Volume 87, Number 2, 2022

Pages 503-517
Systematic Review

Mikel L. Sáez de Asteasu, Cesar Cuevas-Lara, Antonio García-Hermoso, Robinson Ramírez-Vélez, Nicolás Martínez-Velilla, Fabricio Zambom-Ferraresi, Eduardo Lusa Cadore, Mikel Izquierdo
Effects of Physical Exercise on the Incidence of Delirium and Cognitive Function in Acutely Hospitalized Older Adults: A Systematic Review with Meta-Analysis
Abstract: Background: Acute care hospitalization increases the likelihood of developing cognitive impairment and delirium in older adults. Objective: To summarize evidence about the effectiveness of exercise and physical rehabilitation interventions on the incidence of delirium and cognitive impairment in acutely hospitalized older patients. Methods: Relevant articles were systematically searched (PubMed, Web of Science, and CINHAL databases) until 26 August 2021. Randomized and nonrandomized controlled trials of in-hospital physical exercise interventions and rehabilitation programs compared to usual care performed for older patients (>65 years) hospitalized for an acute medical condition were selected. The primary endpoints were changes in the incidence of delirium and cognition during acute hospitalization. The secondary endpoints included functional independence, psychological measures, well-being status, length of hospital stay, transfer after discharge, fall occurrence, hospital readmissions, and mortality rate. The endpoints were evaluated at different time points (at admission, at discharge, and after discharge). Results: Eleven studies from 8 trials (n=3,646) were included. The methodological quality of the studies was mostly high. None of the studies reported any adverse events related to the intervention. Early rehabilitation improved cognitive function at 3 months postdischarge (Hedge’s g=0.33, 95% confidence interval [CI] 0.19 to 0.46, p<0.001). No between-group differences were found for incident delirium and cognitive impairment during hospitalization (all p>0.05). Conclusion: In-hospital physical exercise and early rehabilitation programs seem to be safe and effective interventions for enhancing cognitive function after discharge in older patients hospitalized for an acute medical condition. However, no potential benefits were obtained over usual hospital care for the incidence of delirium.

Pages 519-528
Systematic Review

Elisa Marina González Cordero, Miguel Ángel Cuevas-Budhart, Diana Perez-Moran, Miguel Angel Trejo Villeda, Mercedes Gomez-del-Pulgar Gª-Madrid
Relationship Between the Gut Microbiota and Alzheimer’s Disease: A Systematic Review
Abstract: Background: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated. Objective: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer's disease. Method: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish. Results: Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review. Conclusion: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.

Pages 529-543
Lorena Xolalpa-Cueva, Carlos Antonio García-Carlos, Rocío Villaseñor-Zepeda, Erika Orta-Salazar, Sofia Díaz-Cintra, Fernando Peña-Ortega, George Perry, Siddhartha Mondragón-Rodríguez (Handling Deputy Editor: Jesus Ávila)
Hyperphosphorylated Tau Relates to Improved Cognitive Performance and Reduced Hippocampal Excitability in the Young rTg4510 Mouse Model of Tauopathy
Abstract: Background: Tau hyperphosphorylation at several sites, including those close to its microtubule domain (MD), is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, tau phosphorylation (pTau) at MD sites promotes neuroprotection by preventing seizure-like activity. Objective: To further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (PN30-35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function. Methods: We used immunohistochemistry, T-maze, nesting test, novel object recognition test, open field arena, and electrophysiology. Results: Our results showed that the very young rTg4510 mouse model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from PN30-35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found a significant reduction in the somatic area of pTau positive pyramidal and granule neurons in the young rTg4510 mice. Despite this, improved memory and increased number of dendrites per cell in granule neurons was found. Conclusion: Altogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology.

Pages 545-555
Steffen Wolfsgruber, Luca Kleineidam, Anne-Sophie Weyrauch, Miriam Barkhoff, Sandra Röske, Oliver Peters, Lukas Preis, Daria Gref, Eike Jakob Spruth, Slawek Altenstein, Josef Priller, Klaus Fließbach, Anja Schneider, Jens Wiltfang, Claudia Bartels, Frank Jessen, Franziska Maier, Emrah Düzel, Coraline Metzger, Wenzel Glanz, Katharina Buerger, Daniel Janowitz, Robert Perneczky, Boris-Stephan Rauchmann, Ingo Kilimann, Stefan Teipel, Christoph Laske, Matthias H. Munk, Nina Roy, Annika Spottke, Alfredo Ramirez, Michael T. Heneka, Frederic Brosseron, Michael Wagner, on behalf of the DELCODE study group (Handling Associate Editor: Kerryn Pike)
Relevance of Subjective Cognitive Decline in Older Adults with a First-Degree Family History of Alzheimer’s Disease
Abstract: Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n=82 “AD relatives”; mean age: 65.7 years (SD=4.47); 59% female) and a similar group of n=236 healthy controls without FHAD from the DELCODE study. We measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression.

Pages 557-568
Xinting Ge*, Yuchuan Qiao*, Jiyoon Choi, Rema Raman, John M. Ringman, Yonggang Shi and for Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Enhanced Association of Tau Pathology and Cognitive Impairment in Mild Cognitive Impairment Subjects with Behavior Symptoms
Abstract: Background: Mild cognitive impairment (MCI) individuals with neuropsychiatric symptoms (NPS) are more likely to develop dementia. Objective: We sought to understand the relationship between neuroimaging markers such as tau pathology and cognitive symptoms both with and without the presence of NPS during the prodromal period of Alzheimer’s disease. Methods: A total of 151 MCI subjects with tau positron emission tomographic (PET) scanning with 18F AV-1451, amyloid-β (Aβ) PET scanning with florbetapir or florbetaben, magnetic resonance imaging, and cognitive and behavioral evaluations were selected from the Alzheimer’s Disease Neuroimaging Initiative. A 4-group division approach was proposed using amyloid (A-/A+) and behavior (B-/B+) status: A-B-, A-B+, A+B-, and A+B+. Pearson’s correlation test was conducted for each group to examine the association between tau deposition and cognitive performance. Results: No statistically significant association between tau deposition and cognitive impairment was found for subjects without behavior symptoms in either the A-B- or A+B- groups after correction for false discovery rate. In contrast, tau deposition was found to be significantly associated with cognitive impairment in entorhinal cortex and temporal pole for the A-B+ group and nearly the whole cerebrum for the A+B+ group. Conclusion: Enhanced associations between tauopathy and cognitive impairment are present in MCI subjects with behavior symptoms, which is more prominent in the presence of elevated amyloid pathology. MCI individuals with NPS may thus be at greater risk for further cognitive decline with the increase of tau deposition in comparison to those without NPS.

Pages 569-581
Beatrix Krause-Sorio, Prabha Siddarth, Lisa Kilpatrick, Michaela M. Milillo, Yesenia Aguilar-Faustino, Linda Ercoli, Katherine L. Narr, Dharma S. Khalsa, Helen Lavretsky
Yoga Prevents Gray Matter Atrophy in Women at Risk for Alzheimer’s Disease: A Randomized Controlled Trial
Abstract: Background: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer’s disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment. Objective: In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET). Methods: Eleven women (mean age=61.45, SD=6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY+KK) while eleven women (mean age=64.55, SD=6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha=0.05. Region-of-interest analysis was performed for hippocampus and amygdala. Results: Compared to KY+KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections. Conclusion: Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.

Pages 583-594
Vitaly I. Dobromyslin, Dalila B. Megherbi, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ruth Barrientos)
Augmenting Imaging Biomarker Performance with Blood-Based Gene Expression Levels for Predicting Alzheimer’s Disease Progression
Abstract: Background: Structural brain imaging metrics and gene expression biomarkers have previously been used for Alzheimer’s disease (AD) diagnosis and prognosis, but none of these studies explored integration of imaging and gene expression biomarkers for predicting mild cognitive impairment (MCI)-to-AD conversion 1-2 years into the future. Objective: We investigated advantages of combining gene expression and structural brain imaging features for predicting MCI-to-AD conversion. Selection of the differentially expressed genes (DEGs) for classifying cognitively normal (CN) controls and AD patients was benchmarked against previously reported results. Methods: The current work proposes integrating brain imaging and blood gene expression data from two public datasets (ADNI and ANM) to predict MCI-to-AD conversion. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated in the two independents patient cohorts. Results: Combining DEGs and imaging biomarkers for predicting MCI-to-AD conversion yielded 0.832-0.876 receiver operating characteristic (ROC) area under the curve (AUC), which exceeded the 0.808-0.840 AUC from using the imaging features alone. With using only three DEGs, the CN versus AD predictive model achieved 0.718, 0.858, and 0.873 cross-validation AUC for the ADNI, ANM1, and ANM2 datasets. Conclusion: For the first time we show that combining gene expression and imaging biomarkers yields better predictive performance than using imaging metrics alone. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated to produce consistent results in the two independents patient cohorts. Using an improved feature selection, we show that predictive models with fewer gene expression probes can achieve competitive performance.

Pages 595-607
Shojiro Ichimata, Koji Yoshida, Naomi P. Visanji, Anthony E. Lang, Naoki Nishida, Gabor G. Kovacs (Handling Associate Editor: Giorgio Giaccone)
Patterns of Mixed Pathologies in Down Syndrome
Abstract: Background: Down syndrome (DS) is frequently associated with Alzheimer’s disease (AD)-related neuropathological changes. There are few observations on the spectrum of mixed proteinopathies in DS patients. Objective: This study aimed to evaluate multiple disease-associated proteinopathies in a series of DS cases. Methods: We analyzed the distribution of neurodegenerative disease associated proteins in postmortem brain samples from 11 DS cases (6 females, median age 57, range 38–66 years). Sections were stained for phosphorylated tau, 3-repeat and 4-repeat tau, amyloid-β, alpha synuclein, phosphorylated TDP-43, and p62. A comprehensive anatomical mapping and staging were applied for all proteins. Results: Tau and amyloid-β pathology was prevalent in all cases and compatible with that typically seen in AD with some subtle deviations. Four of 11 cases presented with Lewy-related pathology (LRP). Two cases followed the Braak staging (stage 4 and 5) whereas 2 cases presented with an atypical distribution. Two cases showed limbic predominant age-related TDP-43 encephalopathy (LATE) (stage 1 and stage 2) neuropathologic change. Two cases exhibited aging-related tau astrogliopathy (ARTAG). Conclusion: In addition to subtle deviations from AD regarding the morphology of Aβ deposition and distribution of neuronal tau pathology, we find that the spectrum of mixed-pathologies in DS show distinctive features such as deviations from the Braak staging of LRP and that LATE neuropathologic change and ARTAG pathology can be seen in individuals younger than in sporadic AD cases. Our observations support the notion that DS has distinctive pathogenic pathways from sporadic AD.

Pages 609-617
Victoria Solomon, Madonna Hafez, Haotian Xian, Michael G. Harrington, Alfred Fonteh, Hussein N. Yassine (Handling Associate Editor: J. Wesson Ashford)
An Association Between Saturated Fatty Acid-Containing Phosphatidylcholine in Cerebrospinal Fluid with Tau Phosphorylation
Abstract: Background: Mechanistic studies in animal models implicate a role for saturated fatty acids in neurodegeneration, but validation of this finding in human studies is still lacking. Objective: We investigated how cerebrospinal levels of sphingomyelins (SM) and phosphatidylcholine (PC)-containing saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids associate with total tau and phosphorylated tau (p-tau). Methods: Cerebrospinal fluid (CSF) lipids were measured in two cohorts, a discovery and a confirmation cohort of older non-demented individuals from the University of Southern California and Huntington Medical Research Institutes cohorts. Lipid analysis was performed using hydrophilic interaction liquid chromatography, and individual PC and SM lipid species were measured using tandem mass spectrometry. In addition, CSF levels of Aβ42, total tau, and p-tau-181 were measured using an MSD multiplex assay. Results: The discovery cohort (n=47) consisted of older individuals and more females compared to the confirmation cohort (n=46). Notwithstanding the age and gender differences, and a higher p-tau, Aβ42, and LDL-cholesterol in the discovery cohort, CSF concentrations of dipalmitoyl-PC (PC32a:0) were significantly associated with p-tau in both cohorts. Similarly, total saturated PC but not mono or polyunsaturated PCs correlated with p-tau concentrations in both cohorts. Conclusion: Saturated PC species in CSF associate with early markers of neurodegeneration and are potential early disease progression biomarkers. We propose mechanisms by which saturated PC may promote tau hyperphosphorylation.

Pages 619-633
Changhao Yang*, Beipei Kang*, Zipeng Cao, Jianbin Zhang, Fang Zhao, Diya Wang, Peng Su, Jingyuan Chen (Handling Associate Editor: Ling-Qiang Zhu *These authors contributed equally to this work.
Early-Life Pb Exposure Might Exert Synapse-Toxic Effects Via Inhibiting Synapse-Associated Membrane Protein 2 (VAMP2) Mediated by Upregulation of miR-34b
Abstract: Background: Early-life Pb exposure can cause behavioral and cognitive problems and induce symptoms of hyperactivity, impulsivity, and inattention in children. Studies showed that blood lead levels were highly correlated with neuropsychiatric disorders, and effects of neurotoxicity might persist and affect the incidence of neurodegenerative diseases, for example Alzheimer’s disease (AD). Objective: To explore possible mechanisms of developmental Pb-induced neuropsychiatric dysfunctions. Methods: Children were divided into low blood lead level (BLL) group (0-50.00 g/L) and high BLL group (>50.00 g/L) and blood samples were collected. miRNA array was used to testify miRNA expression landscape between two groups. Correlation analysis and real-time PCR were applied to find miRNAs that altered in Pb and neuropsychiatric diseases. Animal models and cell experiments were used to confirm the effect of miRNAs in response to Pb, and siRNA and luciferase experiments were conducted to examine their effect on neural functions. Results: miRNA array data and correlation analysis showed that miR-34b was the most relevant miRNA among Pb neurotoxicity and neuropsychiatric disorders, and synapse-associated membrane protein 2 (VAMP2) was the target gene regulating synapse function. In vivo and in vitro studies showed Pb exposure injured rats’ cognitive abilities and induced upregulation of miR-34b and downregulation of VAMP2, resulting in decreases of hippocampal synaptic vesicles. Blockage of miR-34b mitigated Pb’s effects on VAMP2 in vitro. Conclusion: Early-life Pb exposure might exert synapse-toxic effects via inhibiting VAMP2 mediated by upregulation of miR-34b and shed a light on the underlying relationship between Pb neurotoxicity and developmental neuropsychiatric disorders.

Pages 635-642
Serena Low, Kiat Sern Goh, Tze Pin Ng, Angela Moh, Su Fen Ang, Jiexun Wang, Keven Ang, Wern Ee Tang, Ziliang Lim, Tavintharan Subramaniam, Chee Fang Sum, Su Chi Lim
Association Between Use of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors and Cognitive Function in a Longitudinal Study of Patients with Type 2 Diabetes
Abstract: Background: The association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) use and cognitive function in type 2 diabetes remains unclear. Objective: Explore the association between SGLT2i and longitudinal changes in cognitive function in adults with type 2 diabetes (T2DM) and assessed the cognitive domains which were impacted by SGLT2i. Methods: We conducted a prospective cohort study of 476 patients aged 60.6±7.4 years with follow-up period up to 6.4 years. Data on SGLT2i use was derived from questionnaire and verified with clinical database. We used Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. The association between SGLT2i use and rate of RBANS score change was examined using multiple linear regression. Results: There were 138 patients (29.0%) on SGLT2i, including 84 (17.7%) for < 3 years and 54 (11.3%) for ≥3 years. SGLT2i use was positively associated with RBANS total score increase in language (coefficient 0.60; 95%CI 0.10-1.11; p=0.019) in unadjusted analysis. This positive association persisted in fully adjusted model (coefficient 0.74; 95%CI 0.12 to 1.36; p=0.019). SGLT2i use for ≥3 years was positively associated with RBANS score increase globally and in language domain in fully adjusted analysis with coefficients 0.54 (95%CI 0.13 to 0.95; p=0.010) and 1.12 (95%CI 0.27 to 1.97; p=0.010) respectively. Conclusion: Our findings revealed a previously unobserved association between ≥3 years SGLT2i use and improved cognitive scores globally and in language domain and executive function. Future studies should investigate the role of SGLT2i in ameliorating cognitive decline.

Pages 643-664
Ioulietta Lazarou, Kostas Georgiadis, Spiros Nikolopoulos, Vangelis P. Oikonomou, Thanos G. Stavropoulos, Anthoula Tsolaki, Ioannis Kompatsiaris, Magda Tsolaki, the RADAR-AD Consortium
Exploring Network Properties Across Preclinical Stages of Alzheimer’s Disease Using a Visual Short-Term Memory and Attention Task with High-Density Electroencephalography: A Brain-Connectome Neurophysiological Study
Abstract: Background: Visual short-term memory (VSTMT) and visual attention (VAT) exhibit decline in the Alzheimer’s disease (AD) continuum; however, network disruption in preclinical stages is scarcely explored. Objective: To advance our knowledge about brain networks in AD and discover connectivity alterations during VSTMT and VAT. Methods: Twelve participants with AD, 23 with mild cognitive impairment (MCI), 17 with subjective cognitive decline (SCD), and 21 healthy controls (HC) were examined using a neuropsychological battery at baseline and follow-up (three years). At baseline, the subjects were examined using high density electroencephalography while performing a VSTMT and VAT. For exploring network organization, we constructed weighted undirected networks and examined clustering coefficient, strength, and betweenness centrality from occipito-parietal regions. Results: One-way ANOVA and pair-wise t-test comparisons showed statistically significant differences in HC compared to SCD (t (36) = 2.43, p = 0.026), MCI (t (42) = 2.34, p = 0.024), and AD group (t (31) = 3.58, p = 0.001) in Clustering Coefficient. Also with regards to Strength, higher values for HC compared to SCD (t (36) = 2.45, p = 0.019), MCI (t (42) = 2.41, p = 0.020), and AD group (t (31) = 3.58, p = 0.001) were found. Follow-up neuropsychological assessment revealed converge of 65% of the SCD group to MCI. Moreover, SCD who were converted to MCI showed significant lower values in all network metrics compared to the SCD that remained stable. Conclusion: The present findings reveal that SCD exhibits network disorganization during visual encoding and retrieval with intermediate values between MCI and HC.

Pages 665-673
Xiaoxin Wang*, Hongru Sun*, Sijia Pan*, Xiao Bai*, Zhuolin Zhu, Runan Zhang, Chunlong Li, Yang Chen, Meitong Bao, Kewei Zhang, Rennan Feng *These authors contributed equally to this work.
Causal Relationships Between Relative Intake from the Macronutrients and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study
Abstract: Background: Some observational studies indicated the associations of relative carbohydrate, sugar, fat, and protein intake and Alzheimer’s disease (AD). But it remains unclear whether the associations are causal. Objective: This study aimed to identify the effects of relative carbohydrate, sugar, fat, and protein intake in the diet on AD. Methods: A two-sample Mendelian randomization was employed. Finally, 14 independent lead SNPs remained in the Social Science Genetic Association Consortium. These SNPs of relative carbohydrate, sugar, fat, and protein intake at the level of genome-wide significance (p < 5×10-8) were used as instrumental variables. The summary data for AD were acquired from the International Genomics of Alzheimer's Project with a total of 54,162 individuals (17,008 AD patients and 37,154 control participants). Results: This two-sample Mendelian randomization indicated that increased relative protein intake (per 1 standard deviation) causally decreased the AD risk (OR=0.48, 95% CI: 0.24–0.95, p=0.036), and increased relative fat intake may decrease the risk of AD (OR=0.22, 95% CI: 0.06–0.86, p=0.029). No statistical significance with AD risk was seen for relative carbohydrate or relative sugar intake. Conclusion: A higher relative intake of protein can causally reduce the risk of AD in the elderly. Additionally, a higher relative intake of fat may be protective against AD. No evidence showed that AD was associated with relative carbohydrate and sugar intake.

Pages 675-684
Tao Wei*, Zheng Guo*, Zhibin Wang, Cancan Li, Wei Zhu, Yulu Zheng, Yunsi Yin, Yingxin Mi, Xinyi Xia, Haifeng Hou, Yi Tang (Handling Associate Editor: Jin-tai Yu) *These authors contributed equally to this work.
Five Major Psychiatric Disorders and Alzheimer’s Disease: A Bidirectional Mendelian Randomization Study
Abstract: Background: Extensive studies put forward the association between Alzheimer’s disease (AD) and psychiatric disorders; however, it remains unclear whether these associations are causal. Objective: We aimed to assess the potential causal relationship between major psychiatric disorders and AD. Methods: A bidirectional two-sample Mendelian randomization (MR) was applied to evaluate potential causality between five psychiatric disorders and AD by selecting the single-nucleotide polymorphisms from the genome-wide association studies as instrumental variables. Inverse-variance weighted (IVW) method was used as the main analyzing approach to estimate possible causal effects, alternative methods including MR-Egger, the MR pleiotropy residual sum and outlier, and leave-one-out analysis method were implemented as sensitivity analyzing approaches to ensure the robustness of results. Results: All forward and reverse MR analyses consistently suggested absent causal relations between psychiatric disorders and AD risk [forward IVW: ORADHD, 1.030, 95% CI, 0.908-1.168, p = 0.674; ORanxiety disorders, 0.904, 95% CI, 0.722-1.131, p = 0.377; ORASD, 0.973, 95% CI, 0.746-1.272, p = 0.846; ORBIP, 1.033, 95% CI, 0.925-1.153, p = 0.564; and ORschizophrenia, 1.039, 95% CI, 0.986 -1.095, p = 0.156; reverse IVW: ORADHD, 0.993, 95% CI, 0.954-1.034, p = 0.746; ORanxiety disorders, 1.000, 95% CI, 0.999-1.000, p = 0.898; ORASD, 1.001, 95% CI, 0.962-1.042, p = 0.949; ORBIP, 0.997, 95% CI, 0.966-1.028, p = 0.831; and ORschizophrenia, 1.013, 95% CI, 0.978-1.051, p = 0.466]. Conclusion: There is no significant evidence supporting the causal association between the five major psychiatric disorders and AD.

Pages 685-699
Mithula Sivasaravanaparan, Louise Ørum Olesen, Maurizio Severino, Christian Ulrich von Linstow, Kate Lykke Lambertsen, Jan Bert Gramsbergen, Jørgen Hasselstrøm, Athanasios Metaxas, Ove Wiborg, Bente Finsen (Handling Associate Editor: Guiseppe Verdile)
Efficacy of Chronic Paroxetine Treatment in Mitigating Amyloid Pathology and Microgliosis in APPSWE/PS1ΔE9 Transgenic Mice
Abstract: Background: Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer’s disease, in addition to exerting an anti-depressant action. Objective: To investigate the efficacy of chronic treatment with the SSRI paroxetine, in mitigating Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of 18-month-old APPswe/PS1ΔE9 mice. Methods: Plaque-bearing APPswe/PS1ΔE9 and wildtype mice were treated with paroxetine per os at a dose of 5 mg/kg/day, from 9 to 18 months of age. The per os treatment was monitored by recording of the body weights and serum paroxetine concentrations, and by assessment of the serotonin transporter occupancy by [3H]DASB-binding in wildtype mice. Additionally, 5,7-dihydroxytryptamine was administered to 9-month-old APPswe/PS1ΔE9 mice, to examine the effect of serotonin depletion on Aβ pathology. Aβ pathology was evaluated by Aβ plaque load estimation and the Aβ42/Aβ40 ratio by ELISA. Results: Paroxetine treatment led to >80% serotonin transporter occupancy. The treatment increased the body weight of wildtype mice, but not of APPswe/PS1ΔE9 mice. The treatment had no effect on the Aβ plaque load (p = 0.39), the number and size of plaques, or the Aβ plaque-induced increases in microglial numbers in the dentate gyrus. Three months of serotonin depletion did not significantly impact the Aβ plaque load or Aβ42/Aβ40 ratio in APPswe/PS1ΔE9 mice at 12 months. Conclusion: Our results show that chronic treatment with the SSRI paroxetine does not mitigate Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of APPswe/PS1ΔE9 mice.

Pages 701-710
Seok Jong Chung*, Yoonkyung Chang*, Jimin Jeon, Jae Il Shin, Tae-Jin Song**, Jinkwon Kim** *,**These authors contributed equally to this work.
Association of Alzheimer’s Disease with COVID-19 Susceptibility and Severe Complications: A Nationwide Cohort Study
Abstract: Background: Identification of patients at high susceptibility and high risk of developing serious complications related to coronavirus disease 2019 (COVID-19) infection is clinically important in the face of the COVID-19 pandemic. Objective: To investigate whether patients with Alzheimer’s disease (AD) are more susceptible to COVID-19 infection and whether they have a higher risk of developing serious complications. Methods: We retrospectively reviewed the Korean nationwide population-based COVID-19 dataset for participants who underwent real-time reverse transcription polymerase chain reaction assays for COVID-19 between January 1 and June 4, 2020. A 1:3 ratio propensity score matching and binary logistic regression analysis were performed to investigate the association between AD and the susceptibility or severe complications (i.e., mechanical ventilation, intensive care unit admission, or death) of COVID-19. Results: Among 195,643 study participants, 5,725 participants had AD and 7,334 participants were diagnosed with COVID-19. The prevalence of participants testing positive for COVID-19 did not differ according to the presence of AD (p = 0.234). Meanwhile, AD was associated with an increased risk of severe COVID-19 complications (OR 2.25 [95% CI 1.54–3.28]). Secondary outcome analyses showed that AD patients had an increased risk for mortality (OR 3.09 [95% CI 2.00–4.78]) but were less likely to receive mechanical ventilation (OR 0.42 [95% CI 0.20–0.87]). Conclusion: AD was not associated with increased susceptibility to COVID-19 infection, but was associated with severe COVID-19 complications, especially with mortality. Early diagnosis and active intervention are necessary for patients with AD suspected COVID-19 infection.

Pages 711-719
Jie-Ming Jian, Dong-Yu Fan, Yuan Cheng, Ying-Ying Shen, Dong-Wan Chen, Hui-Yun Li, Yang Chen, Yuan Zhang, Gui-Hua Zeng, Cheng-Rong Tan, Yu-Hui Liu, Yan-Jiang Wang (Handling Associate Editor: Jin-Tai Yu)
Circulating Naturally Occurring Antibodies to P2RY2 Are Decreased in Alzheimer’s Disease
Abstract: Background: The G protein-coupled receptor P2RY2 protein of the purinergic receptor family is involved in the pathogenesis of Alzheimer’s disease (AD). Naturally occurring antibodies against P2RY2 (NAbs-P2RY2) are present in human plasma, with their clinical relevance in AD unknown. Objective: To explore the alteration of NAbs-P2RY2 in AD patients and its associations with biomarkers and cognition of AD patients. Methods: The levels of naturally occurring antibodies against the four extracellular domains of P2RY2 (NAbs-P2RY2-1, NAbs-P2RY2-2, NAbs-P2RY2-3, and NAbs-P2RY2-4) were measured in the plasma of 55 AD patients, 28 non-AD dementia patients, and 70 cognitively normal participants. The correlations of autoantibody levels with cognitive scale scores, AD plasma biomarkers, and brain amyloid burden were examined. Results: NAbs-P2RY2-1, NAbs-P2RY2-3, and NAbs-P2RY2-4 were reduced in AD patients. Plasma levels of NAbs-P2RY2-2 and NAbs-P2RY2-3 levels were positively associated with cognitive and functional performances. Among these antibodies, plasma NAbs-P2RY2-2 levels were positively associated with plasma amyloid-β 42 levels. While plasma NAbs-P2RY2-3 levels were negatively associated with brain amyloid burden in AD patients. Conclusion: These findings indicate an alteration of humoral immunity against P2RY2 in AD patients. Further mechanistical investigations are needed to reveal the role of NAbs-P2RY2 in the pathogenesis of AD.

Pages 721-730
Peng-Fei Zhang, Zuo-Teng Wang, Ying Liu, Hao Hu, Yan Sun, He-Ying Hu, Ya-Hui Ma, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Peripheral Immune Cells and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE Study
Abstract: Background: Inflammation plays a role in occurrence and progression of Alzheimer’s disease (AD). Whether peripheral immune cells are involved in major pathological processes including amyloid-β plaques and tau tangles is still controversial. Objective: We aimed to examine whether peripheral immune cells counts were associated with early changes in cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively intact older adults. Methods: This study included 738 objective cognitive normal participants from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) database. Group comparisons of peripheral immune cells counts were tested by analysis of covariance. Multiple linear regression models were used to examine the associations of peripheral immune cells counts with CSF AD biomarkers. Results: In preclinical AD, peripheral lymphocytes and eosinophils changed dynamically along with disease progression. Consistently, regression analysis showed that lymphocytes and eosinophils were associated with Aβ pathology. There were no interaction effects of peripheral immune cells counts with APOE ε4, gender, age, and educate. Eosinophil to lymphocyte ratio were also significantly associated with Aβ-related biomarkers. Conclusion: Our findings showed the relationship between peripheral immune cells and Aβ pathological biomarkers, which indicated that peripheral immune might play a role in progression of AD pathology.

Pages 731-740
Andrew Sommerlad*, Hee Kyung Park*, Louise Marston, Gill Livingston (Handling Associate Editor: Lucy Stirland) * These authors contributed equally to this work.
Apathy in UK Care Home Residents with Dementia: Longitudinal Course and Determinants
Abstract: Background: Apathy in dementia is common and associated with worse disease outcomes. Objective: To describe the longitudinal course of apathy in dementia and identify associated sociodemographic and disease-related factors. Methods: Prospective cohort study of UK care home residents with dementia. At baseline, 4, 8, 12, and 16 months, care home staff rated apathy using the Neuropsychiatric Inventory (clinically-significant apathy if ≥4), dementia severity, and provided other sociodemographic information about each participant. We examined the prevalence and persistence of apathy and, in mixed linear models, its association with time, age, sex, dementia severity, antipsychotic use, and baseline apathy and other neuropsychiatric symptoms. Results: Of 1,419 included participants (mean age 85 years (SD 8.5)), 30% had mild dementia, 33% moderate, and 37% severe. The point prevalence of clinically-significant apathy was 21.4% (n=304) and the 16-month period prevalence was 47.3% (n=671). Of participants with follow-up data, 45 (3.8%) were always clinically-significantly apathetic, 3 (0.3%) were always sub-clinically apathetic, and 420 (36.2%) were never apathetic until death or end of follow-up. In adjusted models, apathy increased over time and was associated with having more severe dementia, worse baseline apathy and other neuropsychiatric symptoms. Conclusion: It is important for clinicians to know that most people with dementia are not apathetic, though it is common. Most of those with significant symptoms of apathy improve without specific treatments, although some also relapse, meaning that intervention may not be needed. Future research should seek to target those people with persistent severe apathy and test treatments in this group.

Pages 741-759
Melchor Martínez-Herrera, Susana Figueroa-Gerstenmaier, Perla Y. López-Camacho, Cesar Millan-Pacheco, Miguel A. Balderas-Altamirano, Graciela Mendoza-Franco, Francisco García-Sierra, Lizeth M. Zavala-Ocampo, Gustavo Basurto-Islas (Handling Associate Editor: Jesus Avila)
Multiadducts of C60 Modulate Amyloid-β Fibrillation with Dual Acetylcholinesterase Inhibition and Antioxidant Properties: In Vitro and In Silico Studies
Abstract: Background: Amyloid-β (Aβ) fibrils induce cognitive impairment and neuronal loss, leading to onset of Alzheimer's disease (AD). The inhibition of Aβ aggregation has been proposed as a therapeutic strategy for AD. Pristine C60 has shown the capacity to interact with the Aβ peptide and interfere with fibril formation but induces significant toxic effects in vitro and in vivo. Objective: To evaluate the potential of a series of C60 multiadducts to inhibit the Aβ fibrillization. Methods: A series of C60 multiadducts with four to six diethyl malonyl and their corresponding disodium-malonyl substituents were synthesized as individual isomers. Their potential on Aβ fibrillization inhibition was evaluated in vitro, in cellulo, and silico. Antioxidant activity, acetylcholinesterase inhibition capacity, and toxicity were assessed in vitro. Results: The multiadducts modulate Aβ fibrils formation without inducing cell toxicity, and that the number and polarity of the substituents play a significant role in the adducts efficacy to modulate Aβ aggregation. The molecular mechanism of fullerene-Aβ interaction and modulation was identified. Furthermore, the fullerene derivatives exhibited antioxidant capacity and reduction of acetylcholinesterase activity. Conclusion: Multiadducts of C60 are novel multi-target-directed ligand molecules that could hold considerable promise as the starting point for the development of AD therapies.

Pages 761-769
Lindsey F. Wells, Shannon L. Risacher, Brenna C. McDonald, Martin R. Farlow, Jared Brosch, Sujuan Gao, Liana G. Apostolova, Andrew J. Saykin, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: David Loewenstein)
Measuring Subjective Cognitive Decline in Older Adults: Harmonization Between the Cognitive Change Index and the Measurement of Everyday Cognition Instruments
Abstract: Background: Self and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive function. Objective: We examined the relationship between CCI and ECog self and informant-based evaluations to determine content overlap and provide a co-calibration for converting between these widely used instruments. Methods: 950 participants (57.1% female, mean age=71.2 years) from ADNI and the Indiana ADRC with self-based evaluations and 279 participants (60.9% female, mean age=71.8 years) with informant-based evaluations (Indiana ADRC) were included. Analyzed variables for the CCI and ECog included domain mean scores, memory domain total scores, and total scores for all items. Spearman correlations, regression analyses, and frequency distributions were used to assess the relationship between CCI and ECog. Sex, age, years of education, race/ethnicity, APOE ε4 carrier status, and baseline diagnosis were also analyzed as potentially relevant covariates. Results: CCI and ECog total scores were highly correlated for the self (r=0.795, p<0.001) and informant-based (r=0.840, p<0.001) versions as expected. Frequency distributions of self and informant total scores were generated and plotted separately. Quadratic regressions for self (r2=0.626) and informant (r2=0.741) scores were used to create a translation table between the CCI and ECog total scores. Conclusion: Self and informant total scores can be harmonized and translated between the CCI and ECog to facilitate cross-study and longitudinal assessment of perceived cognitive change, an important patient-reported outcome.

Pages 771-780
Akram A. Hosseini, Thomas Brown, Luca Mannino, Bruno Gran, Kehinde Junaid, Elizabeta B. Mukaetova-Ladinska
Clinical Utility of Cerebrospinal Fluid Aꞵ42 and Tau Measures in Diagnosing Mild Cognitive Impairment in Early Onset Dementia
Abstract: Background: The differentiation of a preclinical or prodromal Alzheimer’s disease (AD) is challenging particularly in patients with early onset Alzheimer’s or related dementias (EOARD). We report our experience on diagnostic lumbar puncture to diagnose EOARD at a tertiary neurocognitive referral center in Nottingham, England from March 2018 to October 2020. Objective: To assess amyloid-β42 (Aβ42), total tau, and Thr181-phosphorylated tau (p-tau) measurements in the cerebrospinal fluid (CSF) in patients with mild cognitive impairment (MCI) and in relation to their follow-up cognitive performance. Methods: Thirty participants aged 32-68 years old (mean 59 years; 57% female) were included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, neuroradiological features (MRI, FDG-PET CT) and CSF Aβ42, total tau, and p-tau measurements. Results: Patients with MCI who progressed to AD (prodromal AD) had significantly higher CSF total (797.63 pg/ml) and p-tau (82.31 pg/ml), and lower Aβ42 levels (398.94 pg/ml) in comparison to their counterparts with stable MCI (total tau 303.67 pg/ml, p-tau 43.56 pg/ml, Aβ42 873.44 pg/ml) (p < 0.001 for CSF total and p-tau measures and p < 0.0001 for CSF Aβ42 measures). None of the CSF biomarkers correlated with any of the cognitive performance measures. Principal component analysis confirmed that the clinical diagnosis of MCI secondary to AD, namely prodromal AD (as per NIA-AA criteria) in younger adults, was associated with decreased CSF Aβ42. Conclusion: In early onset AD, low levels of CSF Aβ42 appear to be more sensitive than total and p-tau measures in differentiating AD MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness of making an earlier diagnosis.

Pages 781-789
Haruo Hanyu, Yumi Koyama, Haruka Horita, Toshinori Aoki, Tomohiko Sato, Naoto Takenoshita, Hidekazu Kanetaka, Soichiro Shimizu, Kentaro Hirao, Sadayoshi Watanabe
Characterization of Alzheimer’s Disease Subtypes Based on Magnetic Resonance Imaging and Perfusion Single-Photon Emission Computed Tomography
Abstract: Background: Alzheimer’s disease (AD) is a biologically heterogenous disease. Previous studies have reported the existence of various AD subtypes, and the various clinical features of the subtypes. However, inconsistent results have been obtained. Objective: To clarify the clinical characteristics of the various AD subtypes, by classifying probable AD into subtypes based on magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) findings. Methods: A total of 245 patients with probable AD were classified into the typical AD (TAD) subtype, limbic-predominant (LP) subtype, hippocampal-sparing (HS) subtype, and minimal-change (MC) subtype, based on the presence of medial temporal lobe atrophy on MRI and posterior cerebral hypoperfusion on SPECT. Demographics, including age, sex, body mass index, disease duration, education years, comorbidities, frailty, leisure activity, and neuropsychological findings were compared between the AD subtypes. Results: The frequency of TAD, LP, HS, and MC subtypes was 49%, 20%, 18%, and 13%, respectively. Patients with the LP subtype were older and characterized by fewer major comorbidities, higher frailty, and slower progression of disease. Patients with the HS subtype were younger and characterized by shorter disease duration, lower frailty, and preserved memory, but had prominent constructional dysfunction. Patients of the MC subtype were characterized by shorter disease duration, lower education level, less leisure activity, less impaired memory and orientation, and slower progression. Conclusion: Patients with different AD subtypes differed in their demographic and clinical features. The characterization of patients’ AD subtypes may provide effective support for the diagnosis, treatment, and care of AD patients.

Pages 791-802
Lou Grangeon, Claire Paquet, Stéphanie Guey, Aline Zarea, Olivier Martinaud, Maud Rotharmel, David Maltête, Muriel Quillard-Muraine, Gael Nicolas, Camille Charbonnier, Hugues Chabriat, David Wallon (Handling Associate Editor: Mana Shams)
Cerebrospinal Fluid Profile of Tau, Phosphorylated Tau, Aβ42, and Aβ40 in Probable Cerebral Amyloid Angiopathy
Abstract: Background: There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers in cerebral amyloid angiopathy (CAA). Objective: To describe the CSF levels of Aβ42, Aβ40, total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile. Methods: We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman’s correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA. Results: We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aβ42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aβ42 level and 14.3% patients with normal Aβ42 level. Compared to AD, CAA showed lower levels of Tau (p=0.008), p-Tau (p=0.004), and Aβ40 (p=0.001) but similar Aβ42 level (p=0.07). No correlation between Aβ42 or Aβ40 levels and neuroimaging was found. Conclusion: CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aβ40 appears as an interesting selective biomarker in differential diagnosis.

Pages 803-805

Andreas Charidimou (Handling Associate Editor: Mana Shams)
Cerebrospinal Fluid Biomarkers for Cerebral Amyloid Angiopathy Diagnosis
Abstract: An accurate diagnosis of sporadic cerebral amyloid angiopathy (CAA) is critical for patient management and research (including clinical trials) for this common small vessel pathology of the brain. While the “big bang” of the CAA field has been the device and wide adoption of the clinico-radiological Boston criteria which allowed for CAA diagnosis during life, these criteria are not without major shortcoming. As it is now becoming evident that CAA is probably not a single disease, but rather represents divergent pathophysiological phenotypes and clinical trajectories, new biomarker-driven diagnostic approaches should be sought. One such complimentary approach for CAA diagnosis is the use of cerebrospinal fluid biomarkers (CSF), which could provide dynamic measures of the underlying disease process and is discussed in this commentary given exciting new advances. A hint on how the practicing clinician could apply the current CSF data for CAA diagnosis is also provided.

Pages 807-816
Herrer Abdulrahman, Marthe Smedinga, Marcel M. Verbeek, Catharina J.M. Klijn, Edo Richard, Marieke Perry
Views on the Desirability of Diagnosing Sporadic Cerebral Amyloid Angiopathy with Biological Evidence
Abstract: Background: Sporadic cerebral amyloid angiopathy (sCAA) research of the past decade has increasingly focused on developing biomarkers that allow for an earlier and more accurate sCAA-diagnosis. Considering that sCAA does not have treatment options available (yet), more fundamental questions concerning the desirability of using such early-sCAA biomarkers in clinical practice need to be addressed. Objective: In this qualitative interview study, we aim to explore the views of vascular neurologists on the purpose and possible consequences of an earlier and more accurate sCAA-diagnosis, using new biomarkers. Methods: Vascular neurologists from around the world were approached via email and interviewed via video call. Topics included views on current sCAA diagnostic practice, considerations on the use of new biomarkers, and expectations and hopes for the future. All interviews were transcribed ad verbatim using a transcription program (Otter.ai). Transcripts were analyzed using inductive content analysis. Results: We interviewed 14 vascular neurologists. Views regarding the desirability of new sCAA-biomarkers differed substantially between interviewees as to when and in whom these biomarkers could be of benefit in clinical practice. These differences were mainly reported with regards to prognosis, risk stratification, and biological precision, between general stroke neurologists and neurologists with specific sCAA-expertise. Conclusion: Views on the use of sCAA-biomarkers in clinical practice differ substantially between vascular neurologists. There is particularly no consensus regarding when, and in whom sCAA biomarkers could be useful in clinical practice.

Pages 817-832
Francisco J. García Pretelt, Jazmín X. Suárez Relevo, David Aguillón, Francisco Lopera, John Fredy Ochoa, Carlos A. Tobón Quintero
Automatic Classification of Subjects of the PSEN1-E280A Family at Risk of Developing Alzheimer’s Disease Using Machine Learning and Resting State Electroencephalography
Abstract: Background: The study of genetic variant carriers provides an opportunity to identify neurophysiological changes in preclinical stages. Electroencephalography (EEG) is a low-cost and minimally invasive technique which, together with machine learning, provide the possibility to construct systems that classify subjects that might develop Alzheimer’s disease (AD). Objective: The aim of this paper is to evaluate the capacity of the machine learning techniques to classify healthy Non-Carriers (NonCr) from Asymptomatic Carriers (ACr) of PSEN1-E280A variant for autosomal dominant Alzheimer’s disease (ADAD), using spectral features from EEG channels and brain-related independent components (ICs) obtained using independent component analysis (ICA). Methods: EEG was recorded in 27 ACr and 33 NonCr. Statistical significance analysis was applied to spectral information from channels and group ICA (gICA), standardized low-resolution tomography (sLORETA) analysis was applied over the IC as well. Strategies for feature selection and classification like Chi-square, mutual informationm and support vector machines (SVM) were evaluated over the dataset. Results: A test accuracy up to 83% was obtained by implementing a SVM with spectral features derived from gICA. The main findings are related to theta and beta rhythms, generated in the parietal and occipital regions, like the precuneus and superior parietal lobule. Conclusion: Promising models for classification of preclinical AD due to PSEN-1-E280A variant can be trained using spectral features, and the importance of the beta band and precuneus region is highlighted in asymptomatic stages, opening up the possibility of its use as a screening methodology.

Pages 833-842
Elise Mansfield, Emilie Cameron, Mariko Carey, Allison Boyes, Balakrishnan Nair, Alix Hall, Rob Sanson-Fisher
Prevalence and Type of Unmet Needs Experienced by People Living with Dementia
Abstract: Background: Accurately identifying the unmet needs of community-dwelling people with dementia allows targeted support to be provided to assist these individuals to stay at home. Objective: We developed a self-report instrument to identify the unmet needs of community-dwelling people with dementia and used this to explore the prevalence and type of unmet needs present in this population. Methods: This was a cross-sectional survey of people with dementia living in the community in Australia. Participants were recruited from geriatric clinics, respite centers, aged care providers, and carers attending support groups. Eligible people with dementia were provided with a study information pack and survey which included the self-report Unmet Needs Instrument for Dementia (UNI-D), sociodemographic characteristics and survey acceptability. Results: The UNI-D contained 26 items across 5 domains and demonstrated acceptable internal consistency, face and construct validity, and acceptability. Ninety-five eligible participants completed the survey (response rate 35%) with 85% identifying at least one unmet need (median=4; IQR=1-9). The items most frequently endorsed included needing more help with remembering things (64%), finding possible treatments for dementia (44%), understanding who to contact regarding a problem or concern related to dementia (36%), and to see friends and family more often (33%). Conclusion: The UNI-D is a promising tool to identify the self-reported needs of people with dementia. The development and rigorous testing of interventions targeting unmet needs related to health and wellbeing, dementia support, and meaningful activities appears warranted.

Pages 843-861
Rui Zhang*, Lei Jiang*, Guofeng Li, JingJing Wu, Pei Tian, Di Zhang, Yushi Qin, Zhongli Shi, ZhaoYu Gao, Nan Zhang, Shuang Wang, Huimin Zhou, Shunjiang Xu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Advanced Glycosylation End Products Induced Synaptic Deficits and Cognitive Decline Through ROS-JNK-p53/miR-34c/SYT1 Axis in Diabetic Encephalopathy
Abstract: Background: miR-34c has been found to be implicated in the pathological process of Alzheimer’s disease, diabetes, and its complications. Objective: To investigate the underlying mechanisms of miR-34c in the pathogenesis of diabetic encephalopathy (DE). Methods: Diabetes mellitus rats were developed by incorporating a high-fat diet and streptozotocin injection. Morris water maze test and novel object recognition test were used to assess the cognitive function of rats. Expression of miR-34c were detected by fluorescence in situ hybridization and qRT-PCR. Immunofluorescence and western blot were used to evaluate synaptotagmin 1 (SYT1) and AdipoR2 or other proteins. Golgi staining was performed to investigate dendritic spine density. Results: The increased miR-34c induced by advanced glycation end-products (AGEs) was mediated by ROS-JNK-p53 pathway, but not ROS-Rb-E2F1 pathway, in hippocampus of DE rats or in HT-22 cells. miR-34c negatively regulated the expression of SYT1, but not AdipoR2, in hippocampal neurons. miR-34c inhibitor rescued the AGE-induced decrease in the density of dendritic spines in primary hippocampal neurons. Administration of AM34c by the intranasal delivery increased the hippocampus levels of SYT1 and ameliorated the cognitive function in DE rats. The serum levels of miR-34c were increased in patients with DE comparing with normal controls. Conclusion: These results demonstrated that AGE-induced oxidative stress mediated increase of miR-34c through ROS-JNK-p53 pathway, resulting in synaptic deficits and cognitive decline by targeting SYT1 in DE, and the miR-34c/SYT1 axis could be considered as a novel therapeutic target for DE patients.

Pages 863-871
Mariko Ueno, Yuta Yoshino, Hiroaki Mori, Yu Funahashi, Hiroshi Kumon, Shinichiro Ochi, Tomoki Ozaki, Ayumi Tachibana, Taku Yoshida, Hideaki Shimizu, Takaaki Mori, Jun-ichi Iga, Shu-ichi Ueno
Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer’s Disease
Abstract: Background: Late-onset Alzheimer’s disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested. Objective: Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population. Methods: A blood expression study (45 AD subjects, 54 controls) in which total RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2*2 frequency and the risk of LOAD. Results: ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p=0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2*2 allele, with an increased AD risk (OR=1.38; 95% CI=1.02-1.85; p=0.0348, I2=81.1%). Conclusion: There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2*2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population.

Pages 873-886
Xiang Liu, Jie Yan, Fangbo Liu, Peipei Zhou, Xinyue Lv, Nengneng Cheng, Li Liu
Overexpression of REST Causes Neuronal Injury and Decreases Cofilin Phosphorylation in Mice
Abstract: Background: RE1-silencing transcription factor (REST) is known to silence target genes involved in synaptic plasticity and neuronal differentiation. Although previous studies implicate REST in neurodegenerative diseases, its function in the progression of Alzheimer’s disease (AD) is uncertain. Objective: The aim of the present work was to explore the mechanisms of AD and determine whether and how REST was involved in the pathogenesis of AD. Methods: We investigated the differentially expressed genes and key transcription factors in AD using bioinformatics analysis. In addition, we assessed the expression of REST under the influence of AD-related factors. Mice overexpressing REST were generated and analyzed by proteomics analysis. We used transmission electron microscopy, Golgi-cox staining, immunohistochemistry, and western blotting to examine the impact of REST on neurons. Results: The results of bioinformatics analysis revealed REST as a hub transcriptional regulator in AD. We demonstrate that the mRNA expression of REST was significantly upregulated compared with that in the control groups, not only in AD patients but also in APP/PS1 transgenic mice, lipopolysaccharide-induced neuroinflammatory mice, and oxidative and glutamate stressed neurons. Using proteomics analysis, we showed that the upregulation of REST increased the expression of genes involved in apoptotic and mitochondrial pathways. Long-term overexpression of REST significantly reduced the number of dendritic spines and increased the mitochondrial defect and apoptosis. Reduction of the cofilin phosphorylation may be one of its mechanisms, and cofilin activity could be affected through the P38 MAPK/CREB signaling pathway. Conclusion: These results demonstrated the possible mechanism underlying AD and indicated REST as a potential therapeutic target for AD.

Pages 887-899
Nicola Girtler, Andrea Chincarini, Andrea Brugnolo, Elisa Doglione, Beatrice Orso, Silvia Morbelli, Federico Massa, Enrico Peira, Erica Biassoni, Andrea Donniaquio, Stefano Grisanti, Matteo Pardini, Dario Arnaldi, Flavio Nobili (Handling Associate Editor: Annachiara Cagnin)
The Free and Cued Selective Reminding Test: Discriminative Values in a Naturalistic Cohort
Abstract: Background: Neuropsychological assessment is still the basis for the first evaluation of patients with cognitive complaints. The Free and Cued Selective Reminding Test (FCSRT) generates several indices that could have different accuracy in the differential diagnosis between Alzheimer’s disease (AD) and other disorders. Objective: In a consecutive series of naturalistic patients, the accuracy of the FCSRT indices in differentiating patients with either mild cognitive impairment (MCI) due to AD or AD dementia from other competing conditions was evaluated. Methods: We evaluated the accuracy of the seven FCSRT indices in differentiating patients with AD from other competing conditions in 434 consecutive outpatients, either at the MCI or at the early dementia stage. We analyzed these data through the receiver operating characteristics curve, and we then generated the odds-ratio map of the two indices with the best discriminative value between pairs of disorders. Results: The immediate and the delayed free total recall, the immediate total recall, and the index of sensitivity of cueing were the most useful indices and allowed to distinguish AD from dementia with Lewy bodies and psychiatric conditions with very high accuracy. Accuracy was instead moderate in distinguishing AD from behavioral variant frontotemporal dementia, vascular cognitive impairment, and other conditions. Conclusion: By using odd-ratio maps and comparison-customized cut-off scores, we confirmed that the FCSRT represents a useful tool to characterize the memory performance of patients with MCI and thus to assist the clinician in the diagnosis process, though with different accuracy values depending on the clinical hypothesis.

Pages 901-917
Camila Gherardelli*, Pedro Cisternas*, Roberto F. Vera-Salazar, Carolina Mendez-Orellana, Nibaldo C. Inestrosa *These authors contributed equally to this work.
Age- and Sex-Associated Glucose Metabolism Decline in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms. Objective: We aimed to study whether AD-related sex differences influence glucose metabolism. Methods: We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development. Results: Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males. Conclusion: Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD.

Pages 919-931
Boris Cheval, Silvio Maltagliati, Stefan Sieber, Stéphane Cullati, Liye Zou, Andreas Ihle, Arthur F. Kramer, Qian Yu, David Sander, Matthieu P. Boisgontier
Better Subjective Sleep Quality Partly Explains the Association Between Self-Reported Physical Activity and Better Cognitive Function
Abstract: Background: Physical activity has been associated with better cognitive function and better sleep quality. Yet, whether the beneficial effect of physical activity on cognitive function can be explained by an indirect pathway involving better sleep quality is unclear. Objective: To investigate whether sleep quality mediates the association between physical activity and cognitive function in adults 50 years of age or older. Methods: 86,541 community-dwelling European adults were included in the study. Physical activity and sleep quality were self-reported. Indicators of cognitive function (immediate recall, delayed recall, verbal fluency) were assessed using objective tests. All measures were collected six times between 2004 and 2017. The mediation was tested using multilevel mediation analyses. Results: Results showed that self-reported physical activity was associated with better self-reported sleep quality, which was associated with better performance in all three indicators of cognitive function, demonstrating an indirect effect of physical activity on cognitive function through sleep quality. The mediating effect of sleep quality accounted for 0.41%, 1.46%, and 8.88% of the total association of physical activity with verbal fluency, immediate recall, and delayed recall, respectively. Conclusion: These findings suggest that self-reported sleep quality partly mediates the association between self-reported physical activity and cognitive function. These results need to be confirmed by device-based data of physical activity and sleep quality.

Pages 933-944
Maria Basta, Alexandros N. Vgontzas, Julio Fernandez-Mendoza, Despina Antypa, Yun Li, Ioannis Zaganas, Symeon Panagiotakis, Efthalia Karagkouni, Panagiotis Simos
Basal Cortisol Levels Are Increased in Patients with Mild Cognitive Impairment: Role of Insomnia and Short Sleep Duration
Abstract: Background: Mild cognitive impairment (MCI) is frequent in elderly and a risk factor for dementia. Both insomnia and increased cortisol levels are risk factors for MCI. Objective: We examined cross-sectionally whether increased cortisol levels are associated with short sleep duration (SSD) and/or the insomnia short sleep duration (ISS) phenotype, in elderly with MCI. Methods: One hundred twenty-four participants with MCI and 84 cognitively non-impaired controls (CNI) ≥60 years underwent medical history, physical examination, neuropsychiatric evaluation, neuropsychological testing, 3-day actigraphy, assessment of subjective insomnia symptoms, and a single morning plasma cortisol level. The short sleep phenotypes were defined by sleep efficiency below the median of the entire sample (i.e., ≤81%) with at least one insomnia symptom (ISS) or without (SSD). ANOVA models were used to compare the various sleep phenotypes to those who did not present either short sleep or insomnia symptoms [non-insomnia (NI)]. Results: MCI participants had higher cortisol levels compared to the CNI group (p=0.009). MCI participants with insomnia (n=44) or SSD (n=38) had higher cortisol levels compared to the NI group (n=42; p=0.014 and p=0.045, respectively). Furthermore, MCI participants with ISS phenotype but not those with insomnia with normal sleep duration had higher cortisol levels compared to NI (p=0.011 and p=0.4, respectively). Both linear trend analyses showed that cortisol reached the highest levels in the ISS phenotype. Conclusion: The ISS and SSD phenotypes are associated with increased cortisol levels in elderly with MCI. Improving sleep quality and duration and decreasing cortisol levels may delay further cognitive decline.

Pages 945-955
Matthew Gabel, Rebecca M. Bollinger, Dean W. Coble, Joshua D. Grill, Dorothy F. Edwards, Jennifer H. Lingler, Erin Chin, Susan L. Stark (Handling Associate Editor: Russell Swerdlow)
Retaining Participants in Longitudinal Studies of Alzheimer’s Disease
Abstract: Background: Retention of study participants is essential to advancing Alzheimer’s disease (AD) research and developing therapeutic interventions. However, recent multi-year AD studies have lost 10% to 54% of participants. Objective: We surveyed a random sample of 443 participants (Clinical Dementia Rating [CDR] ≤ 1) at four Alzheimer Disease Research Centers to elucidate perceived facilitators and barriers to continued participation in longitudinal AD research. Methods: Reasons for participation were characterized with factor analysis. Effects of perceived fulfillment of one’s own goals and complaints on attendance and likelihood of dropout were estimated with logistic regression models. Open-ended responses suggesting study improvements were analyzed with a Latent Dirichlet Allocation topic model. Results: Factor analyses revealed two categories, personal benefit and altruism, as drivers of continued participation. Participants with cognitive impairment (CDR > 0) emphasized personal benefits more than societal benefits. Participants with higher trust in medical researchers were more likely to emphasize broader social benefits. A minority endorsed any complaints. Higher perceived fulfillment of one’s own goals and fewer complaints were related to higher attendance and lower likelihood of dropout. Facilitators included access to medical center support and/or future treatment, learning about AD and memory concerns, and enjoying time with staff. Participants’ suggestions emphasized more feedback about individual test results and AD research. Conclusion: The results confirmed previously identified facilitators and barriers. Two new areas, improved communication about individual test results and greater feedback about AD research, emerged as the primary factors to improve participation.