Volume 88, Number 2, IN PROGRESS

Review
Jing Hao, Yanping Guo*, Keke Guo, Qingcheng Yang
Peripheral Inflammatory Biomarkers of Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease of unknown pathological origin. The clinical diagnosis of AD is time-consuming and needs to a combination of clinical evaluation, psychological testing, and imaging assessments. Biomarkers may be good indicators for the clinical diagnosis of AD; hence, it is important to identify suitable biomarkers for the diagnosis and treatment of AD. Peripheral inflammatory biomarkers have been the focus of research in recent years. This review summarizes the role of inflammatory biomarkers in the disease course of AD.

Review
Narjes Baazaoui, Khalid Iqbal
COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences
Abstract: COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection.

Systematic Review
Blossom C.M. Stephan, Eugene Y.H. Tang, Eduwin Pakpahan, Bijetri Biswas, Alisha Gupta, Andrea McGrattan, Alessandro Bosco, Connor D. Richardson, Louise Robinson, Mario Siervo
Secular Trends in Dementia Free Cognitive Function in Older Adults: A Systematic Review
Abstract: Background: Although numerous studies have reported a decrease in dementia risk in the last two decades, it is unclear whether dementia-free cognitive function is also changing across generations. Objective: The objective was to systematically evaluate the published data on generational differences in cognitive function in the older population. Methods: Searches were performed on PubMed, Embase, and PsychInfo for articles published in English before 20 June 2021. Included studies were from population-based samples that reported generational differences in cognition in individuals without dementia, aged ≥60 years. Results: 28,101 studies were identified and 15 selected covering the period from 1971 to 2015: including studies from China, Europe, and the USA. The results show generally consistent findings of improvements or stability in dementia free cognitive function in later versus earlier born generations, but not for all cognitive domains. Prevalence of mild cognitive impairment and cognitive impairment no dementia has remained stable in the USA, UK, and China over the last two decades. Prevalence of vascular related mild cognitive impairment has increased in China. Improvements in cognition may only partially be explained by increased educational attainment across generations. Conclusion: This review provides evidence for generational effects in dementia-free cognitive function, predominately stability or improvements in performance, in later compared to earlier born individuals across different world regions. There is an urgent need to determine the factors driving such changes and whether they are being experienced in all world regions, particularly low- and middle-income countries where the burden of cognitive impairment is greatest and rising.

Hypothesis
Philip Serwer, Elena T. Wright, Barbara Hunter
Additions to Alpha-Sheet Based Hypotheses for the Cause of Alzheimer’s Disease
Abstract: Protein amyloid-β (Aβ) oligomers with β-sheet-like backbone (β-structured) form extracellular amyloid plaques associated with Alzheimer’s disease (AD). However, the relationship to AD is not known. Some investigations suggest that the toxic Aβ component has α-sheet-like backbone (α-structured) subsequently detoxified by intracellular α-to-β conversion before plaque formation. Our objective is to compare this latter hypothesis with observations made by electron microscopy of thin sections of AD-cerebral cortex. We observe irregular, 200-2,000 nm, intracellular, lipofuscin-like inclusions. Some are light-staining and smooth. Others are dark-staining and made granular by fibers that are usually overlapping and are sometimes individually seen. Aspects unusual for lipofuscin include 1) dark and light inclusions interlocking as though previously one inclusion, 2) dark inclusion-contained 2.6 nm thick sub-fibers that are bent as though α-structured, and 3) presence of inclusions in lysosomes and apparent transfer of dark inclusion material to damaged, nearby lysosomal membranes. These data suggest the following additions to α-structure-based hypotheses: 1) Lipofuscin-associated, α-structured protein toxicity to lysosomal membranes is in the chain of AD causation; 2) α-to-β detoxification of α-structured protein occurs in lipofuscin and causes dark-to-light transition that, when incomplete, is the origin of cell-to-cell transmission essential for development of AD.

Hypothesis
Yi-Liang Tsai, Chieh-Tsung Yen, Yuh-Feng Wang
Astrocyte Dysregulation and Calcium Ion Imbalance May Link the Development of Osteoporosis and Alzheimer’s Disease
Abstract: The typical symptoms of patients with Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and tau hyperphosphorylation. However, recent studies show that these symptoms are not the cause of the disease but are generated after the pathogenesis. Compared with other types of dementia, AD has the obvious features of pineal gland calcification and decreased melatonin production. The pineal gland is mainly composed of pinealocytes that release melatonin and astrocytes. Astrocytes function to maintain a balanced concentration of calcium ions, provide nerve cell nutrients, and migrate nutrients in vivo. Calcium ions are among the most important neurotransmitters. Once triggered, a calcium wave can be formed between astrocytes to activate other astrocytes to transmit information. Most calcium is stored in the skeleton. Bone tissue is composed mainly of osteocytes, osteoblasts, and osteoclasts. Of these, osteocyte is a kind of astrocyte which regulates the activity of osteoclasts and osteoblasts. The pineal gland is composed mainly of astrocytes; osteocytes are also a kind of astrocyte. Therefore, we conclude that when astrocytes are gradually disabled, calcium may be lost from the bones, prompting osteoporosis. The calcium ions then released into the blood may accumulate and cause ectopic calcification in the pineal gland, which promotes the occurrence of AD. Finally, this study used aspects of drugs and hormones (bone and calcium metabolism hormones and melatonin) to infer the hypothesis, which proposes that astrocyte dysregulation promotes the long-term imbalance of calcium ions in vivo and leads to osteoporosis and AD.

Short Communication
Joost M. Riphagen, Roy W.E. van Hooren, Gunter Kenis, Frans R.J. Verhey, Heidi I.L. Jacobs
Distinct Patterns Link the BDNF Val66Met Polymorphism to Alzheimer’s Disease Pathology
Abstract: The brain-derived neurotropic growth factor (BDNF) gene has been linked to dementia, inflammation, and Apolipoprotein E (APOE) ε4 status. We used cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and phosphorylated tau (p-tau) to investigate associations with BDNF polymorphisms and modifications by APOE ε4 or inflammation in a memory clinic population (n=114; subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease). We found distinct pathways to Alzheimer’s disease pathology: Val-Met displayed lower CSF-Aβ42 in APOE ε4+ carriers, independent of p-tau, while Val-Val displayed greater p-tau at higher IL-6 and sub-threshold Aβ42. This may contribute to resolving some inconsistencies in the BDNF literature and provide possible inroads to specific Aβ and tau interventions depending on BDNF polymorphism.

Commentary
Poul F. Høilund-Carlsen, Mona-Elisabeth Revheim, Abass Alavi
Alzheimer’s Disease at a Crossroad: Time to Part from Amyloid to More Promising Aspects—Atherosclerosis for a Start
Abstract: Three decades with the amyloid hypothesis, nearly two with amyloid-PET imaging, and one with testing of anti-amyloid therapy have not yielded benefits to patients with Alzheimer’s disease (AD). It is time to focus on more promising options, e.g., infection, low dose radiation, and atherosclerosis. The relevance of the latter in managing AD has fluctuated from being significant to insignificant. Current methodologies for detecting cerebral atherosclerosis reflect advanced changes in only major arteries. In contrast, 18F-sodium fluoride PET imaging assessing early-stage cerebral atherosclerosis regionally or in the entire vascular bed may provide new insight in this age-related process in dementia.

Miharu Nakanishi, Syudo Yamasaki, Shuntaro Ando, Kaori Endo, Marcus Richards, Mariko Hiraiwa-Hasegawa, Kiyoto Kasai, Atsushi Nishida
Neighborhood Social Cohesion and Dementia-Related Stigma Among Mothers of Adolescents in the Pre- and Current COVID-19 Period: An Observational Study Using Population-Based Cohort Data
Abstract: Background: Middle-aged adults may be the ideal target group for dementia-related stigma reduction interventions to encourage the utilization of services among those who may become family caregivers. Neighborhood social cohesion may diminish dementia-related stigma, particularly in terms of perceived public attitudes. The COVID-19 pandemic can further negatively impact perceived public stigma. Objective: To investigate the association between neighborhood social cohesion and dementia-related stigma during the pre- and current COVID-19 period. Methods: We employed a cross-sectional design using data from a large population-based cohort, the Tokyo Teen Cohort, in Japan. Overall, 2,469 mothers of 16-year-old adolescents self-completed a questionnaire comprising nine dementia-related stigma questions evaluating perceived public and personal attitudes. Neighborhood social cohesion was assessed using a five-item instrument. The participants were divided into two groups according to the time of assessment: prior to the pandemic’s onset (February 2019–March 2020) and during the pandemic (April 2020–July 2021). A multiple regression analysis of stigma was performed using neighborhood social cohesion as an independent variable, and caring experience, age, educational level, and working status as covariates. Results: Personal and perceived public stigma were significantly lower in participants who perceived greater neighborhood social cohesion. However, level of personal and perceived public stigma did not differ between pre- and during the pandemic period. Conclusion: Neighborhood social cohesion may be a modifiable factor for dementia-related stigma. A localized intervention to enhance social cohesion in the neighborhood community would promote the utilization of services among those who may become family caregivers.

Anna Tsiakiri, Pinelopi Vlotinou, Aikaterini Terzoudi, Ioannis Heliopoulos, Konstantinos Vadikolias
Cognitive, Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with Neurocognitive Disorders
Abstract: Background: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions. Objective: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders. Methods: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018–May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020¬–May 2021) during the second wave of COVID-19. Neuropsychological tests were performed at baseline and six months after baseline. Results: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p=0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p=0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p=0.229) and Geriatric Depression Scale (GDS; p=0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group. Conclusion: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences.

Amal A. Wanigatunga, Fangyu Liu, Hang Wang, Jacek K. Urbanek, Yang An, Adam P. Spira, Ryan J. Dougherty, Qu Tian, Abhay Moghekar, Luigi Ferrucci, Eleanor M. Simonsick, Susan M. Resnick, Jennifer A. Schrack (Handling Associate Editor: M. Arfan Ikram)
Daily Physical Activity Patterns as a Window on Cognitive Diagnosis in the Baltimore Longitudinal Study of Aging (BLSA)
Abstract: Background: Gradual disengagement from daily physical activity (PA) could signal present or emerging mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Objective: This study examined whether accelerometry-derived patterns of everyday movement differ by cognitive diagnosis in participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods: Activity patterns, overall and by time-of-day, were cross-sectionally compared between participants with adjudicated normal cognition (n=549) and MCI/AD diagnoses (n=36; 6 participants [17%] living with AD) using covariate-adjusted regression models. Results: Compared to those with normal cognition, those with MCI/AD had 2.1% higher activity fragmentation (SE=1.0%, p=0.036) but similar mean total activity counts/day (p=0.075) and minutes/day spent active (p=0.174). Time-of-day analyses show MCI/AD participants had lower activity counts and minutes spent active during waking hours (6:00 am-5:59 pm; p<0.01 for all). Also, they had lower activity fragmentation from 12:00-5:59 am (p<0.001), but higher fragmentation from 12:00-5:59 pm (p=0.026). Conclusion: Differences in the timing and patterns of physical activity throughout the day linked to MCI/AD diagnoses warrant further investigation into potential clinical utility.

Gabrielle Frame, Adam Schuller, Matthew A. Smith, Samuel D. Crish, Christine M. Dengler-Crish
Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice
Abstract: Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cell (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex- matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.

Ernesto García-Roldán, José Enrique Arriola-Infante, Carlota Méndez-Barrio, Fátima Montiel-Herrera, Gonzalo Mendoza-Vázquez, Alba Marta Marín-Cabañas, Silvia Rodrigo-Herrero, Andrea Luque-Tirado, María Bernal Sánchez-Arjona, Didier Maillet, Emilio Franco-Macías
Testing Visual Binding by the TMA-93 in People Aged 75 and Over
Abstract: Background: TMA-93 examines relational binding using images. The test has been proven to be discriminative for diagnosing early Alzheimer’s disease by biomarkers. Norms for this test are available, but the elderly, at high risk for Alzheimer’s disease, have not yet been widely represented. Objective: To extend normative data on the TMA-93 for people aged 75 and over. Methods: An extension of the Spanish TMA-93 normative study was undertaken. Only cognitively unimpaired people aged 75 and over were included. Age, gender, and educational attainment were registered as socio-demographic variables. Using histograms analysis, median comparisons, and linear regression analysis, we selected variables that demonstrated influence on TMA-93 total scores and provided percentile-base reference data according to combinations of those variables. Results: We included 431 new participants, resulting in a total sample of 657 individuals (median age=78, interquartile range=76-81, range=75-93). Percentile-base reference data stratified by a combination of age ranges (75-79, n=428; and ≥80 years, n=229), and educational attainment (first grade, n=195) revealed that participants achieved a minimum TMA-93 total score of 26/30 at the 50th-percentile regardless of stratum. At the 10th-percentile, a maximum of 24/30 was achieved in the more educated stratum contrasting with a minimum of 19/30 in the less educated stratum. Conclusion: Although mitigated by lower levels of education, performance on the TMA-93 is widely preserved in cognitively unimpaired people aged 75 and over. The test could facilitate the screening of elderly patients with memory complaints.

Laura D. Gamble, Sophie Parker, Catherine Quinn, Holly Q. Bennett, Anthony Martyr, Serena Sabatini, Claire Pentecost, Rachel Collins, Eleanor Dawson, Anna Hunt, Louise Allan, Alistair Burns, Rachael Litherland, Christina Victor, Fiona E. Matthews, Linda Clare
A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study
Abstract: Background: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. Objective: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. Methods: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the ‘pre-pandemic group’ (n=312), assessed at two time points prior to the pandemic, and the ‘pandemic group’, assessed prior to and several months into the pandemic (n=156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, was investigated using mixed effect modelling. Results: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. Conclusion: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.

Jesús Gonzalez-Moreno, Encarnacion Satorres, Gema Soria-Urios, Juan C. Meléndez
Cognitive Stimulation Program Presented Through New Technologies in a Group of People with Moderate Cognitive Impairment
Abstract: Background: Cognitive stimulation is one of the non-pharmacological therapies recommended for intervention in dementia, consisting of activities involving different cognitive domains and involving brain activation. New technologies can be very useful in this field, favoring intervention tasks. Objective: The objective of this work is to test the effectiveness of a cognitive stimulation intervention mediated with new technologies on a group of people with moderate dementia. Methods: This is a quantitative, quasi-experimental study with a control and treatment group, with three measurement times (pre, post, and follow-up months after the end of the intervention). Ninety-eight subjects with moderate dementia were randomly assigned to the treatment group (N = 50) and the control group (N = 48). The treatment group received 16 intervention sessions including attention, executive function, and memory tasks, which were presented using new technologies and the activity was conducted in a group setting. Control group remained on a waiting list. The evaluators did not know which group each subject belonged to. All participants were assessed with a battery of neuropsychological tests. Results: The results show an improvement in post-intervention outcomes in the treatment group compared to the control group on cognitive variables. No differences were found in mood depression. These results fade overtime after a few months without intervention. Conclusion: This type of intervention is useful to maintain cognitive functioning using new technologies and in a group setting, which favors the intervention. The improvements of the intervention disappear at follow-up, which would indicate the need to maintain the intervention over time.

Mackenzie E. Fowler, Nicole C. Wright, Kristen Triebel, Gabrielle B. Rocque, Ryan Irvin, Richard E. Kennedy (Handling Associate Editor: Erin Abner)
The Relationship Between Prior Cancer Diagnosis and All-Cause Dementia Progression Among US Adults
Abstract: Background: Cancer-related cognitive impairment (CRCI), a frequent effect of cancer and its treatments, shares common cognitive symptoms with dementia syndromes. Cross-sectional studies demonstrate an inverse relationship between cancer and dementia. However, the longitudinal relationship between dementia decline and cancer has not been investigated. Objective: To evaluate the association between cancer and longitudinal progression of dementia. Methods: We extracted electronic health record data from July 2003 to February 2020 from a single academic medical center. We identified dementia and cancer history prior to dementia using ICD-9/10 codes. We measured cognitive decline with the Alabama Brief Cognitive Screener (ABCs). We used adjusted linear mixed models to estimate baseline cognition and rate of progression by cancer history, including differences by race. Results: The study included 3,809 participants with dementia, of which 672 (17.6%) had cancer history. Those with cancer history had higher baseline cognition (β: 0.62, 95% CI: -0.02-1.25), but similar rate of decline. Non-Hispanic Blacks had lower cognitive scores at baseline and throughout follow-up regardless of cancer status compared to non-Hispanic Whites and other races/ethnicities with and without cancer history. Conclusion: In this longitudinal retrospective study, participants with cancer history demonstrate better cognition at dementia diagnosis and no difference in cognitive decline than those without cancer history. Smoking and comorbidities attenuate this association and results indicate non-Hispanic Blacks have worse cognitive outcomes in dementia regardless of cancer history than other race/ethnicity groups. Further exploration of the role of smoking, comorbidities, and race/ethnicity on cancer and dementia-related cognitive decline is needed.

Yilin Wang*, Lei Li*, Xiaodong Zhao, Shaomei Sui, Qi Wang, Guizhi Shi, Huilian Xu, Xiujun Zhang Yan He, Jinsong Gu (Handling Associate Editor: Jianping Jia) *These authors contributed equally to this work.
Intestinal Microflora Changes in Patients with Mild Alzheimer’s Disease in a Chinese Cohort
Abstract: Background: Understanding the relationship between Alzheimer's disease (AD) and intestinal flora is still a major scientific topic that continues to advance. Objective: To determine characterized changes in the intestinal microbe community of patients with mild AD. Methods: Comparison of the 16S ribosomal RNA (rRNA) high-throughput sequencing data was obtained from the Illumina MiSeq platform of fecal microorganisms of the patients and healthy controls (HC) which were selected from cohabiting caregivers of AD patients to exclude environmental and dietary factors. Results: We found that the abundance of several bacteria taxa in AD patients was different from that in HC at the genus level, such as Anaerostipes, Mitsuokella, Prevotella, Bosea, Fusobacterium, Anaerotruncus, Clostridium, and Coprobacillus. Interestingly, the abundance of Akkermansia, an emerging probiotic, increased significantly in the AD group compared with that in the HC group. Meanwhile, the quantity of traditional probiotic Bifidobacteria of the AD group also rose. Conclusion: These alterations in fecal microbiome of the AD group indicate that patients with mild AD have unique gut microbial characteristics. These specific AD-associated intestinal microbes could serve as novel potential targets for early intervention of AD.

Daniella Castro Araújo, Adriano Alonso Veloso, Karina Braga Gomes, Leonardo Cruz de Souza, Nivio Ziviani, Paulo Caramelli, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Barbara Borroni)
A Novel Panel of Plasma Proteins Predicts Progression in Prodromal Alzheimer’s Disease
Abstract: Background: A cheap and minimum-invasive method for early identification of Alzheimer's disease (AD) pathogenesis is key to disease management and the success of emerging treatments targeting the prodromal phases of the disease. Objective: To develop a machine learning-based blood panel to predict the progression from mild cognitive impairment (MCI) to dementia due to AD within a four-year time-to-conversion horizon. Methods: We created over one billion models to predict the probability of conversion from MCI to dementia due to AD and chose the best-performing one. We used Alzheimer’s Disease Neuroimaging Initiative (ADNI) data of 379 MCI individuals in the baseline visit, from which 176 converted to AD dementia. Results: We developed a machine learning-based panel composed of 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, Interleukin-3, Interleukin-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), and which yielded an AUC of 0.91, accuracy of 0.91, sensitivity of 0.84, and specificity of 0.98 for predicting the risk of MCI patients converting to dementia due to AD in a horizon of up to four years. Conclusion: The proposed machine learning model was able to accurately predict the risk of MCI patients converting to dementia due to AD in a horizon of up to four years, suggesting that this model could be used as a minimum-invasive tool for clinical decision support. Further studies are needed to better clarify the possible pathophysiological links with the reported proteins.

Alette M. Wessels, Mark Belger, Joseph A. Johnston, Youying Yu, Dorene M. Rentz, Sherie A. Dowsett, Julie Chandler
Demonstration of Clinical Meaningfulness of the Integrated Alzheimer’s Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes
Abstract: Background: The integrated Alzheimer’s Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures. Objective: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study. Methods: Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change. Results: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life. Conclusion: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.

Qing Wang*, Yachen Shi*, Xinyang Qi*, Lingyu Qi, Xiang Chen, Jingping Shi, Chunming Xie, Zhijun Zhang *These authors contributed equally to this work.
Platelet-Derived Amyloid-β Protein Precursor as a Biomarker of Alzheimer’s Disease
Abstract: Background: Platelet proteins may be associated with Alzheimer's disease (AD) pathology. Objective: To investigate the relationship between platelet proteins and cerebrospinal fluid (CSF) biomarkers of AD and cognition in individuals with memory decline to identify effective screening methods for detecting the early stages of the disease. Methods: We classified 68 participants with subjective memory decline according to the ATN framework determined by CSF amyloid-β (A), CSF p-tau (T), and t-tau (N). All participants underwent Mini-Mental State Examination (MMSE) and platelet-related protein content testing. Results: Eighteen participants had normal AD biomarkers (NCs), 24 subjects had non-AD pathologic changes (non-AD), and 26 subjects fell within the Alzheimer’s continuum (AD). The platelet amyloid-β protein precursor (AβPP) ratio in the AD group was significantly lower than in the non-AD and NCs groups, and positively correlated with MMSE scores and CSF amyloid-β42 level, which could affect MMSE scores through CSF amyloid-β42. Levels of platelet phosphorylated-tau 231 and ser396/404 phosphorylated tau were elevated in both AD and non-AD compared to NCs. Additionally, the receiver operating characteristic analysis demonstrated that the platelet AβPP ratio was a sensitive identifier for differentiating the AD from NCs (AUC = 0.846) and non-AD (AUC = 0.768). And ser396/404 phosphorylated tau could distinguish AD from NCs. Conclusion: Our study was the first to find an association between platelet AβPP ratio and CSF biomarkers of AD, which contribute to the understanding of the peripheral changes in AD. These findings may help to discover potential feasible and effective screening tools for AD.

Shunichiro Shinagawa, Ito Kawakami, Emi Takasaki, Masahiro Shigeta, Tetsuaki Arai, Manabu Ikeda
The Diagnostic Patterns of Referring Physicians and Hospital Expert Psychiatrists Regarding Particular Frontotemporal Lobar Degeneration Clinical and Neuropathological Subtypes
Abstract:Background: It is important to make accurate clinical diagnosis of frontotemporal lobar degeneration (FTLD), which in turn, leads to future therapic approaches. The FTLD cases are frequently inaccurately identified, but the frequency of this misidentification according to the underlying pathological subtypes is still unclear. Objective: We aimed to quantify the accuracy of behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) diagnoses by both the patients' referring physicians and hospital expert psychiatrists, and we investigated whether the physicians' and psychiatrists' diagnostic patterns are associated with a specific neuropathology. Methods: We retrospectively analyzed the cases of a series of Japanese patients with pathologically diagnosed FTLD (n=55): the bvFTD group (n=47) consisted of patients with FTLD-tau (n=20), FTLD-TDP (TAR DNA-binding protein of 43-kDA) (n=19), and FTLD-FUS (fused in sarcoma) (n=8). The svPPA patients (n=8) all had FTLD-TDP. Results: Only 31% of the patients' referring physicians mentioned FTD syndrome. The referring psychiatrists and neurologists showed similar diagnostic accuracy. High diagnostic accuracy was observed for the TDP pathology group (mainly svPPA patients). The FTLD-FUS patients were more likely to be diagnosed as having a psychiatric disorder by referring physicians. The hospital expert psychiatrists' accuracy for identifying FTLD-tau pathology was low. Conclusion: The results of our analyses revealed a specific diagnostic pattern associated with particular FTLD pathological subtypes, which will help to improve non-specialists' diagnostic ability.

Sanna Hannonen*, Sami Andberg*, Virve Kärkkäinen*, Minna Rusanen, Juha-Matti Lehtola, Toni Saari, Ville Korhonen, Laura Hokkanen, Merja Hallikainen, Tuomo Hänninen, Ville Leinonen, Kai Kaarniranta, Roman Bednarik, Anne M. Koivisto *These authors contributed equally to this work.
Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer’s Disease
Abstract: Background: Wide-ranging functional defects in eye movements have been reported in Alzheimer’s disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking. Objective: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD. Methods: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE=28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE=27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed. Results: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p<0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p<0.05). The KD error scores in the AD group differed significantly (p<0.01) from the other groups. Conclusion: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics.

Taha I. Huda, Michael J. Diaz, Etienne C. Gozlan, Andrea Chobrutskiy, Boris I. Chobrutskiy, George Blanck
Immunogenomics Parameters for Patient Stratification in Alzheimer’s Disease
Abstract: Background: Despite the fact that only modest adaptive immune system related approaches to treating Alzheimer’s disease (AD) are available, an immunogenomics approach to the study of AD has not yet substantially advanced. Objective: Thus, we sought to better understand adaptive immune receptor chemical features in the AD setting. Methods: We characterized T-cell receptor alpha (TRA) complementarity determining region-3 (CDR3) physicochemical features and identified TRA CDR3 homology groups, represented by TRA recombination reads extracted from 2,665 AD-related, blood- and brain-derived exome files. Results: We found that a higher isoelectric value for the brain TRA CDR3s was associated with a higher (clinically worse) Braak stage and that a number of TRA CDR3 chemical homology groups, in particular representing bloodborne TRA CDR3s, were associated with higher or lower Braak stages. Lastly, greater chemical complementarity of both blood- and brain-derived TRA CDR3s and tau, based on a recently described CDR3-candidate antigen chemical complementarity scoring process (http://adaptivematch.com), was associated with higher Braak stages. Conclusion: Overall, the data reported here raise the questions of (a) whether progression of AD is facilitated by the adaptive immune response to tau; and (b) whether assessment of such an anti-tau immune response could potentially serve as a basis for adaptive immune receptor related, AD risk stratification?

Louis Jacob, Lee Smith, Ai Koyanagi, Marcel Konrad, Josep Maria Haro, Jae Il Shin, Karel Kostev
Sex-Differential Associations Between Body Mass Index and the Incidence of Dementia
Abstract: Background: Little is known about the sex differences in the association between body mass index (BMI) and dementia in late life. Objective: Therefore, this retrospective cohort study aimed to analyze associations between BMI and dementia in older women and men separately in general practices in Germany. Methods: This study included patients followed in one of 832 general practices in Germany between 2006 and 2019 (index date: first visit date). Study variables included dementia (dependent variable), BMI (independent variable), age, sex, and comorbidities (control variables). Kaplan-Meier curves and adjusted Cox regression analyses were conducted to analyze associations between BMI and the 10-year incidence of dementia in women and men, separately. Results: There were 296,767 patients included in this study (mean [standard deviation] age 70.2 [5.9] years; 54.3% women). The proportion of underweight, normal weight, overweight, and obesity was 0.9%, 25.5%, 41.5%, and 32.1%, respectively. The 10-year incidence of dementia significantly decreased with increasing BMI, from 11.5% in women with underweight to 9.1% in those with obesity (log-rank p<0.001). Respective figures in men were 12.0% and 8.2% (log-rank p<0.001). In women, only overweight (versus normal weight) was significantly associated with dementia (HR=0.93, 95%CI=0.88-0.97). In contrast, in men, the only BMI category significantly associated with the incidence of dementia was underweight (HR=1.58, 95% CI=1.11-2.25). Conclusion: In this study conducted in Germany, overweight was negatively associated with dementia in women, whereas there was a positive underweight-dementia relationship in men. More data are needed to confirm or refute these findings in other settings.

Lin Sun*, Chunni Guo*, Yan Song*, Jianhua Sheng, Shifu Xiao, Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Blood BMP6 Associated with Cognitive Performance and Alzheimer’s Disease Diagnosis: A Longitudinal Study of Elders
Abstract: Background: Bone morphogenetic protein (BMP) plays important roles in the pathology of Alzheimer’s disease (AD). Objective: We sought blood BMP6 involved in the processes underlying cognitive decline and detected them in association with AD. Methods: A total of 309 participants in Shanghai Mental Health Center (SMHC) and 547 participants in Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort were included. Blood BMP6 and cognitive functions were measured in all subjects of both cohorts at baseline, and in 482 subjects of ADNI cohort after one year. A total of 300 subjects in ADNI cohort were detected cerebrospinal fluid (CSF) tau biomarker, and 244 received 1-year follow-up. Results: AD patients had lower levels of blood BMP6 compared to normal controls, and BMP6 was positively associated with cognitive functions. Longitudinal BMP6 combing with APOE genotype could distinguish probable AD from normal controls. The influence of blood BMP6 on cognition was modulated by tau pathology. Conclusion: Blood BMP6 was associated with cognitive performance and identified as a potential predictor for probable AD.