Volume 79, Number 1, IN PRESS

Review
Clara Li, Judith Neugroschl, Carolyn W. Zhu, Amy Aloysi, Corbett A. Schimming, Dongming Cai, Hillel Grossman, Jane Martin, Margaret Sewell, Maria Loizos, Xiaoyi Zeng, Mary Sano
Design Considerations for Mobile Health Applications Targeting Older Adults
Abstract: Mobile technologies are becoming ubiquitous in the world, changing the way we communicate and provide patient care and services. Some of the most compelling benefits of mobile technologies are in the areas of disease prevention, health management, and care delivery. For all the advances that are occurring in mobile health, its full potential for older adults is only starting to emerge. Yet, existing mobile health applications have design flaws that may limit usability by older adults. The aim of this paper is to review barriers and identify knowledge gaps where more research is needed to improve the accessibility of mobile health use in aging populations. The same observations might apply to those who are not elderly, including individuals suffering from severe mental or medical illnesses.

Review
Roger Gil, Eva M. Arroyo-Anlló
Alzheimer’s Disease and Face Masks in Times of COVID-19
Abstract: Generalized lockdown caused by COVID-19, necessary yesterday, can no longer be that of tomorrow. It will no longer be possible to cram the humblest into cramped areas, but priority must be given to prevention (certainly with physical barriers, hydro-alcoholic gel, face masks), biological diagnosis, isolation, and also the care of any infected person. COVID-19 has hit the most vulnerable first in terms of biological inequality, such as Alzheimer’s disease (AD) patients. Those with AD can have sensorial deficits and perception troubles, including visual difficulties and the inability to recognize faces and emotions. Face masks and physical distancing can disrupt facial familiarity and make it more difficult to recognize emotional facial expressions. It can provoke distress, which the visitor can perceive and feel obligated to take off the face mask. This gesture should not be considered as an act of indiscipline, but an act of empathy. Transparent face masks could improve the suffering of AD patients, distraught in the presence of their loved ones whose masks hide their faces. Wearing a mask should not be due to fear of punishment, but as an understanding of the responsibility of each individual in the control of the current pandemic. It may be necessary to convince more citizens of this civic duty, using clear and attractive messaging in order to standardize the wearing of face masks for the general public and to adapt them to the needs of patients.

Hypothesis
Kelly C. Bishop, Sehba Husain-Krautter, Jonathan D. Ketcham, Nicolai V. Kuminoff, Corbett Schimming
Analyzing Individual-Level Secondary Data with Instrumental Variable Methods Is Useful for Studying the Effects of Air Pollution on Dementia
Abstract: We hypothesize that analyzing individual-level secondary data with instrumental variable (IV) methods can advance knowledge of the long-term effects of air pollution on dementia. We discuss issues in measurement using secondary data and how IV estimation can overcome biases due to measurement error and unmeasured variables. We link air-quality data from the Environmental Protection Agency’s monitors with Medicare claims data to illustrate the use of secondary data to document associations. Additionally, we describe results from a previous study that uses an IV for pollution and finds that PM2.5’s effects on dementia are larger than non-causal associations.

Short Communication
Emanuela Maderna*, Silvia Visonà*, Vittorio Bolcato, Veronica Redaelli, Paola Caroppo, Lorenza Montalbetti, Giorgio Giaccone, Antonio Osculati *These authors contributed equally to this work.
Neuropathological Alzheimer’s Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes
Abstract: Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer’s disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer’s disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

Short Communication
Nila S. Radhakrishnan, Mariam Mufti, Daniel Ortiz, Suzanne Maye, Jennifer Melara, Duke Lim, Eric I. Rosenberg, Catherine C. Price
Implementing Delirium Prevention in the Era of COVID-19
Abstract: Patients admitted with COVID-19 can develop delirium due to predisposing factors, isolation, and the illness itself. Standard delirium prevention methods focus on interaction and stimulation. It can be challenging to deliver these methods of care in COVID settings where it is necessary to increase patient isolation. This paper presents a typical clinical vignette of representative patients in a tertiary care hospital and how a medical team modified an evidence-based delirium prevention model to deliver high-quality care to COVID-19 patients. The implemented model focuses on four areas of delirium-prevention: Mobility, Sleep, Cognitive Stimulation, and Nutrition. Future studies will be needed to track quantitative outcome measures.

Rebecca Zingel, Jens Bohlken, Steffi Riedel-Heller, Sebastian Barth, Karel Kostev
Association Between Low-Density Lipoprotein Cholesterol Levels, Statin Use, and Dementia in Patients followed in German General Practices
Abstract: Background: No studies have been conducted to date on the association between low-density lipoprotein cholesterol (LDL-C), statin use classified into low, medium, and high statin dosages, and dementia in German general practices. Objective: The goal of this retrospective case-control study was to investigate the relationship between elevated LDL-C, statins, and dementia in elderly persons followed in general practices in Germany. Methods: This study included patients aged 65 or older with an initial dementia diagnosis between January 2015 and December 2019 and at least one documented LDL-C value within the year prior to the dementia diagnosis. These patients were treated in one of 963 general practices which document LDL-C in Germany. Dementia cases were matched to non-dementia controls using propensity scores based on age, sex, and comorbidities. Logistic regression models were conducted to assess a possible association between accelerated LDL-C, statins, and dementia. Results: The study included 12,236 patients with dementia and 12,236 non-dementia controls. In total, 2,528 of the dementia patients were diagnosed with vascular dementia. The use of all dosages of statin use was negatively associated with all-cause dementia (OR: 0.80 for low dose, OR: 0.92 for medium dose, and OR: 0.85 for high dose) and with vascular dementia (OR: 0.61 for low dose, OR: 0.77 for medium dose, and OR: 0.74 for high dose). There was no clinically relevant association between elevated LDL-C and dementia. Conclusion: A negative association was found between all dosage use of statin therapy and all-cause dementia and vascular dementia in elderly patients in general practices in Germany.

Evangeline Yee, Da Ma, Karteek Popuri, Lei Wang, Mirza Faisal Beg, for the Alzheimer’s Disease Neuroimaging Initiative, and the Australian Imaging Biomarkers and Lifestyle flagship study of ageing
Construction of MRI-Based Alzheimer’s Disease Score Based on Efficient 3D Convolutional Neural Network: Comprehensive Validation on 7,902 Images from a Multi-Center Dataset
Abstract: Background: In recent years, many convolutional neural networks (CNN) have been proposed for the classification of Alzheimer’s disease. Due to memory constraints, many of the proposed CNNs work at a 2D slice-level or 3D patch-level. Objective: Here, we propose a subject-level 3D CNN that can extract the neurodegenerative patterns of the whole brain MRI and converted into a probabilistic Dementia score. Methods: We propose an efficient and lightweight subject-level 3D CNN featuring dilated convolutions. We trained our network on the ADNI data on stable Dementia of the Alzheimer’s type (sDAT) from stable normal controls (sNC). To comprehensively evaluate the generalizability of our proposed network, we performed four independent tests which includes testing on images from other ADNI individuals at various stages of the dementia, images acquired from other sites (AIBL), images acquired using different protocols (OASIS), and longitudinal images acquired over a short period of time (MIRIAD). Results: We achieved a 5-fold cross-validated balanced accuracy of 88% in differentiating sDAT from sNC, and an overall specificity of 79.5% and sensitivity 79.7% on the entire set of 7,902 independent test images. Conclusion: Independent testing is essential for estimating the generalization ability of the network to unseen data, but is often lacking in studies using CNN for DAT classification. This makes it difficult to compare the performances achieved using different architectures. Our comprehensive evaluation highlighting the competitive performance of our network and potential promise for generalization.

Warren Barker, Carlos Quinonez, Maria T. Greig, Raquel Behar, Cesar Chirinos, Rosemarie A. Rodriguez, Monica Rosselli, Miriam J. Rodriguez, Rosie Curiel Cid, Tatjana Rundek, Karen McFarland, Kevin Hanson, Glenn Smith, Steven DeKosky, David Vaillancourt, Malek Adjouadi, Michael Marsiske, Nilufer Ertekin-Taner, Todd Golde, David A. Loewenstein, Ranjan Duara
Utility of Plasma Neurofilament Light in the 1Florida Alzheimer’s Disease Research Center
Abstract: Background: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. Objective: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. Methods: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer’s disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. Results: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. Conclusion: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be a used for differentiating neurodegenerative disease from neuropsychiatric disorders.

Linh Tran, Jeah Jung, Caroline Carlin, Sunmin Lee, Chen Zhao, Roger Feldman
Use of Direct-Acting Antiviral Agents and Survival Among Medicare Beneficiaries with Dementia and Chronic Hepatitis C
Abstract: Background: Many patients with Alzheimer’s disease and related dementia (ADRD) have chronic hepatitis C due to the high prevalence of both conditions among elderly populations. Direct-acting antivirals (DAAs) are effective in treating hepatitis C virus (HCV). However, the complexity of ADRD care may affect DAA use and outcomes among patients with HCV and ADRD. Little information exists on uptake of DAAs, factors associated with DAA use, and health benefits of DAAs among patients with HCV and ADRD. Objective: To examine use and survival benefits of DAAs in Medicare patients with HCV and ADRD. Methods: The study included Medicare patients with HCV between 2014 and 2017. We estimated Cox proportional hazards regressions to examine the association between having ADRD and DAA use, and the relation between DAA use and survival among patients with HCV and ADRD. Results: The adjusted hazard of initiating a DAA was 50% lower in patients with ADRD than those without ADRD (adjusted HR = 0.50, 95% CI: 0.46–0.54). The hazard of DAA use among ADRD patients with behavioral disturbances was 68% lower than non-ADRD patients (adjusted HR = 0.32, 95% CI: 0.28–0.37). DAA treatment was associated with a significant reduction in mortality among ADRD patients (adjusted HR = 0.52, 95% CI: 0.44–0.61). Conclusion: The rate of DAA treatment in patients with HCV and ADRD was low, particularly among those with behavioral disturbance. The survival benefits of DAA treatment for patients with ADRD were substantial.

Ana M. Rodríguez-Salgado*, Jorge J. Llibre-Guerra*, Elena Tsoy, Ana Ibis Peñalver-Guia, Giosmany Bringas, Sabrina J. Erlhoff, Joel H. Kramer, Isabel Elaine Allen, Victor Valcour, Bruce L. Miller, Juan J. Llibre-Rodríguez, Katherine L. Possin *These authors contributed equally to this work.
A Brief Digital Cognitive Assessment for Detection of Cognitive Impairment in Cuban Older Adults
Abstract: Background: Rapid technological advances offer a possibility to develop cost-effective digital cognitive assessment tools. However, it is unclear whether these measures are suitable for application in populations from Low and middle-income countries (LMIC). Objective: To examine the accuracy and validity of the Brain Health Assessment (BHA) in detecting cognitive impairment in a Cuban population. Methods: In this cross-sectional study, 146 participants (cognitively healthy=53, mild cognitive impairment (MCI)=46, dementia=47) were recruited at primary care and tertiary clinics. The main outcomes included: accuracy of the BHA and the Montreal Cognitive Assessment (MoCA) in discriminating between controls and cognitively impaired groups (MCI and dementia) and correlations between the BHA subtests of memory, executive functions, and visuospatial skills and criterion-standard paper-and-pencil tests in the same domains. Results: The BHA had an AUC of 0.95 (95% CI: 0.91-0.98) in discriminating between controls and cognitively impaired groups (MCI and dementia, combined) with 0.91 sensitivity at 0.85 specificity. In discriminating between control and MCI groups only, the BHA tests had an AUC of 0.94 (95% CI: 0.90-0.99) with 0.71 sensitivity at 0.85 specificity. Performance was superior to the MoCA across all diagnostic groups. Concurrent and discriminant validity analyses showed moderate to strong correlations between the BHA tests and standard paper-and-pencil measures in the same domain and weak correlations with standard measures in unrelated domains. Conclusion: The BHA has excellent performance characteristics in detecting cognitive impairment including dementia and MCI in a Hispanic population in Cuba and outperformed the MoCA. These results support potential application of digital cognitive assessment for older adults in LMIC.

Cosimo Tuena, Valentina Mancuso*, Chiara Stramba-Badiale*, Elisa Pedroli, Marco Stramba-Badiale, Giuseppe Riva, Claudia Repetto *These authors contributed equally to this work.
Egocentric and Allocentric Spatial Memory in Mild Cognitive Impairment with Real-World and Virtual Navigation Tasks: A Systematic Review
Abstract: Background: Spatial navigation is the ability to estimate one’s position on the basis of environmental and self-motion cues. Spatial memory is the cognitive substrate underlying navigation and relies on two different reference frames: egocentric and allocentric. These spatial frames are prone to decline with aging and impairment is even more pronounced in Alzheimer’s disease (AD) or in mild cognitive impairment (MCI). Objective: To conduct a systematic review of experimental studies investigating which MCI population and tasks are used to evaluate spatial memory and how allocentric and egocentric deficits are impaired in MCI after navigation. Methods: PRISMA and PICO guidelines and were applied to carry out the systematic search. Down and Black checklist was used to assess methodological quality. Results: Our results showed that amnestic MCI and AD pathology are the most investigated typologies; both egocentric and allocentric memory are impaired in MCI individuals, and MCI due to AD biomarkers has specific encoding and retrieval impairments; secondly, spatial navigation is principally investigated with the hidden goal task (virtual and real-world version), and among studies involving virtual reality, the privileged setting consists of non-immersive technology; thirdly, despite subtle differences, real-world and virtual versions showed good overlap for the assessment of MCI spatial memory. Conclusion: Considering that MCI is a subclinical entity with potential risk for conversion to dementia, investigating spatial memory deficits with navigation tasks might be crucial to make accurate diagnosis and rehabilitation.

Mengtian Du, Stacy L. Andersen, Nicole Schupf, Mary F. Feitosa, Megan S. Barker, Thomas T. Perls, Paola Sebastiani
Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study
Abstract: Background: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. Objective: To test whether APOE genotype is associated with change of cognitive function in older adults. Methods: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ε2 or ε4 alleles. Results: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE ε4 allele on Logical Memory. Participants carrying at least one copy of the ε4 allele had lower scores in both immediate (-0.31 points, 95%CI: -0.57, -0.05) and delayed (-0.37 points, 95%CI: -0.64, -0.10) recall comparing to non-ε4 allele carriers. We did not detect any significant longitudinal effect of the ε4 allele. There was no cross-sectional or longitudinal effect of the ε2 allele. Conclusion: The APOE ε4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE ε2 allele was not significantly associated with any of the cognitive test scores.

Grazia Daniela Femminella, Denise Harold, James Scott, Julie Williams, Paul Edison, for the Alzheimer’s Disease Neuroimaging Initiative
The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer’s Disease
Abstract: Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer’s disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. Objective: The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. Methods: AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. Results: Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. Conclusion: Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.

Bing Yang, Siyuan Yang, Yunmei Zhang, Wentao Liu, Yao Gan, Yaling Li, Dengbi Jiang, Yetao Luo, Qinghua Zhao
Stressor-Oriented MUlticomponent Intervention and the WeLl-Being of Patients with Alzheimer’s Disease: A Randomized Controlled Trial (SOUL-P)
Abstract: Background: Patients with Alzheimer's disease (AD) experience various stressors that negatively impact well-being. Most studies have, however, small effect size and are limited by the experiences of severe patients. Therefore, we conducted a single-blind, randomized controlled trial, which has included patients at different stages. Objective: The stressor-oriented multicomponent program was designed as an intervention for AD patients to enhance well-being. Methods: Patients were randomly assigned to control or SOUL-P conditions according to disease severity. The SOUL-P group received 15 intensive sessions over 6 months and 6 maintenance sessions over a 6-month follow-up by a multidisciplinary team comprising psychologists, occupational therapists, and community nurses. The control group received a similar number of sessions by community nurses. Stress-related outcomes (primary stressors and well-being outcomes) were obtained from in-person baseline and follow-up interviews conducted at 6- and 12-months post-baseline. A treatment compliance survey was conducted at the intervention endpoint for patients. Results: Of the 863 patients screened, 218 (25.3%) were eligible. At 6 months, compared to controls, SOUL-P patients had improved quality of life (QoL) (p < 0.001; Cohen d=0.56), depression (p=0.020; Cohen d=-0.33), neurobehavioral symptoms (p=0.034; Cohen d=-0.30), perceived stress (p=0.030; Cohen d=-0.31), and family conflict (p=0.026; Cohen d=-0.32). QoL, depression, perceived stress, and family conflict were still significantly different at 12 months. Most patients were satisfied with SOUL-P, while caregivers in the SOUL-P group reported overloading tasks. Conclusion: SOUL-P may reduce perceived stress and improve psychological outcomes in AD patients. Stressor-based interventions, patient-oriented goals, and a multidisciplinary team are essential features for a successful SOUL-P.

Salla Ylä-Herttuala, Mikko Hakulinen, Pekka Poutiainen, Tiina M. Laitinen, Anne M. Koivisto, Anne M. Remes, Merja Hallikainen, Juha-Matti Lehtola,Toni Saari, Ville Korhonen, Mervi Könönen, Ritva Vanninen, Hanna Mussalo, Tomi Laitinen, Esa Mervaala (Handling Associate Editor: Miguel Castelo-Branco)
Severe Obstructive Sleep Apnea and Increased Cortical Amyloid-β Deposition
Abstract: Background: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer’s disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-β (Aβ) burden and severe OSA in middle-aged patients. Objective: Examine the possible presence of cortical Aβ accumulation in middle-aged patients with severe OSA. Methods: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30/h). Known etiological factors for possible Aβ accumulation were used as exclusion criteria. Aβ uptake was studied with [11C]-PiB -PET, glucose metabolism with [18F]-FDG-PET, and structural imaging with 3.0T MRI. Results: When analyzed individually, in [11C]-PiB-PET a substantial number (~32%) of the patients exhibited statistically significant evidence of increased cortical Aβ uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. Conclusion: Increased [11C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aβ uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aβ clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction.

Linda J.C. van Waalwijk van Doorn, Mohsen Ghafoorian, Esther M.C. van Leijsen, Jurgen A.H.R. Claassen, Andrea Arighi, Marco Bozzali, Jorge Cannas, Enrica Cavedo, Paolo Eusebi, Lucia Farotti, Chiara Fenoglio, Juan Fortea, Giovanni B. Frisoni, Daniela Galimberti, Viviana Greco, Sanna-Kaisa Herukka, Yawu Liu, Alberto Lleó, Alexandre de Mendonça, Flavio M. Nobili, Lucilla Parnetti, Agnese Picco, Maria Pikkarainen, Nicola Salvadori, Elio Scarpini, Hilkka Soininen, Roberto Tarducci, Andrea Urbani, Eduard Vilaplana, Olga Meulenbroek, Bram Platel, Marcel M. Verbeek*, H. Bea Kuiperij* (Handling Associate Editor: Ralph Martins) *These authors contributed equally to this work.
White Matter Hyperintensities Are No Major Confounder for Alzheimer’s Disease Cerebrospinal Fluid Biomarkers
Abstract: Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer’s disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2=0.084, p=0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2=0.105, p=0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

Ivan Koychev*, Katrin Jansen*, Alina Dette, Liu Shi, Heinz Holling *The authors contributed equally to the manuscript.
Blood-Based ATN Biomarkers of Alzheimer’s Disease: A Meta-Analysis
Abstract: Background: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer’s disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers. Objective: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40, Aβ42, Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers. Methods: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and controls. Results: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42, t-tau, and p-tau181. Conclusion: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation.

Sara Becker*, Olga Boettinger*, Patricia Sulzer, Markus A. Hobert, Kathrin Brockmann, Walter Maetzler, Daniela Berg, Inga Liepelt-Scarfone, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Katherine Gifford) *These authors contributed equally to this work.
Everyday Function in Alzheimer’s and Parkinson’s Patients with Mild Cognitive Impairment
Abstract: Background: Instrumental activities of daily living (IADL) impairment can begin in mild cognitive impairment (MCI), and is the core criteria for diagnosing dementia in both Alzheimer’s (AD) and Parkinson’s (PD) diseases. The Functional Activities Questionnaire (FAQ) has high discriminative power for dementia and MCI in older age populations, but is influenced by demographic factors. It is currently unclear whether the FAQ is suitable for assessing cognitive-associated IADL in non-demented PD patients, as motor disorders may affect ratings. Objective: To compare IADL profiles in MCI patients with PD (PD-MCI) and AD (AD-MCI) and to verify the discriminative ability of the FAQ for MCI in patients with (PD-MCI) and without (AD-MCI) additional motor impairment. Methods: Data of 42 patients each of PD-MCI, AD-MCI, PD cognitively normal (PD-CN), and healthy controls (HC), matched according to age, gender, education, and global cognitive impairment were analyzed. ANCOVA and binary regressions were used to examine the relationship between the FAQ scores and groups. FAQ cut-offs for PD-MCI (versus PD-NC) and AD-MCI (versus HC) were separately identified using receiver operating characteristic analyses. Results: FAQ total score did not differentiate between MCI groups. PD-MCI subjects had greater difficulties with tax records and traveling while AD-MCI individuals were more impaired in managing finances and remembering appointments. Classification accuracy of the FAQ was good for diagnosing AD-MCI (69%, cut-off ≥1) compared to HC, and sufficient for differentiating PD-MCI (38.1%, cut-off ≥3) from PD-CN. Conclusion: The FAQ task profiles and classification accuracy differed between MCI related to PD and AD.

Haripriya Vittal Rao*, Syed Waseem Bihaqi*, Jaclyn Iannucci, Abhik Sen, Paula Grammas (Handling Associate Editor: Elizabeth Rhea) *These authors contributed equally to this work.
Thrombin Signaling Contributes to High Glucose-Induced Injury of Human Brain Microvascular Endothelial Cells
Abstract: Background: Diabetes is one of the strongest disease-related risk factors for Alzheimer’s disease (AD). In diabetics, hyperglycemia-induced microvascular complications are the major cause of end-organ injury, contributing to morbidity and mortality. Microvascular pathology is also an important and early feature of AD. The cerebral microvasculature may be a point of convergence of both diseases. Several lines of evidence also implicate thrombin in AD as well as in diabetes. Objective: Our objective was to investigate the role of thrombin in glucose-induced brain microvascular endothelial injury. Methods: Cultured Human brain microvascular endothelial cells (HBMVECs) were treated with 30 mM glucose ± 100 nM thrombin and ± 250 nM Dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9. Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates were performed. Results: Treatment of HBMVECs with 30 mM glucose increased thrombin activity and expression of inflammatory proteins TNFα, IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran. Direct treatment of brain endothelial cells with thrombin upregulated p38MAPK and CREB, and induced TNFα, IL6, MMP2, and MMP9 as well as oxidative stress proteins NOX4 and iNOS. Inhibition of thrombin, thrombin receptor PAR1 or p38MAPK decrease expression of inflammatory and oxidative stress proteins, implying that thrombin may play a central role in glucose-induced endothelial injury. Conclusion: Since preventing brain endothelial injury would preserve blood-brain barrier integrity, prevent neuroinflammation, and retain intact functioning of the neurovascular unit, inhibiting thrombin, or its downstream signaling effectors, could be a therapeutic strategy for mitigating diabetes-induced dementia.

Maya Arvidsson Rådestig, Johan Skoog, Henrik Zetterberg, Jürgen Kern, Anna Zettergren, Simona Sacuiu, Margda Waern, Hanna Wetterberg, Kaj Blennow, Ingmar Skoog*, Silke Kern* *These authors share last authorship.
Cognitive Performance and Cerebrospinal Fluid Markers in Preclinical Alzheimer’s Disease: Results from the Gothenburg H70 Birth Cohort Studies
Abstract: Background: We have previously shown that older adults with preclinical Alzheimer’s disease (AD) pathology in cerebrospinal fluid (CSF) had slightly worse performance in Mini-Mental State Examination (MMSE) than participants without preclinical AD pathology. Objective: We therefore aimed to compare performance on neurocognitive tests in a population-based sample of 70-year-olds with and without CSF AD pathology. Methods: The sample was derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants (n=316, 70 years old) underwent comprehensive cognitive examinations, and CSF Aβ-42, Aβ-40, T-tau, and P-tau concentrations were measured. Participants were classified according to the ATN system, and according to their Clinical Dementia Rating (CDR) score. Cognitive performance was examined in the CSF amyloid, tau, and neurodegeneration (ATN) categories. Results: Among participants with CDR 0 (n=259), those with amyloid (A+) and/or tau pathology (T+, N+) showed similar performance on most cognitive tests compared to participants with A-T-N-. Participants with A-T-N+ performed worse in memory (Supra span (p=0.003), object Delayed (p=0.042) and Immediate recall (p=0.033)). Among participants with CDR 0.5 (n=57), those with amyloid pathology (A+) scored worse in category fluency (p=0.003). Conclusion: Cognitively normal participants with amyloid and/or tau pathology performed similarly to those without any biomarker evidence of preclinical AD in most cognitive domains, with the exception of slightly poorer memory performance in A-T-N+. Our study suggests that preclinical AD biomarkers are altered before cognitive decline.

Qingze Zeng, Kaicheng Li, Xiao Luo, Shuyue Wang, Xiaopei Xu, Zheyu Li, Tianyi Zhang, Xiaocao Liu, Yanv Fu, Xiaojun Xu, Chao Wang, Tao Wang, Jiong Zhou, Zhirong Liu, Yanxing Chen, Peiyu Huang, Minming Zhang, and for the Alzheimer’s Disease Neuroimaging Initiative
Distinct Atrophy Pattern of Hippocampal Subfields in Patients with Progressive and Stable Mild Cognitive Impairment: A Longitudinal MRI Study
Abstract: Background: Predicting the prognosis of mild cognitive impairment (MCI) has outstanding clinical value, and the hippocampal volume is a reliable imaging biomarker of AD diagnosis. Objective: We aimed to longitudinally assess hippocampal sub-regional difference (volume and asymmetry) among progressive MCI (pMCI), stable MCI (sMCI) patients, and normal elderly. Methods: We identified 29 pMCI, 52 sMCI, and 102 normal controls (NC) from the ADNI database. All participants underwent neuropsychological assessment and 3T MRI scans three times. The time interval between consecutive MRI sessions was about 1 year. Volumes of hippocampal subfield were measured by Freesurfer. Based on the analysis of variance, repeated measures analyses, and receiver operating characteristic curves, we compared cross-sectional and longitudinal alteration sub-regional volume and asymmetry index. Results: Compared to NC, both MCI groups showed significant atrophy in all subfields. At baseline, pMCI have a smaller volume than sMCI in the bilateral subiculum, molecular layer (ML), the molecular and granule cell layers of the dentate gyrus, cornu ammonis 4, and right tail. Furthermore, repeated measures analyses revealed that pMCI patients showed a faster volume loss than sMCI in bilateral subiculum and ML. After controlling for age, gender, and education, most results remained unchanged. However, none of the hippocampal sub-regional volumes performed better than the whole hippocampus in ROC analyses, and no asymmetric difference between pMCI and sMCI was found. Conclusion: The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry may have smaller value in predicting the MCI prognosis.

Joakim Bastrup, Kathrine H. Hansen, Thomas B.G. Poulsen, Kenneth Kastaniegaard, Ayodeji A. Asuni, Søren Christensen, Dorthe Belling, Lone Helboe, Allan Stensballe*, Christiane Volbracht* * Shared senior authorship.
Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently. Objective: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). Methods: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient. Results: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice. Conclusion: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.

Elyse Couch, Christoph Mueller, Gayan Perera, Vanessa Lawrence, Matthew Prina
The Association Between a Previous Diagnosis of Mild Cognitive Impairment as a Proxy for an Early Diagnosis of Dementia and Mortality: A Study of Secondary Care Electronic Health Records
Abstract: Background: Dementia policy states that the early diagnosis of dementia can keep people living well for longer; however, there is little robust evidence to support this. Mild cognitive impairment (MCI) is considered a prodrome to dementia and can aid with the earlier diagnosis of dementia. Objective: The objective of this study was to use a previous diagnosis of MCI, before dementia, as a proxy for early diagnosis to investigate the relationship between an early diagnosis and mortality. Methods: A retrospective cohort study of electronic health care records from South London and Maudsley NHS. Patients aged 50+, diagnosed with dementia between January 2008 and November 2018, were divided into two groups: those with a previous diagnosis of MCI (early diagnosis) and those without. Cox regression models used to compare the risk of mortality between groups. Results: Of 18,557 participants, 5.6% (n= 1,030) had an early diagnosis; they had fewer cognitive, psychiatric, and functional problems at dementia diagnosis. The early diagnosis group had a reduced hazard of mortality (HR= 0.86, CI= 0.77–0.97). However, the magnitude of this effect depended on the scale used to adjust for cognitive difficulties. Conclusion: A previous diagnosis of MCI is a helpful proxy for early diagnosis. There is some evidence that an early diagnosis is associated with a reduced risk of mortality; however, it is not clear how Mini-Mental State Exam scores affect this relationship. While these findings are promising, we cannot be conclusive on the relationship between an early diagnosis and mortality.

Robert C. Sergott, Annaswamy Raji, James Kost, Cyrille Sur, Saheeda Jackson, Amy Locco, Arpankumar Patel, Christine Furtek, Britta Mattson, Michael F. Egan (Handling Associate Editor: Manju Subramanian)
Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer’s Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy
Abstract: Background: We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer’s disease (AD). Objective: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. Methods: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. Results: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson’s r values ≤0.23, p-values <0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant. Conclusion: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline.

Lærke Taudorf, Ane Nørgaard, Gunhild Waldemar, Thomas Munk Laursen (Handling Associate Editor: Anders Wimo)
Mortality in Dementia from 1996 to 2015: A National Registry-Based Cohort Study
Abstract: Background: It remains unclear whether the increased focus on improving healthcare and providing appropriate care for people with dementia has affected mortality. Objective: To assess survival and to conduct a time-trend analysis of annual mortality rate ratios (MRR) of dementia based on healthcare data from an entire national population. Methods: We assessed survival and annual MRR in all residents of Denmark ≥65 years from 1996–-2015 using longitudinal registry data on dementia status and demographics. For comparison, mortality and survival were calculated for acute ischemic heart disease (IHD) and cancer. Results: The population comprised 1,999,366 people (17,541,315 person years). There were 165,716 people (529,629 person years) registered with dementia, 131,321 of whom died. From 1996–2015, the age-adjusted MRR for dementia declined (women: 2.76 to 2.05; men: 3.10 to 1.99) at a similar rate to elderly people without dementia. The sex-, age-, and calendar-year-adjusted MRR was 2.91 (95% CI: 2.90–2.93) for people with dementia. MRR declined significantly more for acute IHD and cancer. In people with dementia, the five-year survival for most age-groups was at a similar level or lower as that for acute IHD and cancer. Conclusion: Although mortality rates declined over the 20-year period, MRR stayed higher for people with dementia, while the MRR gap, compared with elderly people without dementia, remained unchanged. For the comparison, during the same period, the MRR gap narrowed between people with and without acute IHD and cancer. Consequently, initiatives for improving health and decreasing mortality in dementia are still highly relevant.

Lin Sun*, PhD, Wei Li*, Ling Yue, Shifu Xiao *These authors contributed equally to this work.
Blood TDP-43 Combing with Demographics Information Predicts Dementia Occurrence in Community Non-Dementia Elderly
Abstract: Background: TAR DNA-binding protein-43 (TDP-43) and neurofilament light chain (NfL) are promising fluid biomarkers of disease progression for various dementia. Objective: We would explore whether blood levels of NfL and TDP-43 could predict the long-term progression to dementia, and the relationship of TDP-43 levels between cerebrospinal fluid (CSF) and blood. Methods: A total of 86 non-dementia elderly received 7-year follow-up, and were divided into 49 stable normal control (NC)/mild cognitive impairment (MCI) subjects, 19 subjects progressing from NC to MCI, and 18 subjects progressing from NC/MCI to dementia. Blood TDP-43 and NfL levels, and cognitive functions were measured in all subjects. Furthermore, another cohort of 23 dementia patients, including 13 AD and 10 non-AD patients received blood and CSF measurements of TDP-43. Results: In cohort 1, compared to stable NC/MCI group, there were higher levels of blood TDP-43 at baseline in subjects progressing from NC/MCI to dementia. The combination of baseline blood TDP-43 levels with demographics including age, education, and diabetes had the detection for dementia occurrence. Baseline blood levels of NfL are negatively associated with cognitive function at 7-year follow-up. In cohort 2, we found there were no relationship between CSF and blood levels of TDP-43. Moreover, the levels of TDP-43 in CSF was positively associated with the age of patients, especially in AD group. Conclusion: Single blood TDP-43 could not estimate dementia occurrence; however, TDP-43 combined with demographics has the predictive effect for dementia occurrence and NfL level is associated with a decrease of cognitive function.

Jelena Zugic Soares, Renate Pettersen, Jūratė Šaltytė Benth, Karin Persson, Carsten Strobel, Geir Selbæk, Nenad Bogdanovic
Vitamin D Levels, APOE Allele, and MRI Volumetry Assessed by NeuroQuant in Norwegian Adults with Cognitive Symptoms
Abstract: Allele ε4 of the apolipoprotein (APOE ɛ4) gene is the strongest known genetic risk factor for late-onset sporadic Alzheimer's disease. A possible relationship between vitamin D and APOE is not yet clear. Objective: In this exploratory, cross-sectional study, we examined the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and brain volumes and the associations of both serum levels of 25(OH)D and APOE polymorphism to brain volumes in 127 persons (mean age 66 years) with cognitive symptoms. Methods: All subjects were examined with fully automated software for MRI volumetry, NeuroQuant. Results: After adjustment for relevant covariates, higher serum 25(OH)D levels were associated with greater volumes of cortical gray matter on both left (p=0.02) and right (p=0.04) sides. When both 25(OH)D levels and APOE genotype were used as the main covariates, no significant associations were found between vitamin D level and brain volume in any of the 11 brain regions. In adjusted models, only homozygous but not heterozygous APOE ɛ4 allele carriers had significantly larger inferior lateral ventricles (p=0.003) and smaller hippocampal volume (p=0.035) than those without ε4. Homozygous APOE ɛ4 carriers also had significantly higher vitamin D levels (p=0.009) compared to persons without the APOE ɛ4 allele. Conclusion: Higher vitamin D levels might have a preserving effect on cortical grey matter volume.

Kaancan Deniz*, Charlotte C.G. Ho*, Kimberly G. Malphrus, Joseph S. Reddy, Thuy Nguyen, Troy P. Carnwath, Julia E. Crook, John A. Lucas, Neill R. Graff-Radford, Minerva M. Carrasquillo, Nilüfer Ertekin-Taner (Handling Associate Editor: Olivia Belbin) *These authors contributed equally to this work.
Plasma Biomarkers of Alzheimer’s Disease in African Americans
Abstract: Background/Objective: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer’s disease (AD) pathology and neuroinflammation are associated with disease status in African Americans. Methods: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer’s Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations. Results: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOE ε4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42. Conclusion: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

Andrea Stojakovic, Su-Youne Chang, Jarred Nesbitt, Nicholas P. Pichurin, Mark A. Ostroot, Tomonori Aikawa, Takahisa Kanekiyo, Eugenia Trushina
Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice
Abstract: Background: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5-18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.

Silke Kuske*, Sandra Olivia Borgmann*, Florian Wolf, Christian Bleck *These authors contributed equally to this work.
Emotional Safety in the Context of Dementia: A Multiperspective Qualitative Study
Abstract: Background: Current research acknowledges the relevance of the emotional safety of people living with dementia. However, available evidence regarding this topic is limited. A comprehensive view of this topic that equally considers the perspectives of people living in an early stage of dementia, relatives, and public stakeholders is lacking. Objective: This study aimed to obtain a multiperspective view of emotional safety in the context of dementia in the living environment. Methods: A descriptive qualitative study was conducted based on data collected through semi-structured guided interviews (n=14), focus groups (n=3), guided feedback, and participatory approaches. People living in an early stage of dementia (N=6), relatives of people living with dementia (N=11), and public stakeholders (N=15) were included. Results: Considering “social togetherness”, “personal condition”, “health”, “physical environment”, and “society” in the light of “living and learning in relations” are preconditions for understanding emotional safety in the context of dementia. “Living and learning in relations” refers to the interaction of people in the context of dementia and relations to the topic of dementia. The focus lies on the (collective) learning. The individuality of each person and his or her situation is central, related to dementia-related, psychosocial, biographical, physical, and economic factors. Conclusion: Our study highlights the relevance of research on emotional safety in the context of dementia. Approaches to improving the emotional safety of people living in an early stage of dementia should consider the complex situations of each target group in relation to each other at the micro, meso, and macro levels.

Janina Krell-Roesch, Jeremy A. Syrjanen, Jelena Bezold, Sandra Trautwein, Bettina Barisch-Fritz, Klaus Boes, Alexander Woll, Erica Forzani, Walter K. Kremers, Mary M. Machulda, Michelle M. Mielke, David S. Knopman, Ronald C. Petersen, Maria Vassilaki, Yonas E. Geda
Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging
Abstract: Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ε4 status. Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p=0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p=0.030), attention (0.032 [0.017], p=0.050), and global cognition (0.039 [0.016], p=0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE ε4 carriership did not moderate the association between PA and cognition. Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

Thomas G. Beach, Michael Malek-Ahmadi
Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old
Abstract: Background: Clinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the rate of cognitive decline. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. Objective: As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown; our objective is to provide this information. Methods: We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association intermediate or high AD Neuropathological Change levels, excluding those with known autosomal dominant AD-related mutations. Results: Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20% in the 70s and beyond. Lewy body disease is the most common comorbidity at younger ages but actually is less common at later ages, while for most others, their prevalence increases with age. Conclusion: Alzheimer’s disease neuropathological comorbidities are highly prevalent even in the younger-old.

Max Toepper, Philipp Schulz, Thomas Beblo, Martin Driessen
Predicting On-Road Driving Skills, Fitness to Drive, and Prospective Accident Risk in Older Drivers and Drivers with Mild Cognitive Impairment: The Importance of Non-Cognitive Risk Factors
Abstract: Background: On-road driving behavior can be impaired in older drivers and particularly in drivers with mild cognitive impairment (MCI). Objective: To determine whether cognitive and non-cognitive risk factors for driving safety may allow an accurate and economic prediction of on-road driving skills, fitness to drive, and prospective accident risk in healthy older drivers and drivers with MCI, we examined a representative combined sample of older drivers with and without MCI (N = 74) in an observational on-road study. In particular, we examined whether non-cognitive risk factors improve predictive accuracy provided by cognitive factors alone. Methods: Multiple and logistic hierarchical regression analyses were utilized to predict different driving outcomes. In all regression models, we included cognitive predictors alone in a first step and added non-cognitive predictors in a second step. Results: Results revealed that the combination of cognitive and non-cognitive risk factors significantly predicted driving skills (R2adjusted = 0.30) and fitness to drive (81.2% accuracy) as well as the number (R2adjusted = 0.21) and occurrence (88.3% accuracy) of prospective minor at-fault accidents within the next 12 months. In all analyses, the inclusion of non-cognitive risk factors led to a significant increase of explained variance in the different outcome variables. Conclusion: Our findings suggest that a combination of the most robust cognitive and non-cognitive risk factors may allow an economic and accurate prediction of on-road driving performance and prospective accident risk in healthy older drivers and drivers with MCI. Therefore, non-cognitive risk factors appear to play an important role.

Núria Montagut, Sergi Borrego-Écija, Magdalena Castellví, Immaculada Rico, Ramón Reñé, Mircea Balasa, Albert Lladó, Raquel Sánchez-Valle
Errorless Learning Therapy in Semantic Variant of Primary Progressive Aphasia
Abstract: Background: The semantic variant of primary progressive aphasia (svPPA) is characterized by a progressive loss of semantic knowledge impairing the ability to name and to recognize the meaning of words. Objective: We aimed to evaluate the immediate and short-term effect of errorless learning speech therapy on the naming and recognition of commonly used words in patients with svPPA. Methods: Eight participants diagnosed with svPPA received 16 sessions of intensive errorless learning speech therapy. Naming and word comprehension tasks were evaluated at baseline, immediately postintervention, and at follow-up after 1, 3, and 6 months. These evaluations were performed using two item sets (a trained list and an untrained list). Results: In the naming tasks, patients showed a significant improvement in trained items immediately after the intervention, but that improvement decayed progressively when therapy ended. No improvements were found either in trained comprehension or in untrained tasks. Conclusion: Errorless learning therapy could improve naming ability in patients with svPPA. This effect may be due to the relative preservation of episodic memory, but the benefit is not maintained over time, presumably because there is no consolidation.

Colin Birkenbihl, Sarah Westwood, Liu Shi, Alejo Nevado-Holgado, Eric Westman, Simon Lovestone on behalf of the AddNeuroMed Consortium, Martin Hofmann-Apitius
ANMerge: A Comprehensive and Accessible Alzheimer’s Disease Patient-Level Dataset
Abstract: Background: Accessible datasets are of fundamental importance to the advancement of Alzheimer’s disease (AD) research. The AddNeuroMed consortium conducted a longitudinal observational cohort study with the aim to discover AD biomarkers. During this study, a broad selection of data modalities was measured including clinical assessments, magnetic resonance imaging, genotyping, transcriptomic profiling, and blood plasma proteomics. Some of the collected data were shared with third-party researchers. However, this data was incomplete, erroneous, and lacking in interoperability. Objective: To provide the research community with an accessible, multimodal, patient-level AD cohort dataset. Methods: We systematically addressed several limitations of the originally shared data and provided additional unreleased data to enhance the patient-level dataset. Results: In this work, we publish and describe ANMerge, a new version of the AddNeuroMed dataset. ANMerge includes multimodal data from 1,702 study participants and is accessible to the research community via a centralized portal. Conclusion: ANMerge is an information rich patient-level data resource that can serve as a discovery and validation cohort for data-driven AD research, such as, for example, machine learning and artificial intelligence approaches.

Mayra L. Estrella, Ramon A. Durazo-Arvizu, Linda C. Gallo, Wassim Tarraf, Carmen R. Isasi, Krista M. Perreira, Donglin Zeng, Maria J. Marquine, Richard B. Lipton, Hector M. González, Martha L. Daviglus, Melissa Lamar (Handling Associate Editor: Megan Zuelsdorff)
Psychosocial Factors Associated with Cognitive Function Among Middle-Aged and Older Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos and its Sociocultural Ancillary Study
Abstract: Background: Evidence suggests that psychosocial factors are associated with cognitive health in older adults; however, associations of psychosocial factors with cognition remain largely unexamined in middle-aged and older Hispanics/Latinos. Objective: To examine the cross-sectional associations of psychosocial factors with cognitive function among middle-aged and older Hispanics/Latinos living in the US. Methods: Baseline (2008-2011) data from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study (n=2,818; ages 45–74) were used to examine the associations of each psychosocial factor with global cognition (GC), verbal learning, verbal memory, verbal fluency, and processing speed independent of age, sex, education, Hispanic/Latino background, income, language, and depressive symptoms. Psychosocial variables included: intrapersonal factors (ethnic identity, optimism, and purpose in life), interpersonal factors (family cohesion, familism, social network embeddedness, and social support), and social stressors (perceived ethnic discrimination, loneliness, and subjective social status). Results: In fully-adjusted models, purpose in life and social support were each positively associated with all five cognitive variables. Loneliness was negatively associated with GC, verbal learning, memory, and processing speed. Ethnic identity was positively and familism negatively associated with GC, verbal fluency, and processing speed. Family cohesion was positively associated with verbal learning. Conclusion: These findings extend previous evidence from older, largely non-Hispanic White cohorts to show that higher purpose in life and social support are also strongly associated with cognitive health among middle-aged and older Hispanics/Latinos. We also highlight that intrapersonal factors, interpersonal factors, and social stressors have differential relationships with individual cognitive tests.

Jairo Ramos, Aneesa R. Chowdhury, Laura J. Caywood, Michael Prough, M. Denise Fuzzell, Sarada Fuzzell, Kristy Miskimen, Patrice L. Whitehead, Larry D. Adams, Renee Laux, Yeunjoo Song, Paula Ogrocki, Alan J. Lerner, Jeffery M. Vance, Jonathan L. Haines, William K Scott, Margaret A. Pericak-Vance, Michael L. Cuccaro
Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish
Abstract: Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade, which along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment (CI). Objective: The objective of this study was to examine the association of education with cognitive function in individuals from the OOA. We hypothesized that small differences in educational attainment at lower levels of formal education were associated with risk for CI. Methods: Data of 2,426 individuals from the OOA aged 54-99 were analyzed. The Modified Mini-Mental State Examination (3MS-R) was used to classify participants as CI or normal. Individuals were classified in three education categories: <8, 8, and >8 years of education. To measure the association of education with cognitive status, a logistic regression model was performed adding age and sex as covariates. Results: Our results showed that individuals who attained lowest levels of education (8 years (OR=2.96 and 1.85). Conclusion: Even within a setting of low levels of formal education, small differences in educational attainment can still be associated with the risk of cognitive impairment. Given the homogeneity of the OOA, these results are less likely to be biased by differences in socioeconomic backgrounds.

Panagiotis Alexopoulos, Rigas Soldatos, Evagellia Kontogianni, Maria Frouda, Souzana Ιoanna Aligianni, Maria Skondra, Maria Passa, Georgia Konstantopoulou, Evangelia Stamouli, Evgenia Katirtzoglou, Anastasios Politis, Polychronis Εconomou, Maria Alexaki, Kostas Siarkos, Antonios Politis
COVID-19 Crisis Effects on Caregiver Distress in Neurocognitive Disorder
Abstract: Background: Τhe outbreak of the COVID-19 pandemic seems to have mental health implications for both people with neurocognitive disorder and their caregivers. Objective: The study aimed to shed light on relations between caregiver mental reaction to the pandemic and caregiver distress related to neuropsychiatric symptoms, memory impairment progression, and functional impairment of people with neurocognitive disorder during the period of confinement in Greece. Methods: The study included caregivers of patients with mild (N=13) and major (N=54) neurocognitive disorder. The caregiver-based telephone interview was based on items of the neuropsychiatric inventory questionnaire, the AD8 Dementia Screening Instrument, and the Bristol Activities of Daily Living Scale. Regarding the mental impact of the COVID-19 crisis on caregivers, four single questions referring to their worries in the last seven days were posed, in addition to the scales Generalized Anxiety Disorder 7-Item (GAD-7) and the 22-item Impact of Event Scale-revised (IES-R). A stepwise linear regression model was employed for studying the relationship between caregiver distress and demographic and clinical data and caregiver mental reaction to COVID-19 pandemic outbreak. Results: Caregiver distress severity during the confinement period was influenced not only by memory deficits (p=0.009) and neuropsychiatric symptoms (p<0.001) of patients, but also by caregiver hyperarousal (p=0.003) and avoidance symptoms (p=0.033) and worries directly linked to the COVID-19 crisis (p=0.022). Conclusion: These observations provide further evidence for the urgent need for support of caregivers of patients with neurocognitive disorder during the COVID-19 pandemic.