Volume 81, Number 1, IN PRESS

Review
Alvaro Miranda, Enrique Montiel, Henning Ulrich, Cristian Paz (Handling Associate Editor: Sergio Ferreira)
Selective Secretase Targeting for Alzheimer’s Disease Therapy
Abstract: Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Review
Jianwei Yang, Longfei Jia, Yan Li, Qiongqiong Qiu, Meina Quan, Jianping Jia
Fluid Biomarkers in Clinical Trials for Alzheimer’s Disease: Current and Future Application
Abstract: Alzheimer’s disease (AD) research is entering a unique moment in which enormous information about the molecular basis of this disease is being translated into therapeutics. However, almost all drug candidates have failed in clinical trials over the past 30 years. These many trial failures have highlighted a need for the incorporation of biomarkers in clinical trials to help improve the trial design. Fluid biomarkers measured in cerebrospinal fluid and circulating blood, which can reflect the pathophysiological process in the brain, are becoming increasingly important in AD clinical trials. In this review, we first succinctly outline a panel of fluid biomarkers for neuropathological changes in AD. Then, we provide a comprehensive overview of current and future application of fluid biomarkers in clinical trials for AD. We also summarize the many challenges that have been encountered in efforts to integrate fluid biomarkers in clinical trials, and the barriers that have begun to be overcome. Ongoing research efforts in the field of fluid biomarkers will be critical to make significant progress in ultimately unveiling disease-modifying therapies in AD.

Review
Roger Gaudreault, Vincent Hervé, Theo G.M. van de Ven, Normand Mousseau, Charles Ramassamy
Polyphenol-Peptide Interactions in Mitigation of Alzheimer’s Disease: Role of Biosurface-Induced Aggregation
Abstract: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, responsible for nearly two-thirds of all dementia cases. In this review, we report the potential AD treatment strategies focusing on natural polyphenol molecules (green chemistry) and more specifically on the inhibition of polyphenol-induced amyloid aggregation/disaggregation pathways: in bulk and on biosurfaces. We discuss how these pathways can potentially alter the structure at the early stages of AD, hence delaying the aggregation of amyloid-β (Aβ) and tau. We also discuss multidisciplinary approaches, combining experimental and modelling methods, that can better characterize the biochemical and biophysical interactions between proteins and phenolic ligands. In addition to the surface-induced aggregation, which can occur on surfaces where protein can interact with other proteins and polyphenols, we suggest a new concept referred as “confinement stability”. Here, on the contrary, the adsorption of Aβ and tau on biosurfaces other than Aβ- and tau-fibrils, e.g., red blood cells, can lead to confinement stability that minimizes the aggregation of Aβ and tau. Overall, these mechanisms may participate directly or indirectly in mitigating neurodegenerative diseases, by preventing protein self-association, slowing down the aggregation processes, and delaying the progression of AD.

Review
Alvin Surya Tjahyo, Joan Gandy, Judi Porter, Christiani Jeyakumar Henry (Handling Associate Editor: Nenad Naumovski)
Is Weight Loss More Severe in Older People with Dementia?
Abstract: Weight loss, a hallmark feature of dementia, is associated with higher mortality in older people. However, there is a lack of consensus in the literature as to whether the weight loss commonly observed in older people with dementia results from reduced energy intake and/or increased energy expenditure. Understanding the cause of energy imbalance in older people with dementia would allow more targeted interventions to avoid detrimental health effects in this vulnerable group. In this paper, we review studies that have considered weight change, energy intake, and energy expenditure in older people with and without dementia. We critically assess the studies’ methodology and outline the various factors which may decrease and increase energy intake and expenditure respectively in older people with and without dementia. Current available literature does not support the view that there is a lower energy intake and/or a higher energy expenditure in older people with dementia when compared to those without dementia. The need for more high-quality studies is also highlighted in order to shed more light towards this issue which continues to elude researchers and clinicians alike.

Hypothesis
Sofia Toniolo, Francesco Di Lorenzo, Marta Scarioni, Kristian Steen Frederiksen*, Flavio Nobili* *These authors contributed equally to this work.
Is the Frontal Lobe the Primary Target of SARS-CoV-2?
Abstract: Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

Commentary
Daniel Oudin Åström, Rolf Adolfsson, David Segersson, Bertil Forsberg, Anna Oudin
Local Contrasts in Concentration of Ambient Particulate Air Pollution (PM2.5) and Incidence of Alzheimer’s Disease and Dementia: Results from the Betula Cohort in Northern Sweden
Abstract: Exposure to fine particulate air pollution (PM2.5) is emerging as a risk factor for Alzheimer's disease (AD), but existing studies are still limited and heterogeneous. We have previously studied the association between dementia (AD and vascular dementia) and PM2.5 stemming from vehicle exhaust and wood-smoke in the Betula cohort in Northern Sweden. The aim of this commentary is to estimate the association between total PM2.5 and dementia in the Betula cohort, which is more relevant to include in future meta-estimates than the source-specific estimates. The hazard ratio for incident dementia associated with a 1 µg/m3 increase in local PM2.5 was 1.38 (95% confidence interval: 0.99 – 1.92). The interpretation of our results is that they indicate an association between local contrasts in concentration of PM2.5 at the residential address and incidence of dementia in a low-level setting.

Commentary
Irundika H.K. Dias, Helen R. Griffiths
Current and Future Directions for Targeting Lipoxin A4 in Alzheimer’s Disease
Abstract: Neuroinflammation has been implicated in Alzheimer’s disease onset and progression. Chronic neuroinflammation is initiated by amyloid-β-activated microglial cells that secrete immuno-modulatory molecules within the brain and into the vasculature. Inflammation is normally self-limiting and actively resolves by “switching off” the generation of pro-inflammatory mediators and by non-phlogistic clearance of spent cells and their debris to restore tissue homeostasis. Deficits in these anti-inflammatory/pro-resolution pathways may predispose to the development of chronic inflammation. The synthesis of endogenous lipid mediators from arachidonic acid, lipoxins via cyclooxygenase 2 and lipoxygenases, and conversion of exogenous polyunsaturated fatty acids, namely docosahexaenoic acid and eicosapentaenoic acid, to resolvins contributes to effective, timely resolution of acute inflammation. Work by Xiuzhe et al., 2020 in the Journal of Alzheimer’s Disease reported that plasma level of LXA4 is related to cognitive status in ischemic stroke patients suggesting that decreased LXA4 may be a potential risk factor for post post-stroke cognitive impairment. As evident by recent clinical trials and development of drug analogues, there is recent drive to search for lipoxin analogues as therapeutics for inflammatory diseases. Understanding how bioactive lipid signaling is involved in resolution will increase our understanding of controlling inflammation and may facilitate the discovery of new classes of therapeutic pro-resolution agents for evaluation in AD prevention studies.

Galit Yogev-Seligmann*, Tamir Eisenstein*, Elissa Ash, Nir Giladi, Haggai Sharon, Shikma Nachman, Einat Kodesh, Talma Hendler, Yulia Lerner (Handling Associate Editor: Madeleine Hackney) *These authors contributed equally to this work.
Neurocognitive Plasticity Is Associated with Cardiorespiratory Fitness Following Physical Exercise in Older Adults with Amnestic Mild Cognitive Impairment
Abstract: Background: Aerobic training has been shown to promote structural and functional neurocognitive plasticity in cognitively intact older adults. However, little is known about the neuroplastic potential of aerobic exercise in individuals at risk of Alzheimer’s disease (AD) and dementia. Objective: We aimed to explore the effect of aerobic exercise intervention and cardiorespiratory fitness improvement on brain and cognitive functions in older adults with amnestic mild cognitive impairment (aMCI). Methods: 27 participants with aMCI were randomized to either aerobic training (n=13) or balance and toning (BAT) control group (n=14) for a 16-week intervention. Pre- and post-assessments included functional MRI experiments of brain activation during associative memory encoding and neural synchronization during complex information processing, cognitive evaluation using neuropsychological tests, and cardiorespiratory fitness assessment. Results: The aerobic group demonstrated increased frontal activity during memory encoding and increased neural synchronization in higher-order cognitive regions such as the frontal cortex and temporo-parietal junction (TPJ) following the intervention. In contrast, the BAT control group demonstrated decreased brain activity during memory encoding, primarily in occipital, temporal, and parietal areas. Increases in cardiorespiratory fitness were associated with increases in brain activation in both the left inferior frontal and precentral gyri. Furthermore, changes in cardiorespiratory fitness were also correlated with changes in performance on several neuropsychological tests. Conclusion: Aerobic exercise training may result in functional plasticity of high-order cognitive areas, especially, frontal regions, among older adults at risk of AD and dementia. Furthermore, cardiorespiratory fitness may be an important mediating factor of the observed changes in neurocognitive functions.

Jonathan Graff-Radford, Timothy G. Lesnick, Michelle M. Mielke, Eleni Constantopoulos, Alejandro Rabinstein, Scott A. Przybelski, Prashanthi Vemuri, Hugo Botha, David T. Jones, Vijay K. Ramanan, Ronald C. Petersen, David S. Knopman, Bradley F. Boeve, Melissa E. Murray, Dennis W. Dickson, Clifford R. Jack, Jr., Kejal Kantarci, R. Ross Reichard (Handling Associate Editor: Jun Ni)
Cerebral Amyloid Angiopathy Burden and Cerebral Microbleeds: Pathological Evidence for Distinct Phenotypes
Abstract: Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective: To determine whether CMBs on antemortem MRI correlate with CAA. Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal and cortical components correlated with number of lobar CMBs. Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.

Shabina A. Hayat, Robert Luben, Kay-Tee Khaw, Carol Brayne (Handling Associate Editor: Saima Hilal)
The Relationship Between Cognitive Performance Using Tests Assessing a Range of Cognitive Domains and Future Dementia Diagnosis in a British Cohort: A Ten-Year Prospective Study
Abstract: Background: Exploring the domains of cognitive function which are most strongly associated with future dementia may help with understanding risk factors for, and the natural history of dementia. Objective: To examine the association of performance on a range of cognitive tests (both global and domain specific) with subsequent diagnosis of dementia through health services in a population of relatively healthy men and women and risk of future dementia. Methods: We examined the association between performance on different cognitive tests as well as a global score and future dementia risk ascertained through health record linkage in a cohort of 8,581 individuals (aged 48-92 years) between 2004-2019 with almost 15 years follow-up (average of 10 years) before and after adjustment for socio-demographic, lifestyle, and health characteristics. Results: Those with poor performance for global cognition (bottom 10%) were almost four times as likely to receive a dementia diagnosis from health services over the next 15 years than those who performed well HR=3.51 (95%CI 2.61, 4.71 p<0.001) after adjustment for socioeconomic, lifestyle, and biological factors and also prevalent disease. Poor cognition performance in multiple tests was associated with 10-fold increased risk compared to those not performing poorly in any test HR=10.82 (95% CI 6.85, 17.10 p<0.001). Conclusion: Deficits across multiple cognitive domains substantially increase risk of future dementia over and above neuropsychological test scores ten years prior to a clinical diagnosis. These findings may help further understanding of the natural history of dementia and how such measures could contribute to strengthening future models of dementia.

Luciana Mascarenhas Fonseca, Guilherme Prado Mattar , Glenda Guerra Haddad, Ekaterina Burduli, Sterling M. McPherson, Laura Maria de Figueiredo Ferreira Guilhoto, Mônica Sanches Yassuda, Geraldo Filho Busatto, Cassio Machado de Campos Bottino, Marcelo Queiroz Hoexter, Naomi Sage Chaytor (Handling Associate Editor: Elizabeth Head)
Neuropsychiatric Symptoms of Alzheimer’s Disease in Down Syndrome and Its Impact on Caregiver Distress
Abstract: Background: Neuropsychiatric symptoms (NPS) are non-cognitive manifestations common to dementia and other medical conditions, with important consequences for the patient, caregivers, and society. Studies investigating NPS in individuals with Down syndrome (DS) and dementia are scarce. Objective: Characterize NPS and caregiver distress among adults with DS using the Neuropsychiatric Inventory (NPI). Methods: We evaluated 92 individuals with DS (≥30 years of age), divided by clinical diagnosis: stable cognition, prodromal dementia, and AD. Diagnosis was determined by a psychiatrist using the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX-DS). NPS and caregiver distress were evaluated by an independent psychiatrist using the NPI, and participants underwent a neuropsychological assessment with Cambridge Cognitive Examination (CAMCOG-DS). Results: Symptom severity differed between-groups for delusion, agitation, apathy, aberrant motor behavior, nighttime behavior disturbance, and total NPI scores, with NPS total score being found to be a predictor of AD in comparison to stable cognition (OR for one-point increase in the NPI=1.342, p=0.012). Agitation, apathy, nighttime behavior disturbances, and total NPI were associated with CAMCOG-DS, and 62% of caregivers of individuals with AD reported severe distress related to NPS. Caregiver distress was most impacted by symptoms of apathy followed by nighttime behavior, appetite/eating abnormalities, anxiety, irritability, disinhibition, and depression (R2=0.627,F(15,76)=8.510, p<0.001). Conclusion: NPS are frequent and severe in individuals with DS and AD, contributing to caregiver distress. NPS in DS must be considered of critical relevance demanding management and treatment. Further studies are warranted to understand the biological underpinnings of such symptoms.

Dong Bai*, Junting Fan*, Mengyue Li*, Cuixia Dong, Yiming Gao, Min Fu, Guowei Huang, Huan Liu *These authors contributed equally to this work.
Effects of Folic Acid Combined with DHA Supplementation on Cognitive Function and Amyloid-β-Related Biomarkers in Older Adults with Mild Cognitive Impairment by a Randomized, Double Blind, Placebo-Controlled Trial
Abstract: Background: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed. Objective: To explore the effects of 6-month folic acid+DHA on cognitive function in patients with MCI. Methods: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients aged >60 years into four regimen groups randomly: folic acid (0.8 mg/day)+DHA (800 mg/day), folic acid (0.8 mg/day), DHA (800 mg/day), and placebo, for 6 months. Cognitive function and blood amyloid-β peptide (Aβ) biomarker levels were measured at baseline and 6 months. Cognitive function was also measured at 12 months. Results: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acid+DHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acid+DHA increased blood folate (folic acid+DHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (-6.51, -10.57 to -2.45) compared to placebo. DHA lower the Aβ40 levels (-40.57, -79.79 to -1.35) compared to placebo (p<0.05), and folic acid+DHA reduced the Aβ42 (-95.59, -150.76 to -40.43) and Aβ40 levels (-45.75, -84.67 to -6.84) more than DHA (p<0.05). Conclusion: Folic acid and DHA improve cognitive function and reduce blood Aβ production in MCI patients. Combination therapy may be more beneficial in reducing blood Aβ-related biomarkers.

Maria Alice Tourinho Baptista, Nathália Kimura, Isabel Barbeito Lacerda, Felipe de Oliveira Silva, Marcia Cristina Nascimento Dourado (Handling Associate Editor: Paulo Caramelli)
Domains of Awareness in Young and Late Onset Dementia
Abstract: Background: There is a lack of research investigating whether there are differences in the domains of awareness according to the age at onset of dementia. Objective: This study is designed to investigate differences in awareness of cognitive functioning and health condition, functional activity impairments, emotional state, and social functioning and relationships among people with young onset (YOD) and late onset dementia (LOD); and examine associations between awareness and its domains with cognition, functionality, neuropsychiatric symptoms, social and emotional functioning, and quality of life (QoL) in both groups. Methods: A group of 136 people with dementia and their respective caregivers (YOD = 50 and LOD = 86) were consecutively selected. We assessed awareness of disease, dementia severity, cognition, functionality, neuropsychiatric symptoms, social and emotional functioning, and QoL. Results: People with YOD had more neuropsychiatric symptoms than people with LOD. People with YOD were more aware of disease (total score), of their cognitive functioning and health condition and of their functional activity impairments, even if this group was more severely cognitive impaired and had a worse level of functionality than LOD group. Multivariate linear regressions showed that functionality has a wide relationship to awareness for people with YOD. While neuropsychiatric symptoms and QoL has a greater relation to awareness for people with LOD. Conclusion: Different clinical variables are associated to different domains in YOD and LOD groups, reinforcing the heterogeneity of awareness in dementia.

Emilia Schwertner, Renata Zelic, Juraj Secnik, Björn Johansson, Bengt Winblad, Maria Eriksdotter, Dorota Religa
Biting the Bullet: Firearm Ownership in Persons with Dementia. A Registry-Based Observational Study
Abstract: Background: In Sweden, 2,296,000 firearms were legally owned by private persons in 2017 and there were 150,000 persons living with a dementia diagnosis. A proportion of these persons owning a firearm may pose safety concerns. Objective: The aim was to describe firearm ownership in persons with dementia in Sweden and examine which characteristics are explaining physicians’ decision to report a person to the police as unsuitable to possess a firearm. Methods: This was a registry-based observational study. 65,717 persons with dementia registered in the Swedish Dementia Registry were included in the study. Logistic regression was used to evaluate which of the persons’ characteristics were most important in predicting the likelihood of being reported as unsuitable to possess a firearm. Relative importance of predictors was quantified using standardized coefficients (SC) and dominance analysis (DA). Results: Out of 53,384 persons with dementia, 1,823 owned a firearm and 419 were reported to the police as unsuitable owners. Firearm owners were predominantly younger, males, living alone, and without assistance of homecare. The most important predictors of being reported to the police were: living with another person (SC=0.23), frontotemporal dementia (SC=0.18), antipsychotics prescription (SC=0.18), being diagnosed in a memory/cognitive clinic (SC=-0.27), female gender (SC=0.18), mild (SC=-0.25) and moderate (SC=-0.21) dementia, and hypnotics prescription (SC=0.17). Conclusion: Firearm owners with dementia were mostly younger males who were still living more independent lives. The decision to remove a weapon was not solely based on a diagnosis of dementia but a combination of factors was considered.

Kylie R. Kadey, John L. Woodard, Allison C. Moll, Kristy A. Nielson, J. Carson Smith, Sally Durgerian, Stephen M. Rao
Five-Year Change in Body Mass Index Predicts Conversion to Mild Cognitive Impairment or Dementia Only in APOE ε4 Allele Carriers
Abstract: Background: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ε4 (APOE ε4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia. Objective: The aim of this study was to investigate the interaction between APOE ε4 status and baseline (bBMI) and five-year BMI change (ΔBMI) on conversion to MCI or dementia in initially cognitively healthy older adults. Methods: The associations between bBMI, ΔBMI, APOE ε4 status, and conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer’s Coordinating Center (NACC) database. Results: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p < 0.001, OR = 2.06. Neither bBMI (OR=0.99, 95% CI=0.96-1.02) nor the bBMI by APOE interaction (OR=1.02, 95% CI=0.96-1.08) predicted conversion. Although ΔBMI also did not significantly predict conversion (OR=0.90, 95% CI=0.78-1.04), the interaction between ΔBMI and carrier status was significant (OR=0.72, 95% CI=0.53-0.98). For carriers only, each one-unit decline in BMI over five years was associated with a 27% increase in the odds of conversion (OR=0.73, 95% CI=0.57-0.94). Conclusion: A decline in BMI over five years, but not bBMI, was strongly associated with conversion to MCI or dementia only for APOE ε4 carriers. Interventions and behaviors aimed at maintaining body mass may be important for long term cognitive health in older adults at genetic risk for AD.

Qiang Tong, Liam Chen
Associations of Alzheimer’s Disease Neuropathologic Changes with Clinical Presentations of Parkinson’s Disease
Abstract: Background: Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the two most prevalent neurodegenerative diseases associated with age. Pathological studies have shown that these two diseases share a certain degree of neuropathological overlap. AD neuropathologic change contributes to cognitive impairment in PD. However, the impact of AD pathology on other clinical phenotypes in PD remains largely unknown. Objective: Herein we aimed to assess the impact of co-occurring AD neuropathologic change on the clinical phenotypes of PD. Methods: We examined 46 autopsy brains of PD patients and available clinical information to retrospectively assess the effects of comorbid AD pathology on dementia, hallucinations, and dyskinesia commonly seen in advanced PD. Results: AD neuropathology significantly increased the risk of hallucinations and dementia, but not dyskinesia in PD patients. Surprisingly, diffuse Lewy body pathology, but not AD pathology, was associated with the occurrence of dementia and hallucinations. Most importantly, we reported that the severity of neuronal loss in the locus coeruleus (LC), but not the severity of neuronal loss in the substantia nigra (SN), was associated with the occurrence of dyskinesia in advanced PD patients, while neither Lewy body scores in SN nor LC had significant effects. Conclusion: We show for the first time that neuronal loss in LC contributes to dyskinesia. Understanding the relationships between the two distinct pathologies and their relevant clinical phenotypes will be crucial in the development of effective disease-modifying therapies for PD.

Cynthia M. Stonnington, Jianfeng Wu, Jie Zhang, Jie Shi, Robert J. Bauer III, Vivek Devadas, Yi Su, Dona E.C. Locke, Eric M. Reiman, Richard J. Caselli, Kewei Chen, Yalin Wang, for the Alzheimer’s Disease Neuroimaging Initiative
Improved Prediction of Imminent Progression to Clinically Significant Memory Decline Using Surface Multivariate Morphometry Statistics and Sparse Coding
Abstract: Background: Besides their other roles, brain imaging and other biomarkers of Alzheimer’s disease (AD) have the potential to inform a cognitively unimpaired (CU) person’s likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79% sensitivity/78% specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures. Objective: To improve the same prediction by using different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI). Methods: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years (“progressors”) and 80 matched adults who remained CU for at least 4 years (“nonprogressors”). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI. Results: We achieved 92% prediction accuracy in the Arizona cohort, 92% prediction accuracy in the ADNI cohort, and 90% prediction accuracy when combining the two demographically distinct cohorts, as compared to 79% (Arizona) and 72% (ADNI) prediction accuracy using hippocampal volume. Conclusion: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers.

Dandan Gao*, Junkui Shang*, Ruihua Sun, Yingying Shi, Haisong Jiang, Mingming Ma, Jiewen Zhang *These authors contributed equally to this work.
Changes in the Morphology, Number, and Protein Levels of Plasma Exosomes in CADASIL Patients
Abstract: Background: Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. However, whether plasma exosomes change in CADASIL patients is still unclear. Objective: We are aimed to investigate the differences of plasma exosomes between CADASIL patients and healthy controls. Methods: The subjects included 30 CADASIL patients and 30 healthy controls without NOTCH3 mutation. The severity of white matter lesions (WMLs) of CADASIL patients was quantified by Fazekas score. Transmission electron microscopy and nanoparticle tracking analysis were performed to characterize plasma exosomes. In addition, NOTCH3, Neurofilament light and Aβ42 levels in plasma exosomes were quantified by enzyme-linked immunosorbent assays. Results: We found that exosomes from CADASIL patients were lower in quantity. In addition, CADASIL plasma exosomes had significantly lower levels of NOTCH3 and significantly increased levels of NFL than those of matched healthy subjects. Interestingly, plasma exosome NOTCH3 levels of CADASIL patients significantly correlated with severity of WMLs. Conclusion: The exosome NOTCH3 may be related to the pathological changes of CADASIL, which provides a basis for the pathogenesis research of CADASIL. In addition, plasma exosome NOTCH3 and NFL levels may act as biomarkers to monitor and predict disease progression and measure therapeutic effectiveness in the future clinical trials.

Unnur D. Teitsdottir, Skarphedinn Halldorsson, Ottar Rolfsson, Sigrun H. Lund, Maria K. Jonsdottir, Jon Snaedal, Petur H. Petersen
Cerebrospinal Fluid C18 Ceramide Associates with Markers of Alzheimer’s Disease and Inflammation at the Pre- and Early Stages of Dementia
Abstract: Background: Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer‘s disease (AD) pathology might be critical in developing effective treatments. Objective: To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia. Methods: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n=34) or non-AD (n=26) pathology profiles. Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory. Results: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aβ42: st.β=-0.36, p=0.007; T-tau: st.β=0.41, p=0.005) and inflammatory marker S100B (st.β=0.51, p=0.001) with C18 ceramide levels. Conclusion: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target.

Cecilia S. Lee, Michael L. Lee, Laura E. Gibbons, Ryan T. Yanagihara, Marian Blazes, Jason P. Kam, Susan M. McCurry, James D. Bowen, Wayne C. McCormick, Aaron Y. Lee, Eric B. Larson*, Paul K. Crane* (Handling Associate Editor: Manju Subramanian) *These authors contributed equally to this work and should be considered co-senior authors.
Associations Between Retinal Artery/Vein Occlusions and Risk of Vascular Dementia
Abstract: Background: Vascular disease is a risk factor for Alzheimer’s disease (AD) and related dementia in older adults. Retinal artery/vein occlusion (RAVO) is an ophthalmic complication of systemic vascular pathology. Whether there are associations between RAVO and dementia risk is unknown. Objective: To determine whether RAVOs are associated with an increased risk of developing vascular dementia or AD. Methods: Data from Adult Changes in Thought (ACT) study participants were analyzed. This prospective, population-based cohort study followed older adults (age ≥ 65 years) who were dementia-free at enrollment for development of vascular dementia or AD based on research criteria. RAVO diagnoses were extracted from electronic medical records. Cox-regression survival analyses were stratified by APOE ε4 genotype and adjusted for demographic and clinical factors. Results: On review of 41,216 person-years (4,743 participants), 266 (5.6%) experienced RAVO. APOE ε4 carriers who developed RAVO had greater than four-fold higher risk for developing vascular dementia (Hazard Ratio [HR] 4.54, 95% Confidence Interval [CI] 1.86, 11.10, p = 0.001). When including other cerebrovascular disease (history of carotid endarterectomy or transient ischemic attack) in the model, the risk was three-fold higher (HR 3.06, 95% CI 1.23, 76.2). No other conditions evaluated in the secondary analyses were found to confound this relationship. There was no effect in non-APOE ε4 carriers (HR 1.03, 95% CI 0.37, 2.80). There were no significant associations between RAVO and AD in either APOE group. Conclusion: Older dementia-free patients who present with RAVO and carry the APOE ε4 allele appear to be at higher risk for vascular dementia.

Xuanting Li*, Junliang Yuan*, Wei Qin, Lei Yang, Shuna Yang, Yue Li, Wenli Hu (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Cerebral Microbleeds Are Associated with Impairments in Executive Function and Processing Speed
Abstract: Background: Cerebral microbleed (CMB) is an increasingly important risk factor for cognitive impairment due to population aging. Controversies, however, remain regarding the exact association between CMB and cognitive dysfunction. Objective: We aimed to determine the relationship between CMB burden and cognitive impairment, and also explore the characteristics of cognitive decline in CMB patients for middle-aged and elderly people. Methods: The present cross-sectional study included 174 participants (87 CMB patients and 87 controls) who underwent brain magnetic resonance imaging and a battery of neuropsychological test. Global cognitive function was measured using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Compound z-scores were calculated for three cognitive subdomains: memory, executive function and processing speed. Results: CMB patients had lower scores of MMSE (p<0.001) and MoCA (p<0.001). Patients at each category of CMB count had worse performance in global cognitive function and all three cognitive subdomains (p<0.001). In multiple linear regression models, CMB patients had significantly greater declines in executive function (p<0.001), processing speed (p<0.001), and MoCA (p = 0.003) with increasing number of CMB. We found no relationship between CMB location and cognition (p>0.05). Conclusion: CMB is associated with impairment in global cognition as well as for all tested subdomains. Strongest effect sizes were seen for tests which rely on executive functioning, where performance deficits increased in proportion to degree of CMB burden. Prospective studies are needed to evaluate whether the association between CMB and executive dysfunction is causal.

Ya-Hui Ma*, Ya-Yu Wang*, Lan Tan*, Wei Xu, Xue-Ning Shen, Hui-Fu Wang, Xiao-He Hou, Xi-Peng Cao, Yan-Lin Bi, Qiang Dong, Jiu-Long Yang, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE Study
Abstract: Background: Although social networks are deemed as moderators of incident Alzheimer’s disease (AD), few data are available on the mechanism relevant to AD pathology. Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). Methods: We studied participants from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ1-42 and Aβ1-40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used. Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ1-42 and T-tau/Aβ1-42 and high Aβ1-42/Aβ1-40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE ɛ4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β = -0.005, p < 0.001), Aβ1-42/Aβ1-40 (β = 0.481, p = 0.001), and T-tau/Aβ1-42 (β = -0.047, p < 0.001) were noted in preclinical AD stage than controls. Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations.

Danmin Pan, Jin-Hua Gu, Jin Zhang, Yae Hu, Fei Liu, Khalid Iqbal, Nevena Cekic, David J. Vocadlo, Chun-Ling Dai, Cheng-Xin Gong (Handling Associate Editor: Tao Ma)
Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice
Abstract: Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer’s disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). Methods: STZ was injected into the lateral ventricle of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. Results: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. Conclusion: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD.

Gihwan Byeon, Min Soo Byun, Dahyun Yi, Jun Ho Lee, So Yeon Jeon, Kang Ko, Gijung Jung, Jun-Young Lee, Yu Kyeong Kim, Yun-Sang Lee, Koung Mi Kang, Chul-Ho Sohn, Dong Young Lee for the KBASE research group
Synergistic Effect of Serum Homocysteine and Diabetes Mellitus on Brain Alterations
Abstract: Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM. Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments. Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11C] Pittsburgh Compound B (PiB) PET, [18F] AV-1451 PET, and brain MRI. Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer’s disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD. Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM.

Robert Morris, Hunter Luboff, Rahul P. Jose, Kyle Eckhoff, Kun Bu, Minh Pham, Dekai Rohlsen-Neal, Feng Cheng
Bradycardia Due to Donepezil in Adults: Systematic Analysis of FDA Adverse Event Reporting System
Abstract
Background: Bradycardia is a physiological condition characterized by a decrease in heart rate and is a side effect of many drug classes. Bradycardia has been reported as an adverse event for patients receiving donepezil for Alzheimer’s disease (AD) treatment. Objective: The purpose of the paper is to systematically investigate the association between the occurrence of bradycardia in adults and the usage of donepezil using clinical data derived from the FDA Adverse Event Reporting System (FAERS) database. Methods: The risk of bradycardia in patients who only took donepezil was compared with those of patients who only took over-the-counter medications, multiple arrhythmia drugs, or other medications for AD treatment. In addition, this study sought to determine if this heightened bradycardia risk was influenced by sex, age, and dosage. Results: The results indicated that there was a significant greater likelihood of reporting bradycardia in patients administered donepezil than most of the drugs investigated. There was no significant association between age or the dosage of donepezil and the likelihood of reporting bradycardia. However, males were found to be more likely than females to report bradycardia as an adverse event. Tumor necrosis factor inhibition and stimulation of endothelial nitric oxide synthase were proposed to be the primary mechanism of actions which confer elevated bradycardia risk when using donepezil. Conclusion: These findings identified strong association between the usage of donepezil and bradycardia in adults as well as provide insight into the underlying molecular mechanisms that induce bradycardia by donepezil.

Shunya Ikeda, Masaru Mimura, Manabu Ikeda, Kenji Wada-Isoe, Mie Azuma, Sachie Inoue, Kiyoyuki Tomita
Economic Burden of Alzheimer’s Disease Dementia in Japan
Abstract: Background: Alzheimer’s disease dementia (ADD) is the leading cause of long-term care in Japan. Objective: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families. Methods: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged 20–69 and informal care costs for all ADD family caregivers were estimated. Results: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR-0.5, CDR-1, and CDR-2, respectively, but increased to JPY 447 billion (48%) for CDR-3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20–69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion. Conclusion: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address.

Mark Jitlal*, Guru N.K. Amirthalingam*, Tasvee Karania, Eve Parry, Aidan Neligan, Ruth Dobson, Alastair J Noyce, Charles R. Marshall (Handling Associate Editor: Karel Kostev) *These authors contributed equally to this work.
The Influence of Socioeconomic Deprivation on Dementia Mortality, Age at Death, and Quality of Diagnosis: A Nationwide Death Records Study in England and Wales 2001-2017
Abstract: Background: Socioeconomic deprivation may be an important determinant of dementia risk, mortality, and access to diagnostic services. Premature mortality from other causes and under-representation of deprived individuals in research may lead to this effect being overlooked. Objective: We assessed the relationship between deprivation and dementia mortality using comprehensive death certificate data for England and Wales from 2001 to 2017. Methods: We used standardized mortality ratios (SMR) and a Poisson model to compare likelihood of dying from dementia in each deprivation decile. We also examined the associations of deprivation with age at death from dementia, and with likelihood of receiving a diagnosis of unspecified dementia. Results: Risk of dying from dementia was higher in more deprived deciles (Mean SMR [95%CI] in decile 1: 0.528 [0.506 to 0.550], decile 10: 0.369 [0.338 to 0.400]). In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of all dementia deaths that year). There were dose-response associations of deprivation with likelihood of being older at death with dementia (odds ratio [95%CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and with likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95%CI] for decile 10: 0.78 [0.76 to 0.80] relative to decile 1). Conclusion: Socioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may have a role in the prevention of dementia mortality.

Antonios Douros, Christina Santella, Sophie Dell’Aniello, Laurent Azoulay, Christel Renoux, Samy Suissa, Paul Brassard (Handling Associate Editor: William Grant)
Infectious Disease Burden and the Risk of Alzheimer’s Disease: A Population-Based Study
Abstract: Background: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer’s disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. Objective: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. Methods: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed >2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. Results: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12-30 years (OR, 1.11; 95% CI, 1.05-1.17). The risk did not increase with cumulative number of infections. Conclusion: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection.

Anna K. Edlund, Kewei Chen, Wendy Lee, Hillary Protas, Yi Su, Eric Reiman, Richard Caselli, Henrietta M. Nielsen
Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ε3/ε4 Carriers
Abstract: Background: Altered cerebral glucose metabolism, especially prominent in APOE ε4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ε3/ε4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ε3/ε4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ε3/ε4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.

Michael J. Kleiman, Elan Barenholtz, James E. Galvin for the Alzheimer’s Disease Neuroimaging Initiative
Screening for Early-Stage Alzheimer’s Disease Using Optimized Feature Sets and Machine Learning
Abstract: Background: Detecting early-stage Alzheimer’s disease in clinical practice is difficult due to a lack of efficient and easily administered cognitive assessments that are sensitive to very mild impairment, a likely contributor to the high rate of undetected dementia. Objective: We aim to identify groups of cognitive assessment features optimized for detecting mild impairment that may be used to improve routine screening. We also compare the efficacy of classifying impairment using either a two-class (impaired versus non-impaired) or three-class using the Clinical Dementia Rating (CDR 0 versus CDR 0.5 versus CDR 1) approach. Methods: Supervised feature selection methods generated groups of cognitive measurements targeting impairment defined at CDR 0.5 and above. Random forest classifiers then generated predictions of impairment for each group using highly stochastic cross-validation, with group outputs examined using general linear models. Results: The strategy of combining impairment levels for two-class classification resulted in significantly higher sensitivities and negative predictive values, two metrics useful in clinical screening, compared to the three-class approach. Four features (delayed WAIS Logical Memory, trail-making, patient and informant memory questions), totaling about 15 minutes of testing time (~30 minutes with delay), enabled classification sensitivity of 94.53% (88.43% positive predictive value, PPV). The addition of four more features significantly increased sensitivity to 95.18% (88.77% PPV) when added to the model as a second classifier. Conclusion: The high detection rate paired with the minimal assessment time of the four identified features may act as an effective starting point for developing screening protocols targeting cognitive impairment defined at CDR 0.5 and above.

Takumi Ashizawa, Ataru Igarashi, Yukinori Sakata, Mie Azuma, Kenichi Fujimoto, Tsukasa Kobayashi, Yoshimasa Takase, Shunya Ikeda
Impact of the Severity of Alzheimer’s Disease on the Quality of Life, Activities of Daily Living, and Caregiving Costs for Institutionalized Patients on Anti-Alzheimer Medications in Japan
Abstract: Background: Alzheimer's disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals. Objective: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly. Methods: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients’ claims data. The patients were subcategorized into the following three groups according to the MMSE score: mild (21 ≤ MMSE ≤ 30), moderate (11 ≤ MMSE ≤ 20), and severe (0 ≤ MMSE ≤ 10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test. Results: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1 ± 6.4 years, 76.7% women) in the mild (n = 53, 84.0 ± 6.9 years, 71.7%), moderate (n = 118, 86.6 ± 5.9 years, 76.3%), and severe (n = 116, 86.6 ± 6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly. Conclusion: AD severity has an impact on QoL, ADL, and caregiving costs.

Dickson Wong*, Dana N. Broberg*, Jagroop Doad, Joseph U. Umoh, Miranda Bellyou, Chris J. D. Norley, David Holdsworth, Manuel Montero-Odasso, Olivier Beauchet, Cedric Annweiler, Robert Bartha (Handling Associate Editor: Benedict Albensi) *These authors contributed equally to this work.
Effect of Memantine Treatment and Combination with Vitamin D Supplementation on Body Composition in the APP/PS1 Mouse Model of Alzheimer’s Disease Following Chronic Vitamin D Deficiency
Abstract: Background: Vitamin D deficiency and altered body composition are common in Alzheimer’s disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-β exposure and glutamate toxicity. Objective: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. Methods: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n=14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin D-deficient group (n=14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n=14), while the other had both memantine and 10 IU/g vitamin D (n=14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. Results: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p<0.01) and absolute skeletal tissue mass (9.3% increase, p<0.05) and volume (9.2% increase, p<0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. Conclusion: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD.

Lin-Lin Li*, Ya-Hui Ma*, Yan-Lin Bi*, Fu-Rong Sun, Hao Hu, Xiao-He Hou, Wei Xu, Xue-Ning Shen, Qiang Dong, Lan Tan, Jiu-Long Yang, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Serum Uric Acid May Aggravate Alzheimer’s Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study
Abstract: Background: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. Objective: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. Methods: We analyzed cognitively intact participants (n=839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. Results: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p=0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p=0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1-42 (p=0.019) and Aβ1-42/Aβ1-40 (p=0.027) were decreased and CSF p-Tau/Aβ1-42 (p=0.009) and t-Tau/Aβ1-42 (p=0.043) were increased with the highest (>75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. Conclusion: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

Naoko Miyagawa, Takayoshi Ohkubo, Akira Fujiyoshi, Akihiko Shiino, Randi Chen, George Webster Ross, Bradley Willcox, Katsuyuki Miura, Hirotsugu Ueshima, Kamal Masaki (Handling Associate Editor: M. Cristina Polidori)
Factors Associated with Lower Cognitive Performance Scores Among Older Japanese Men in Hawaii and Japan
Abstract: Background: Few studies have compared factors related to cognitive function among people with similar genetic backgrounds but different lifestyles. Objective: We aimed to identify factors related to lower cognitive scores among older Japanese men in two genetically similar cohorts exposed to different lifestyle factors. Methods: This cross-sectional study of community-dwelling Japanese men aged 71-81 years included 2,628 men enrolled in the Kuakini Honolulu-Asia Aging Study based in Hawaii and 349 men in the Shiga Epidemiological Study of Subclinical Atherosclerosis based in Japan. We compared participant performance through Cognitive Abilities Screening Instrument (CASI) assessment in Hawaii (1991-1993) and Japan (2009-2014). Factors related to low cognitive scores (history of cardiovascular disease, cardiometabolic factors, and lifestyle factors) were identified with questionnaires and measurements. Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (ORs) of a low (<82) CASI score based on different factors. Results: CASI scores were lower in Hawaii than in Japan [21.2% (n=556) versus 12.3% (n=43), p<0.001], though this was not significant when adjusted for age and educational attainment (Hawaii 20.3% versus Japan 17.9%, p=0.328). History of stroke (OR=1.65, 95% confidence interval=1.19-2.29) was positively associated with low cognitive scores in Hawaii. Body mass index ≥25 kg/m2 tended to be associated with low cognitive scores in Japan; there was a significant interaction between the cohorts. Conclusion: Cognitive scores differences between cohorts were mostly explained by differences in educational attainment. Conversely, cardiovascular diseases and cardiometabolic factors differentially impacted cognitive scores among genetically similar older men exposed to different lifestyle factors.

Monica E. Nelson, Ross Andel, Zuzana Nedelska, Julie Martinkova, Katerina Cechova, Hana Markova, Veronika Matuskova, Tomas Nikolai, Ondrej Lerch, Martina Parizkova, Jan Laczo, Martin Vyhnalek, Jakub Hort
The Association Between Homocysteine and Memory in Older Adults
Abstract: Background: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia. Objective: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ε4 allele, B vitamins, creatinine, total cholesterol, or triglycerides. Methods: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n=60) or amnestic mild cognitive impairment (aMCI; n=144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation. Results: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b=-0.03, SE=0.01, p=0.017) and in participants with SCD (b=-0.06, SE=0.03, p=0.029), but less so in aMCI (b=-0.03, SE=0.02, p=0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b=-0.04, SE=0.02, p=0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ε4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b=-0.04, SE=0.02, p=0.046), but not at/above the median (p=0.247). Conclusion: Higher homocysteine levels may adversely influence memory performance, particularly in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention.