further characterized using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. Results: Our results showed that the KEGG pathways of the module turquoise were mainly associated with viral infection signaling, specifically Herpes simplex virus, Human papillomavirus, and Epstein-Barr virus infections. A total of 126 genes were enriched in viral infection signaling pathways. In addition, based on values of module membership and gene significance, a total of 508 genes within the module were selected for further analysis. By intersecting these 508 genes with those 126 genes enriched in viral infection pathways, we identified 4 hub genes that were associated with both viral infection and AD: TLR2, COL1A2, NOTCH3, and ZNF132. Conclusion: Through bioinformatics analysis, we demonstrated a potential link between viral infection and AD. These findings may provide a platform to further our understanding of AD pathogenesis.

Pages 1063-1075
Weihua Li*, Zhilian Zhao*, Min Liu, Shaozhen Yan, Yanhong An, Liyan Qiao, Guihong Wang, Zhigang Q, Jie Lu *These authors contributed equally to this work
Multimodal Classification of Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: Integrated 18F-FDG PET and DTI Study
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory impairment. Amnestic mild cognitive impairment (aMCI) is the intermediate stage between normal cognitive aging and early dementia caused by AD. It can be challenging to differentiate aMCI patients from healthy controls (HC) and mild AD patients. Objective: To validate whether the combination of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and diffusion tensor imaging (DTI) will improve classification performance compared with that based on a single modality. Methods: A total of thirty patients with AD, sixty patients with aMCI, and fifty healthy controls were included. AD was diagnosed according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable. aMCI diagnosis was based on Petersen’s criteria. The 18F-FDG PET and DTI measures were each used separately or in combination to evaluate sensitivity, specificity, and accuracy for differentiating HC, aMCI, and AD using receiver operating characteristic analysis together with binary logistic regression. The rate of accuracy was based on the area under the curve (AUC). Results: For classifying AD from HC, we achieve an AUC of 0.96 when combining two modalities of biomarkers and 0.93 when using 18F-FDG PET individually. For classifying aMCI from HC, we achieve an AUC of 0.79 and 0.76 using the best individual modality of biomarkers. Conclusion: Our results show that the combination of two modalities improves classification performance, compared with that using any individual modality.

Pages 1077-1093
Jesse Britz, Emmanuel Ojo, Asmita Dhukhwa, Takashi Saito, Takaomi C. Saido, Erin R. Hascup, Kevin N. Hascup, Shelley A. Tischkau
Assessing Sex-Specific Circadian, Metabolic, and Cognitive Phenotypes in the AβPP/PS1 and APPNL-F/NL-F Models of Alzheimer’s Disease
Abstract: Background: Circadian disruption has long been recognized as a symptom of Alzheimer’s disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits. Objective: This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months. Methods: Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes. Results: Sex-dependent hyperactivity in AβPP/PS1 mice was observed. In comparison to C57BL/6J animals, 6-month-old male AβPP/PS1 demonstrated nighttime hyperactivity, as did 12-month-old females. Female AβPP/PS1 animals performed significantly worse on a MWM task than AβPP/PS1 males at 12 months and trended toward increased plaque pathology. APPNL-F/NL-F 12-month-old males performed significantly worse on the MWM task compared to 12-month-old females. Significantly greater plaque pathology occurred in AβPP/PS1 animals as compared to APPNL-F/NL-F animals. Female AβPP/PS1 animals performed significantly worse than APPNL-F/NL-F animals in spatial learning and memory tasks, though this was reversed in males. Conclusion: Taken together, this study provides novel insights into baseline sex differences, as well as characterizes baseline diurnal activity variations, in the AβPP/PS1 and APPNL-f/NL-F AD mouse models.

Pages 1095-1105
Lee Smith, Jae Il Shin, Hans Oh, Christina Carmichael, Louis Jacob, Sinisa Stefanac, Rosie K. Lindsay, Pinar Soysal, Nicola Veronese, Mark A. Tully, Laurie Butler, Yvonne Barnett, Ai Koyanagi
Body Mass Index and Mild Cognitive Impairment Among Middle-Aged and Older Adults from Low- and Middle-Income Countries
Abstract: Background: The effect of weight modification on future dementia risk is currently a subject of debate and may be modified by age. Objective: The aim of the present study was to investigate the association between body mass index (BMI) status with mild cognitive impairment (MCI) (a preclinical stage of dementia) in middle-aged and older adults residing in six low- and middle-income countries using nationally representative data. Methods: Cross-sectional data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer’s Association criteria. BMI (kg/m2) was based on measured weight and height and categorized as: underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). Multivariable logistic regression analysis and meta-analysis were conducted to assess associations. Results: Data on 32,715 individuals aged ≥50 years with preservation in functional abilities were analyzed [mean (SD) age 62.1 (15.6) years; 51.7% females]. Among those aged 50-64 years, compared to normal weight, underweight (OR=1.44; 95%CI=1.14-1.81), overweight (OR=1.17; 95%CI=1.002-1.37), and obesity (OR=1.46; 95%CI=1.09-1.94) were all significantly associated with higher odds for MCI. In those aged ≥65 years, underweight (OR=0.71; 95%CI=0.54-0.95) and overweight (OR=0.72; 95%CI=0.55-0.94) were associated with significantly lower odds for MCI, while obesity was not significantly associated with MCI. Conclusion: The results of the study suggest that the association between BMI and MCI is likely moderated by age. Future longitudinal studies are required to confirm or refute the present findings before recommendations for policy and practice can be made.

Pages 1107-1113
Gerard Mayà*, Jordi Sarto*, Yaroslau Compta, Mircea Balasa, Teresa Ximelis, Iban Aldecoa, Ellen Gelpi, Raquel Sánchez-Valle, Laura Molina-Porcel *These authors contributed equally to this work.
Assessment of Cognitive Symptoms in Brain Bank-Registered Control Subjects: Feasibility and Utility of a Telephone-Based Screening
Abstract: Background: For neuroscience research, the study of brain tissue of neurologically unimpaired subjects is crucial to interpret findings in neurodegenerative diseases. Sub-optimal neurological follow-up and the presence of neuropathological lesions in supposedly asymptomatic subjects casts doubt as to whether these subjects present an undetected underlying neurodegenerative disease or are resilient to neurodegeneration. Objective: We aimed to assess whether the control donors registered in the Neurological Tissue Bank-Hospital Clínic-IDIBAPS (NTB-HCI) are still free of cognitive symptoms at follow-up and to evaluate the feasibility and utility of a telephone-based screening. Methods: All control subjects older than 65 years registered at the NTB-HCI database were selected for the study. After a structured telephone interview, those subjects already diagnosed with a neurological disease were excluded. Then, a cognitive screening was performed, including the telephone version of the Mini-Mental State Examination (t-MMSE) and the eight-item interview (AD-8) to the subject and to one informant. Results: In total, 73.8% of the registered donors collaborated in the study. Only 21.4% had at least one of the three cognitive screening tools impaired, and 2.7% had a profile highly suggestive of cognitive impairment. AD-8i correlated moderately with t-MMSE. Conclusion: Telephone-based neurologic screening in control donors is feasible and was within the normal range in most of the subjects in our cohort. Albeit, the involvement of neurologists and periodic neurological screenings are desirable in a control subjects brain donor program, AD8-i could be used to screen the control’s neurological status in the absence of accurate clinical data at the time of the death.

Pages 1115-1127
Fatemah Sakr, Martin Dyrba, Anja U. Bräuer, Stefan Teipel for the Alzheimer’s Disease Neuroimaging Initiative
Association of Lipidomics Signatures in Blood with Clinical Progression in Preclinical and Prodromal Alzheimer’s Disease
Abstract: Background: Lipidomics may provide insight into biochemical processes driving Alzheimer’s disease (AD) pathogenesis and ensuing clinical trajectories. Objective: To identify a peripheral lipidomics signature associated with AD pathology and investigate its potential to predict clinical progression. Methods: We used Bayesian elastic net regression to select plasma lipid classes associated with the CSF pTau/Aβ42 ratio as a biomarker of AD pathology in preclinical and prodromal AD cases from the ADNI cohort. Consensus clustering of the selected lipid classes was used to identify lipidomic endophenotypes and study their association with clinical progression. Results: In the APOE4-adjusted model, ether-glycerophospholipids, lyso-glycerophospholipids, free-fatty acids, cholesterol esters, and complex sphingolipids were found to be associated with the CSF pTau/Aβ42 ratio. We found an optimal number of five lipidomic endophenotypes in the prodromal and preclinical cases, respectively. In the prodromal cases, these clusters differed with respect to the risk of clinical progression as measured by clinical dementia rating score conversion. Conclusion: Lipid alterations can be captured at the earliest phases of AD. A lipidomic signature in blood may provide a dynamic overview of an individual’s metabolic status and may support identifying different risks of clinical progression.

Pages 1129-1142
Yu-Ling Chang, Di-Hua Luo, Tsung-Ren Huang, Joshua O.S. Goh, Su-Ling Yeh, Li-Chen Fu (Handling Associate Editor: David Libon)
Identifying Mild Cognitive Impairment by Using Human–Robot Interactions
Abstract: Background: Mild cognitive impairment (MCI), which is common in older adults, is a risk factor for dementia. Rapidly growing health care demand associated with global population aging has spurred the development of new digital tools for the assessment of cognitive performance in older adults. Objective: To overcome methodological drawbacks of previous studies (e.g., use of potentially imprecise screening tools that fail to include patients with MCI), this study investigated the feasibility of assessing multiple cognitive functions in older adults with and without MCI by using a social robot. Methods: This study included 33 older adults with or without MCI and 33 healthy young adults. We examined the utility of five robotic cognitive tests focused on language, episodic memory, prospective memory, and aspects of executive function to classify age-associated cognitive changes versus MCI. Standardized neuropsychological tests were collected to validate robotic test performance. Results: The assessment was well received by all participants. Robotic tests assessing delayed episodic memory, prospective memory, and aspects of executive function were optimal for differentiating between older adults with and without MCI, whereas the global cognitive test (i.e., Mini-Mental State Examination) failed to capture such subtle cognitive differences among older adults. Furthermore, robot-administered tests demonstrated sound ability to predict the results of standardized cognitive tests, even after adjustment for demographic variables and global cognitive status. Conclusion: Overall, our results suggest the human–robot interaction approach is feasible for MCI identification. Incorporating additional cognitive test measures might improve the stability and reliability of such robot-assisted MCI diagnoses.

Pages 1143-1151
Chen Wen, Yan-Lin Bi, Hao Hu, Shu-Yi Huang, Ya-Hui Ma, He-Ying Hu, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Association of Subjective Cognitive Decline with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE Study
Abstract: Background: Subjective cognitive decline (SCD) might occur at the early stages of dementia. Individuals with SCD have an increased risk of subsequent objective cognitive decline and greater rates of progression to dementia. Objective: We aimed to explore the associations between SCD and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology in cognitively normal individuals. Methods: A total of 1,099 cognitively normal elders with available data on CSF biomarkers of AD pathology (Aβ42, P-tau, and T-tau) were included in our analysis. Linear regression was used to examine the associations of SCD status and SCD severity with CSF biomarkers. Additionally, a review was conducted to discuss the associations between SCD and CSF biomarkers of AD pathology. Results: After adjustments for covariates, SCD and SCD severity showed significant associations with CSF Aβ42 (SCD: β=-0.0003, p=0.0263; SCD severity: β=-0.0004, p=0.0046), CSF T-tau/Aβ42 ratio (SCD: β=0.1080, p=0.1080; SCD severity: β=0.1129, p=0.0009) and CSF P-tau/Aβ42 ratio (SCD: β=0.0167, p=0.0103; SCD severity: β=0.0193, p=0.0006) rather than T-tau and P-tau compared with cognitively normal individuals. In the review, a total of 28 studies were finally included after reviewing 174 articles. CSF Aβ42 was lower in SCD than cognitively normal (CN) individuals, but higher than those with objective cognitive decline. However, CSF tau pathology showed no difference between SCD and CN. Conclusion: The results indicated that pathophysiological changes in CSF Aβ pathology occurred in individuals with SCD, which provide new insights into early intervention of AD.

Pages 1153-1161
Miri Lutski, Iris Rasooli, Shelley Sternberg, John Lemberger, Nisim Mery, Tamy Shohat, Inbar Zucker
Prevalence and Incidence Rates of Dementia: A Nationwide Population-Based Study of Electronic Health Records in Israel
Abstract: Background: Data on the rate of dementia is essential for planning and developing appropriate services at the national level. Objective: We report the prevalence and incidence of dementia, based on electronic health records available for the whole population. Methods: This national dementia dataset was established as a part of the National Program to Address Alzheimer’s and Other Types of Dementia. Data from medical health records for all persons aged 45+ in Israel, for 2016, were extracted from the databases of the four health maintenance organizations. Dementia cases were identified based on either recorded dementia diagnosis, through International Classification of Diseases (ICD-9 and ICD-10) or dispensation of anti-dementia drugs. The date of first diagnosis was determined by the earliest recording. Results: A total of 65,951 persons with dementia, aged 45+, were identified from electronic health data. Based on both ICD codes and anti-dementia drugs, the prevalence rates of dementia among individuals aged 45+ and 65+ in 2016 were 2.5% and 6.4%, respectively, and the incidence rates were 0.49% and 1.3%, respectively. Based on ICD codes alone, the prevalence rates of dementia among individuals aged 45+ and 65+ in 2016 were 2.1% and 5.4% respectively, and the incidence rates were 0.36% and 0.96% respectively. The rates were higher among females compared to males and paradoxically lower in lower socioeconomic status compared to higher statuses. Conclusion: This data collection reflects the present access of dementia patients to medical care resources and provides the basis for service planning and future dementia policies.

Pages 1163-1174
Li Yang, Cheng Xuan, Caiyan Yu, Pinpin Zheng, Jing Yan
Diagnostic Model of Alzheimer’s Disease in the Elderly Based on Protein and Metabolic Biomarkers
Abstract: Background: With the accelerating aging process, the number of participants with Alzheimer’s disease (AD) is rising sharply, causing a huge economic burden. Objective: This study aimed to identify blood protein and metabolic biomarkers and explore the diagnostic model for AD among elderly in southeast China. Methods: We established a cohort among population with high risk AD in Zhejiang Province in 2018. Case and control groups each consisting of 45 subjects, matched for gender and age, were randomly selected from the cohort. Based on bioinformatics research, PRM/MRM technology was used to detect candidate biomarkers. Ensemble-based feature selection and machine learning methods was used to screen important variables as risk indicators for AD. Based on the risk biomarkers, the risk diagnostic model of AD in the elderly was constructed and evaluated. Results: Cystine and CPB2 were evaluated as biomarkers. The diagnostic model is constructed using logistic regression algorithm with the best cutoff value, sensitivity, specificity, and accuracy of 0.554, 0.895, 0.976, and 0.938, respectively, which determined by Youden's index. The results showed that the model with protein and metabolite had a high efficiency. Conclusion: It showed that the diagnostic model constructed by Cystine and CPB2 had a good performance on sample classification. This study was of great significance for the early screening and diagnosis of AD, timely intervention, control and delay the development of dementia in southeast China.

Pages 1175-1187
Hannah J. Kimmel, Deborah A. Levine, Rachael T. Whitney, Jane Forman, Brenda L. Plassman, Angela Fagerlin, Kathleen Anne Welsh-Bohmer, Bailey K. Reale, Andrzej T. Galecki, Emilie Blair, Kenneth M. Langa, Bruno Giordani, Colleen Kollman, Jing Wang, Darin B. Zahuranec (Handling Associate Editor: Darshini Ayton)
A Mixed-Methods Study of the Impact of Mild Cognitive Impairment Diagnosis on Patient and Care Partner Perception of Health Risks
Abstract: Background: Older patients (65 years) with mild cognitive impairment (MCI) are undertreated for cardiovascular disease (CVD). One reason for this disparity could be that patients with MCI might underestimate the chances of CVD and overestimate dementia. Objective: To compare conceptions of health risk between older patients with MCI and normal cognition (NC) and their care partners. Methods: We conducted a multi-center mixed-methods study of patient-care partner dyads completing written quantitative surveys (73% response rate; 127 dyads: 66 MCI and 61 NC) or semi-structured interviews (20 dyads: 11 MCI, and 9 NC). Surveys assessed two-year patient risks of dementia, heart attack, stroke, and fall. Interviews assessed similar health risks and reasons for risk perceptions. Results: On surveys, a similarly low proportion of MCI and NC patients felt they were at risk of stroke (5% versus 2%; p=0.62) and heart attack (2% versus 0%; p=0.99). More MCI than NC patients perceived dementia risk (26% versus 2%; p<0.001). Care partners’ survey findings were similar. Interviews generally confirmed these patterns and also identified reasons for future health concerns. For both MCI and NC dyads, personal experience with cognitive decline or CVD (personal or family history) increased concerns about each disease. Additionally, perceptions of irreversibility and lack of treatment for cognitive decline increased concern about dementia. Conclusion: Less use of CVD treatments in MCI seems unlikely to be driven by differential perceptions of CVD risk. Future work to improve awareness of CVD risks in older patients and dementia risk in patients with MCI are warranted.

Pages 1189-1194
Koh Tadokoro, Toru Yamashita, Junko Sato, Yoshio Omote, Mami Takemoto, Ryuta Morihara, Koichiro Nishiura, Tomiko Tani, Koji Abe
Chronic Beneficial Effect of Makeup Therapy on Cognitive Function of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software
Abstract: Background: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. Objective: To evaluate the therapeutic effect of makeup therapy. Methods: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n=16) or skin care plus makeup therapy (makeup therapy group, n=18) once every 2 weeks for 3 months were assessed. Results: Three months of makeup therapy significantly improved the Mini-Mental State Examination (MMSE) score compared with control patients (*p < 0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression (*p < 0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r = 0.43, *p < 0.05). Conclusion: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software.

Pages 1195-1204
Fangcheng Fan, Hua Liu, Xiaojie Shi, Yangwen Ai, Qingshan Liu, Yong Cheng
The Efficacy and Safety of Alzheimer’s Disease Therapies: An Updated Umbrella Review
Abstract: Background: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer’s disease (AD) are sparse. Objective: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. Methods: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. Results: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. Conclusion: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

Pages 1205-1217
C. Aaron Smith*, Haddon Smith*, Lisa Roberts, Lori Coward, Gregory Gorman, Amrisha Verma, Qiuhong Li, Thomas W. Buford, Christy S. Carter, Patricia Jumbo-Lucioni *These authors contributed equally to this work.
Probiotic Releasing Angiotensin (1-7) in a Drosophila Model of Alzheimer’s Disease Produces Sex-Specific Effects on Cognitive Function
Abstract: Background: While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer’s disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. Objective: Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. Methods: Flies overexpressing the human amyloid-β protein precursor and its β-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. Results: Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. Conclusion: In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response.

Pages 1219-1231
Rinske A. Haverkamp, René J.F. Melis, Jurgen A.H.R. Claassen , Rianne A.A. de Heus (Handling Associate Editor: Rónán O’Caoimh)
Day-To-Day Home Blood Pressure Variability and All-Cause Mortality in a Memory Clinic Population
Abstract: Background: High day-to-day blood pressure variability (BPV) has been associated with an increased risk for cognitive decline and mortality in the general population. Whether BPV is associated with increased all-cause mortality in older people with cognitive impairment is unknown. Objective: To investigate the association between day-to-day home BPV and all-cause mortality in older patients attending a memory clinic. Methods: We included 279 patients attending a memory clinic, who measured home blood pressure (BP) for 7 consecutive days in the morning and evening. Within-subject BPV was defined as the variation independent of the mean (VIM). Time-to-death was verified through the Dutch population registry. Cox proportional hazard regression was used. Separate analyses were performed for morning-to-morning and evening-to-evening BPV. Results: Mean age was 73±9 years, dementia and mild cognitive impairment were diagnosed in 35% and 34% respectively, and mean home BP was 139/79 mmHg. After a mean follow-up of 3.2 years, 52 patients had died. Neither day-to-day systolic nor diastolic VIM were associated with mortality (adjusted hazard ratio [HR] systolic VIM: 0.99, 95%-CI 0.92-1.06, p=0.770, HR diastolic VIM: 1.04, 95%-CI 0.93-1.17, p=0.517). When morning and evening measurements were analyzed separately, systolic morning-to-morning VIM was associated with mortality (adjusted HR: 1.09, 95%-CI 1.01-1.18, p=0.033). Conclusion: In this study, day-to-day BPV was not associated with all-cause mortality in patients attending a memory clinic. However, morning-to-morning BPV was. Due to the short assessment window, there is still a lack of clarity; hence future research is warranted to clarify the role of all BPV components in aging.

Pages 1233-1250
Gang Wang, Wenju Zhou, Deping Kong, Zongshuai Qu, Maowen Ba, Jinguang Hao, Tao Yao, Qunxi Dong, Yi Su, Eric M. Reiman, Richard J. Caselli, Kewei Chen, Yalin Wang, for the Alzheimer’s Disease Neuroimaging Initiative**
Studying APOE ε4 Allele Dose Effects with a Univariate Morphometry Biomarker
Abstract Background: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ε4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. Objective: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ε4 dose effects among the longitudinal APOE ε4 homozygotes (HM, N=30), heterozygotes (HT, N=49) and non-carriers (NC, N=61). Methods: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. Results: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ε4 genotypes than the hippocampal volume measurements. And different APOE ε4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. Conclusion: The UMIs may capture the APOE ε4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ε4 on the hippocampal morphology in cognitively normal individuals.

Pages 1251-1265
Shefali Chaudhary, Simon Zhornitsky, Herta H. Chao, Christopher H. van Dyck, Chiang-Shan R. Li
Cerebral Volumetric Correlates of Apathy in Alzheimer’s Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort
Abstract: Background: Affecting nearly half of the patients with Alzheimer’s disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. Objective: To identify neuroanatomical correlates of AD-associated apathy. Methods: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls evaluated with the Apathy Evaluation Scale. esults: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. Conclusion: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

Pages 1267-1282
Stefan J. Teipel, Martin Dyrba, Tommaso Ballarini, Frederic Brosseron, Davide Bruno, Katharina Buerger, Nicoleta-Carmen Cosma, Peter Dechent, Laura Dobisch, Emrah Düzel, Michael Ewers, Klaus Fliessbach, John D. Haynes, Daniel Janowitz, Ingo Kilimann, Christoph Laske, Franziska Maier, Coraline D. Metzger, Matthias H. Munk, Oliver Peters, Nunzio Pomara, Lukas Preis, Josef Priller, Alfredo Ramírez, Nina Roy, Klaus Scheffler, Anja Schneider, Björn H. Schott, Annika Spottke, Eike J. Spruth, Michael Wagner, Jens Wiltfang, Frank Jessen, Michael T. Heneka
Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer’s Disease Spectrum
Abstract: Background: Inflammation has been described as a key pathogenic event In Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

Pages 1283-1300
Christian Ulrich von Linstow, Jonas Waider, Marianne Skov-Skov Bergh, Marco Anzalone, Cecilie Madsen, Aina Battle Nicolau, Martin Wirenfeldt, Klaus-Peter Lesch, Bente Finsen
The Combined Effects of Amyloidosis and Serotonin Deficiency by Tryptophan Hydroxylase-2 Knockout Impacts Viability of the APP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-β (Aβ). Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1)E9 transgenic mice. Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (-/-) were allowed to survive until 6 months old with APP/PS1, Tph2-/-, and wildtype mice. Survival and weight were recorded. Levels of Aβ42/40/38, soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ42 and Aβ40 in neocortex and hippocampus, and with only mild changes of soluble Aβ42/Aβ40. However, sAβPPα and sAβPPβ in hippocampus and Aβ38 and Aβ40 in cerebrospinal fluid were reduced. 3xTg-/- mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2-/- mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg-/- mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice.

Pages 1301-1308
Joseph Malone, Jeah Jung, Linh Tran, Chen Zhao
Periodontal Disease and Risk of Dementia in Medicare Patients with Hepatitis C Virus
Abstract: Background: Periodontal disease and hepatitis C virus (HCV) represent chronic infectious states that are common in elderly adults. Both conditions have independently been associated with an increased risk for dementia. Chronic infections are thought to lead to neurodegenerative changes in the central nervous system possibly by promoting a proinflammatory state. This is consistent with growing literature on the etiological role of infections in dementia. Few studies have previously evaluated the association of periodontal disease with dementia in HCV patients. Objective: To examine whether periodontal disease increases the risk of developing Alzheimer’s disease and related dementias (ADRD) among HCV patients in Medicare claims data. Methods: We used Medicare claims data for HCV patients to assess the incidence rate of ADRD with and without exposure to periodontal disease between 2014 and 2017. Cox multivariate regression was used to estimate the association between periodontal disease and development of ADRD, controlling for age, gender, race, ZIP-level income and education, and medical comorbidities. Results: Of 439,760 HCV patients, the incidence rate of ADRD was higher in patients with periodontal diseases compared to those without (10.84% versus 9.26%, p<0.001), and those with periodontal disease developed ADRD earlier compared to those without periodontal disease (13.99 versus 21.60 months, p<0.001). The hazard of developing ADRD was 1.35 times higher in those with periodontal disease (95% CI, 1.30 to 1.40, p< 0.001) after adjusting for all covariates, including age. Conclusion: Periodontal disease increased the risk of developing ADRD among HCV patients in a national Medicare claims dataset.

Pages 1309-1320
Alireza Salami, Rolf Adolfsson, Micael Andersson, Kaj Blennow, Anders Lundquist, Annelie Nordin Adolfsson, Michael Schöll, Henrik Zetterberg, Lars Nyberg
Association of APOE ε4 and Plasma p-tau181 with Preclinical Alzheimer’s Disease and Longitudinal Change in Hippocampus Function
Abstract: Background: The Apolipoprotein E (APOE) ε4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ε4 carriers with elevated tau might be at the higher risk for AD progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ε4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ε4 carriers. Objective: We related ε4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity. Methods: Longitudinal population-based study. Plasma p-tau181 was analyzed in 142 clinically defined Alzheimer’s disease (AD) cases and 126 controls. The longitudinal analysis involved 87 non-demented individuals with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding. Results: Increased p-tau181 was observed for both ε4 carriers and non-carriers close to AD, but exclusively for ε4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ε4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity. Conclusion: Our findings support an association of APOE ε4 and p-tau181 with preclinical AD and hippocampus functioning.

Pages 1321-1328
Hao-Lun Sun*, Fa-Ying Zhou*, Dong-Wan Chen, Cheng-Rong Tan, Gui-Hua Zeng, Yu-Hui Liu, Jun Wang, Xian-Le Bu, Yan-Jiang Wang, Hui-Yun Li, Wang-Sheng Jin (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer’s Disease
Abstract: Background: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer’s disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. Objective: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. Methods: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Results: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. Conclusion: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

Pages 1329-1342
Jiu Chen, Rong Chen, Chen Xue, Wenzhang Qi, Guanjie Hu, Wenwen Xu, Shanshan Chen, Jiang Rao, Fuquan Zhang, Xiangrong Zhang
Hippocampal-Subregion Mechanisms of Repetitive Transcranial Magnetic Stimulation Causally Associated with Amelioration of Episodic Memory in Amnestic Mild Cognitive Impairment
Abstract: Background: Altered hippocampal subregions (HIPsub) and their network connectivity relate to episodic memory decline in amnestic mild cognitive impairment (aMCI), which is significantly limited by over-dependence on correlational associations. Objective: To identify whether restoration of HIPsub and its network connectivity using repetitive transcranial magnetic stimulation (rTMS) is causally linked to amelioration of episodic memory in aMCI. Methods: In the first cohort, analysis of HIPsub grey matter (GM) and its functional connectivity was performed to identify an episodic memory-related circuit in aMCI by using a pattern classification approach. In the second cohort, this circuit was experimentally modulated with rTMS. Structural equation modeling was employed to investigate rTMS regulatory mechanism in amelioration of episodic memory. Results: First, in the first cohort, this study identified HIPsub circuit pathology of episodic memory decline in aMCI patients. Second, in the second cohort, restoration of HIPc GM and its connectivity with left middle temporal gyrus (MTG.L) are causally associated with amelioration of episodic memory in aMCI after 4 weeks of rTMS. Especially important, the effects of HIPc GM changes on the improvement of episodic memory were significantly mediated by HIPc connectivity with MTG.L changes in aMCI. Conclusion: This study provides novel experimental evidence about a biological substrate for the treatment of the disabling episodic memory in aMCI patients. Correction of breakdown in HIPc structure and its connectivity with MTG can causally ameliorate episodic memory in aMCI.

Pages 1343-1356
Maria Rosaria Tropea, Giulia Sanfilippo, Federico Giannino, Valentina Davì, Walter Gulisano, Daniela Puzzo
Innate Preferences Affect Results of Object Recognition Task in Wild Type and Alzheimer’s Disease Mouse Models
Abstract: Background: Object recognition task (ORT) is a widely used behavioral paradigm to assess memory in rodent models, due to its easy technical execution, the lack of aversive stressful stimuli, and the possibility to repeat the test on the same animals. However, mouse exploration might be strongly influenced by a variety of variables. Objective: To study whether innate preferences influenced exploration in male and female wild type mice and the Alzheimer’s disease (AD) model 3xTg. Methods: We first evaluated how object characteristics (material, size, and shape) influence exploration levels, latency, and exploration modality. Based on these findings, we evaluated whether these innate preferences biased the results of ORT performed in wild type mice and AD models. Results: Assessment of Exploration levels, i.e., the time spent in exploring a certain object in respect to the total exploration time, revealed an innate preference for objects made in shiny materials, such as metal and glass. A preference for bigger objects characterized by higher affordance was also evident, especially in male mice. When performing ORT, exploration was highly influenced by these innate preferences. Indeed, both wild type and AD mice spent more time in exploring the metal object, regardless of its novelty. Furthermore, the use of objects with higher affordance such as the cube was a confounding factor leading to “false” results that distorted ORT interpretation. Conclusion: When designing exploration-based behavioral experiments aimed at assessing memory in healthy and AD mice, object characteristics should be carefully evaluated to improve scientific outcomes and minimize possible biases.

Pages 1357-1372
Seyul Kwak, Dae Jong Oh, Yeong-Ju Jeon, Da Young Oh, Su Mi Park, Hairin Kim, Jun-Young Lee
Utility of Machine Learning Approach with Neuropsychological Tests in Predicting Functional Impairment of Alzheimer’s Disease
Abstract: Background: In assessing the levels of clinical impairment in dementia, a summary index of neuropsychological batteries has been widely used in describing the overall functional status. Objective: It remains unexamined how complex patterns of the test performances can be utilized to have specific predictive meaning when the machine learning approach is applied. Methods: In this study, the neuropsychological battery (CERAD-K) and assessment of functioning level (Clinical Dementia Rating scale and Instrumental Activities of Daily Living) were administered to 2,642 older adults with no impairment (n = 285), mild cognitive impairment (n = 1,057), and Alzheimer's disease (n = 1,300). Predictive accuracy on functional impairment level with the linear models of the single total score or multiple subtest scores (Model 1, 2) and support vector regression with low or high complexity (Model 3, 4) were compared across different sample sizes. Results: The linear models (Model 1, 2) showed superior performance with relatively smaller sample size, while nonlinear models with low and high complexity (Model 3, 4) showed an improved accuracy with a larger dataset. Unlike linear models, the nonlinear models showed a gradual increase in the predictive accuracy with a larger sample size (n > 500), especially when the model training is allowed to exploit complex patterns of the dataset. Conclusion: Our finding suggests that nonlinear models can predict levels of functional impairment with a sufficient dataset. The summary index of the neuropsychological battery can be augmented for specific purposes, especially in estimating the functional status of dementia.

Pages 1373-1398
Sze Chung Yuen, Simon Ming-Yuen Lee, Siu-wai Leung
Putative Factors Interfering Cell Cycle Re-Entry in Alzheimer’s Disease: An Omics Study with Differential Expression Meta-Analytics and Co-Expression Profiling
Abstract:Background: Neuronal cell cycle re-entry (CCR) is a mechanism, along with amyloid-β (Aβ) oligomers and hyperphosphorylated tau proteins, contributing to toxicity in Alzheimer’s disease (AD). Objective: This study aimed to examine the putative factors in CCR based on evidence corroboration by combining meta-analysis and co-expression analysis of omic data. Methods: The differentially expressed genes (DEGs) and CCR-related modules were obtained through the differential analysis and co-expression of transcriptomic data, respectively. Differentially expressed microRNAs (DEmiRNAs) were extracted from the differential miRNA expression studies. The dysregulations of DEGs and DEmiRNAs as binary outcomes were independently analyzed by meta-analysis based on a random-effects model. The CCR-related modules were mapped to human protein-protein interaction databases to construct a network. The importance score of each node within the network was determined by the PageRank algorithm, and nodes that fit the pre-defined criteria were treated as putative CCR-related factors. Results: The meta-analysis identified 18,261 DEGs and 36 DEmiRNAs, including genes in the ubiquitination proteasome system, mitochondrial homeostasis, and CCR, and miRNAs associated with AD pathologies. The co-expression analysis identified 156 CCR-related modules to construct a protein-protein interaction network. Five genes, UBC, ESR1, EGFR, CUL3, and KRAS, were selected as putative CCR-related factors. Their functions suggested that the combined effects of cellular dyshomeostasis and receptors mediating Aβ toxicity from impaired ubiquitination proteasome system are involved in CCR. Conclusion: This study identified five genes as putative factors and revealed the significance of cellular dyshomeostasis in the CCR of AD.