Volume 95, Number 3, IN PRESS

Shameka L. Cody, Gabe H. Miller, Pariya L. Fazeli, Ge Wang, Wei Li, Burel R. Goodin, David E. Vance
Preventing Neurocognitive Decline in Adults Aging with HIV: Implications for Practice and Research
Abstract: Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer’s disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer’s disease in PLWH.

Sneha R. Sharma, Yu Chen
Rheumatoid Arthritis and Cognitive Impairment or Dementia: An Updated Review of Epidemiological Data
Abstract: Rheumatoid arthritis (RA) is hypothesized to be associated with cognitive impairment and dementia, including Alzheimer’s disease, through shared biological processes related to inflammation. It is important to elucidate this potential relationship as both conditions confer increased morbidity and even mortality among older adults. This narrative review provides a survey of recent epidemiologic studies, examining the association between rheumatoid arthritis and either dementia or cognitive impairment. Sixteen studies were included after searching in PubMed and EMBASE. All were published between 2012 and 2022 and were characterized as epidemiologic studies (either cohort, cross-sectional, or case-control). Studies varied in location, design, measures of exposure and outcome, and covariates considered. Of the 16 studies included, only five found statistically significant positive associations between RA and dementia or cognitive impairment. One study found an inverse relationship, while five studies found no associations at all. The remaining five studies found variable statistically significant associations between demographic or RA disease characteristics and cognitive measures. Given these mixed findings, further studies at both the mechanistic and population level are needed to clarify the possible shared biological underpinnings of these two conditions.

Yingying Wu, Ulrich L.M. Eisel
Microglia-Astrocyte Communication in Alzheimer’s Disease
Abstract: Microglia and astrocytes are regarded as active participants in the central nervous system under various neuropathological conditions, including Alzheimer’s disease (AD). Both microglia and astrocyte activation have been reported to occur with a spatially and temporarily distinct pattern. Acting as a double-edged sword, glia-mediated neuroinflammation may be both detrimental and beneficial to the brain. In a variety of neuropathologies, microglia are activated before astrocytes, which facilitates astrocyte activation. Yet reactive astrocytes can also prevent the activation of adjacent microglia in addition to helping them become activated. Studies describe changes in the genetic profile as well as cellular and molecular responses of these two types of glial cells that contribute to dysfunctional immune crosstalk in AD. In this paper, we construct current knowledge of microglia-astrocyte communication, highlighting the multifaceted functions of microglia and astrocytes and their role in AD. A thorough comprehension of microglia-astrocyte communication could hasten the creation of novel AD treatment approaches.

Systematic Review
Roman Sattarov, Håkan Toresson, Camilla Orbjörn, Niklas Mattsson-Carlgren
Direct Conversion of Fibroblast into Neurons for Alzheimer’s Disease Research: A Systematic Review
Abstract: Background: Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder without a cure. Innovative disease models, such as induced neurons (iNs), could enhance our understanding of AD mechanisms and accelerate treatment development. However, a review of AD human iN studies is necessary to consolidate knowledge. Objective: The objective of this review is to examine the current body of literature on AD human iN cells and provide an overview of the findings to date. Methods: We searched two databases for relevant studies published between 2010 and 2023, identifying nine studies meeting our criteria. Results: Reviewed studies indicate the feasibility of generating iNs directly from AD patients' fibroblasts using chemical induction or viral vectors. These cells express mature neuronal markers, including MAP-2, NeuN, synapsin, and tau. However, most studies were limited in sample size and primarily focused on autosomal dominant familial AD (FAD) rather than the more common sporadic forms of AD. Several studies indicated that iNs derived from FAD fibroblasts exhibited abnormal amyloid-β metabolism, a characteristic feature of AD in humans. Additionally, elevated levels of hyperphosphorylated tau, another hallmark of AD, were reported in some studies. Conclusion: Although only a limited number of small-scale studies are currently available, AD patient-derived iNs hold promise as a valuable model for investigating AD pathogenesis. Future research should aim to conduct larger studies, particularly focusing on sporadic AD cases, to enhance the clinical relevance of the findings for the broader AD patient population. Moreover, these cells can be utilized in screening potential novel treatments for AD.

Systematic Review
Federico Emanuele Pozzi, Ildebrando Appollonio, Carlo Ferrarese, Lucio Tremolizzo (Handling Associate Editor: Helen Macpherson)
Can Traditional Board Games Prevent or Slow Down Cognitive Impairment? A Systematic Review and Meta-Analysis
Abstract: Background: Traditional board games can entail significant skills encompassing several cognitive functions across different domains. Therefore, they may potentially represent effective cognitive interventions in the aging population with or without Alzheimer’s disease or other types of dementia. Objective: We aimed at verifying the hypothesis that traditional board games can prevent or slow down cognitive decline, through a systematic review on traditional board games and dementia. Methods: We searched five databases with tailored search strings. We included studies assessing the impact of board games on elderly subjects at risk of or suffering from cognitive impairment, or subjects with cognitive impairment irrespective of age. Studies where the effect of board games was not separated by cards or other games were excluded. A meta-analysis was performed for specific cognitive and non-cognitive outcomes. Results: Board games improved mental function, as measured by Montreal Cognitive Assessment (p=0.003) and Mini-Mental State Examination (p=0.02). Ska and Go improved Trail Making Test – A, while Mahjong improved executive functions. There was no consistent effect across different games on Digit Span or Categorical Fluency. Chess improved quality of life measured with the WHO-QoL-OLD scale (p<0.00001). Mahjong temporarily improved depressive symptoms. Go increased BDNF levels and left middle temporal gyrus and bilateral putamen metabolism. Conclusions: Traditional board games may slow global cognitive decline and improve the quality of life in elderly subjects. Different games have varying impacts on specific cognitive domains, possibly mediated by functional and biological factors.

Short Communication
Rifat B. Alam, Abir Rahman, Susan Aguiñaga, Andiara Schwingel
The Moderating Role of Race and Ethnicity in the Association Between Cognitive Performance and Functional Abilities in Later Life
Abstract: This study examined ethnic/racial influences on the relationship of cognitive performance and functional abilities of 2,713 older individuals from the National Health and Nutrition Examination Survey (NHANES). Functional domains included activities of daily living (ADL), instrumental ADL, and leisure and social activities. In adjusted logistic regression models, low cognitive performance as assessed by the Digit Symbol Substitution Test was found significantly associated with functional limitation in each domain. However, moderation analysis revealed that being Hispanic and non-Hispanic Black may weaken this association demonstrating protective effects of underrepresented ethnic/racial status. Future studies should investigate perceived discrimination and resilience.

Neda Heidarzadeh, Sylvie Ratté
‘Eye-Tracking’ with Words for Alzheimer’s Disease Detection: Time Alignment of Words Enunciation with Image Regions During Image Description Tasks
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that results in cognitive decline, dementia, and eventually death. Diagnosing early signs of AD can help clinicians to improve the quality of life. Objective: We developed a non-invasive approach to help neurologists and clinicians to distinguish probable AD patients and healthy controls (HC). Methods: The patients' gaze points were followed based on the words they used to describe the Cookie Theft (CT) picture description task. We hypothesized that the timing of words enunciation aligns with the participant's eye movements. The moments that each word was spoken were then aligned with specific regions of the image. We then applied machine learning algorithms to classify probable AD and HC. We randomly selected 60 participants (30 AD and 30 HC) from the Dementia Bank (Pitt Corpus). Results: Five main classifiers were applied to different features extracted from the recorded audio and participants' transcripts (AD and HC). Support vector machine and logistic regression had the highest accuracy (up to 80% and 78.33%, respectively) in three different experiments. Conclusions: In conclusion, point-of-gaze can be applied as a non-invasive and less expensive approach compared to other available methods (e.g., eye tracker devices) for early-stage AD diagnosis.

Jiani Bei, Ernesto G. Miranda-Morales, Qini Gan, Yuan Qiu, Sorosh Husseinzadeh, Jia Yi Liew, Qing Chang, Balaji Krishnan, Angelo Gaitas, Subo Yuan, Michelle Felicella, Wei Qiao Qiu, Xiang Fang, Bin Gong
Circulating Exosomes from Alzheimer’s Disease Suppress Vascular Endothelial-Cadherin Expression and Induce Barrier Dysfunction in Recipient Brain Microvascular Endothelial Cell
Abstract: Background: Blood-brain barrier (BBB) breakdown is a crucial aspect of Alzheimer's disease (AD) progression. Dysfunction in BBB is primarily caused by impaired tight junction and adherens junction proteins in brain microvascular endothelial cells (BMECs). The role of adherens junctions in AD-related BBB dysfunction remains unclear. Exosomes from senescent cells have unique characteristics and contribute to modulating the phenotype of recipient cells. However, it remains unknown if and how these exosomes cause BMEC dysfunction in AD. Objective: This study aimed to investigate the impact of AD circulating exosomes on brain endothelial dysfunction. Methods: Exosomes were isolated from sera of AD patients and age- and sex-matched cognitively normal controls using size-exclusion chromatography. The study measured the biomechanical nature of BMECs' endothelial barrier, the lateral binding forces between live BMECs. Paracellular expressions of the key adherens junction protein vascular endothelial (VE)-cadherin were visualized in BMEC cultures and a 3D BBB model using human BMECs and pericytes. VE-cadherin signals were also examined in brain tissues from AD patients and normal controls. Results: Circulating exosomes from AD patients reduced VE-cadherin expression levels and impaired barrier function in recipient BMECs. Immunostaining analysis demonstrated that AD exosomes damaged VE-cadherin integrity in a 3D microvascular tubule formation model. The study found that AD exosomes weakened BBB integrity depending on their RNA content. Additionally, diminished microvascular VE-cadherin expression was observed in AD brains compared to controls. Conclusion: These findings highlight the significant role of circulating exosomes from AD patients in damaging adherens junctions of recipient BMECs, dependent on exosomal RNA.

Teresa Rognoni, Marta Fernández-Matarrubia, Miguel Ángel Martinez-González, Jordi Salas-Salvadó, Dolores Corella, Olga Castañer, J. Alfredo Martínez, Ángel M.Alonso-Gómez, Enrique Gómez-Gracia, Jesús Vioque, Dora Romaguera, José López-Miranda, Ramón Estruch, Francisco J. Tinahones, José Manuel Santos-Lozano, Lluis Serra-Majem, Naomi Cano Ibañez, Josep A. Tur, Rafael Micó Pérez, Xavier Pintó, Miguel Delgado-Rodríguez, María Ortiz Ramos, Josep Vidal, Clotilde Vázquez, Lidia Daimiel, Emilio Ros, Nuria Goñi-Ruiz, Nancy Babio, José V. Sorlí, Helmut Schröder, Antonio García-Rios, Laura Compañ-Gabucio, Julia Warnberg, M Ángeles Zulet, Alice Chaplin, Emilio Sacanella, Amira Bouzalmate-Hajjaj, Lucas Tojal-Sierra, Miguel Damas-Fuentes, Zenaida Vázquez, Carlos Gómez-Martínez, Carmen Saiz, Mireia Malcampo, Ana M. Ortiz-Morales, Vanessa Martínez-Avilés, Jesús García-Gavilan, Itziar Abete, Montserrat Fitó, Estefanía Toledo
Two-Year Changes in Physical Activity and Concurrent Changes in Cognitive Function in a Cohort of Adults with Metabolic Syndrome
Abstract: Background: It has been proposed that physical activity (PA) could prevent cognitive decline. Objective: To evaluate the association between changes in PA and changes in cognitive function in a cohort of adults with metabolic syndrome. Methods: Longitudinal observational study including 5,500 adults (mean age 65 years, SD=5; women=49.3%) with metabolic syndrome. Participants underwent physical activity measurements and cognitive evaluation at baseline and at two-years of follow-up. PA was quantified using the Minnesota questionnaire-shortened version. Cognitive function was evaluated using a battery of tests: Mini-Mental Test Examination, Clock Drawing Test, Trail Making Test A and B, Verbal Fluency Test, and Digit Span. The primary outcome was two-year change in cognition, measured through the Global Composite Score (GCS) of all neuropsychological tests. Multivariable-adjusted linear regression models were fitted with baseline PA and their changes as the main exposures and changes in cognitive function as the outcome. Results: No significant association was found between PA levels (or their changes) and changes in the GCS of cognitive function. A greater increase in PA levels was associated with a more favorable two-year change in the Trail Making Test A (Q4 versus Q1: Q1: b = –2.24 s, 95% CI –4.36 to –0.12 s; p-trend=0.024). No significant association was found for other neuropsychological test. Conclusion: Our results do not support an association between increases in PA and the evolution of the global cognitive function at two-year follow-up in an intervention trial which included PA promotion in one of its two randomized arms, but they suggested a possible beneficial effect of PA on attentional function in older adults.

Rumi Wang, Chen Kuang, Chengyu Guo, Yong Chen, Canyang Lia, Yoshihiro Matsumura, Masashi Ishimaru, Alice J. Van Pelt, Fei Chen (Handling Associate Editor: Jin-Tai Yu)
Automatic Detection of Putative Mild Cognitive Impairment from Speech Acoustic Features in Mandarin-Speaking Elders
Abstract: Background: To date, the reliable detection of mild cognitive impairment (MCI) remains a significant challenge for clinicians. Very few studies investigated the sensitivity of acoustic features in detecting Mandarin-speaking elders at risk for MCI, defined as “putative MCI” (pMCI). Objective: This study sought to investigate the possibility of using automatically extracted speech acoustic features to detect elderly people with pMCI and reveal the potential acoustic markers of cognitive decline at an early stage. Methods: Forty-one older adults with pMCI and 41 healthy elderly controls completed four reading tasks (syllable utterance, tongue twister, diadochokinesis, and short sentence reading), from which acoustic features were extracted automatically to train machine learning classifiers. Correlation analysis was employed to evaluate the relationship between classifier predictions and participants’ cognitive ability measured by Mini-Mental State Examination 2. Results: Classification results revealed that some temporal features (e.g., speech rate, utterance duration, and the number of silent pauses), spectral features (e.g., variability of F1 and F2), and energy features (e.g., SD of peak intensity and SD of intensity range) were effective predictors of pMCI. The best classification result was achieved in the Random Forest classifier (accuracy=0.81, AUC=0.81). Correlation analysis uncovered a strong negative correlation between participants’ cognitive test scores and the probability estimates of pMCI in the Random Forest classifier, and a modest negative correlation in the Support Vector Machine classifier. Conclusions: The automatic acoustic analysis of speech could provide a promising non-invasive way to assess and monitor the early cognitive decline in Mandarin-speaking elders.

Nicholas J. Schork, Jeremy A. Elman, for the Alzheimer’s Disease Neuroimaging Initiative
Pathway-Specific Polygenic Risk Scores Correlate with Clinical Status and Alzheimer’s Disease-Related Biomarkers
Abstract: Background: APOE is the largest genetic risk factor for Alzheimer’s disease (AD), but there is a substantial polygenic component. Polygenic risk scores (PRS) can summarize small effects across the genome but may obscure differential risk across molecular processes and pathways that contribute to heterogeneity of disease presentation. Objective: We examined polygenic risk impacting specific AD-associated pathways and its relationship with clinical status and biomarkers of amyloid, tau, and neurodegeneration (A/T/N). Methods: We analyzed data from 1,411 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We applied pathway analysis and clustering to identify AD-associated “pathway clusters” and construct pathway-specific PRSs (excluding the APOE region). We tested associations with diagnostic status, abnormal levels of amyloid and ptau, and hippocampal volume. Results: Thirteen pathway clusters were identified, and eight pathway-specific PRSs were significantly associated with AD diagnosis. Amyloid-positivity was associated with endocytosis and fibril formation, response misfolded protein, and regulation protein tyrosine PRSs. Ptau positivity and hippocampal volume were both related to protein localization and mitophagy PRS, and ptau-positivity was also associated with an immune signaling PRS. A global AD PRS showed stronger associations with diagnosis and all biomarkers compared to pathway PRSs. Conclusions: Pathway PRS may contribute to understanding separable disease processes, but do not add significant power for predictive purposes. These findings demonstrate that AD-phenotypes may be preferentially associated with risk in specific pathways, and defining genetic risk along multiple dimensions may clarify etiological heterogeneity in AD. This approach to delineate pathway-specific PRS can be used to study other complex diseases.

Maria Vassilaki, Sunyang Fu, Luke R. Christenson, Muskan Garg, Ronald C. Petersen, Jennifer St. Sauver, Sunghwan Sohn (Handling Associate Editor: Qiang (Shawn) Cheng)
Characterizing Performance Gaps of a Code-Based Dementia Algorithm in a Population-Based Cohort of Cognitive Aging
Abstract: Background: Multiple algorithms with variable performance have been developed to identify dementia using combinations of billing codes and medication data that are widely available from electronic health records (EHR). If the characteristics of misclassified patients are clearly identified, modifying existing algorithms to improve performance may be possible. Objective: To examine the performance of a code-based algorithm to identify dementia cases in the population-based Mayo Clinic Study of Aging (MCSA) where dementia diagnosis (i.e., reference standard) is actively assessed through routine follow-up and describe the characteristics of persons incorrectly categorized. Methods: There were 5,316 participants (age at baseline (mean (SD)): 73.3 (9.68) years; 50.7% male) without dementia at baseline and available EHR data. ICD-9/10 codes and prescription medications for dementia were extracted between baseline and one year after an MCSA dementia diagnosis or last follow-up. Fisher's exact or Kruskal-Wallis tests were used to compare characteristics between groups. Results: Algorithm sensitivity and specificity were 0.70 (95% CI: 0.67, 0.74) and 0.95 (95% CI: 0.95, 0.96). False positives (i.e., participants falsely diagnosed with dementia by the algorithm) were older, with higher Charlson comorbidity index, more likely to have mild cognitive impairment (MCI), and longer follow-up (versus true negatives). False negatives (versus true positives) were older, more likely to have MCI, or have more functional limitations. Conclusions: We observed a moderate-high performance of the code-based diagnosis method against the population-based MCSA reference standard dementia diagnosis. Older participants and those with MCI at baseline were more likely to be misclassified.

Shanquan Chen, Yuqi Wang, Christoph Mueller
Code-Based Algorithms for Identifying Dementia in Electronic Health Records: Bridging the Gap Between Theory and Practice
Abstract: Code-based algorithms are crucial tools in the detection of dementia using electronic health record data, with broad applications in medical research and healthcare. Vassilaki et al.'s study explores the efficacy of code-based algorithms in dementia detection using electronic health record data, achieving approximately 70% sensitivity and positive predictive value. Despite the promising results, the algorithms fail to detect around 30% of dementia cases, highlighting challenges in distinguishing cognitive decline factors. The study emphasizes the need for algorithmic improvements and further exploration across diverse healthcare systems and populations, serving as a critical step toward bridging gaps in dementia care and understanding.

Yaqi Wang*, Kai Yang*, Pengrui Fu, Xiaolei Zheng, Hui Yang, Qingbo Zhou, Wen Ma, Ping Wang (Handling Associate Editor: Madeleine Hackney) *These authors contributed equally to this work.
The Ability to Use Contextual Information in Object and Scene Recognition in Patients with Mild Cognitive ImpairmentAbstract: Background: The ability to understand and make use of object-scene relationships are critical for object and scene recognition. Objective: The current study assessed whether patients with mild cognitive impairment (MCI), possibly in the preclinical phase of Alzheimer’s disease, exhibited impairment in processing contextual information in scene and object recognition. Methods: In Experiment 1, subjects viewed images of foreground objects in either semantic consistent or inconsistent scenes under no time pressure, and they verbally reported the names of foreground objects and backgrounds. Experiment 2 replicated Experiment 1, except that subjects were required to name scene first. Experiment 3 examined object and scene recognition accuracy baselines, recognition difficulty, familiarity with objects/scenes, and object-scene consistency judgements. Results: There were contextual consistency effects on scene recognition for MCI and healthy subjects, regardless of response sequence. Scenes were recognized more accurately under the consistent condition than the inconsistent condition. Additionally, MCI patients were more susceptible to incongruent contextual information, possibly due to inhibitory deficits or over-dependence on semantic knowledge. However, no significant differences between MCI and healthy subjects were observed in consistency judgement, recognition accuracy, recognition difficulty and familiarity rating, suggesting no significant impairment in object and scene knowledge among MCI subjects. Conclusions: The study indicates that MCI patients retain relatively intact contextual processing ability but may exhibit inhibitory deficits or over-reliance on semantic knowledge.

Marcia C. de Oliveira Otto, Jason H.Y. Wu, Evan L. Thacker, Heidi Tsz Mung Lai, Rozenn N. Lemaitre, Nikhil Padhye, Xiaoling Song, Irena B. King, Oscar Lopez, David S. Siscovick, Dariush Mozaffarian
Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults
Abstract: Background: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown. Objective: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18:3], EPA [20:5], DPA [22:5], DHA [22:6]) and omega-6 (LA [18:2], AA [20:4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged ≥65 years in the Cardiovascular Health Study. Methods: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes. Results: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA. Conclusion: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

Jiwei Jiang, Anxin Wang, Yaou Liu, Zeshan Yao, Mengfan Sun, Tianlin Jiang, Wenyi Li, Shirui Jiang, Xiaoli Zhang, Yanli Wang, Yuan Zhang, Ziyan Jia, Xinying Zou, Jun Xu (Handling Associate Editor: Ling-Qiang Zhu)
Spatiotemporal Characteristics of Regional Brain Perfusion Associated with Neuropsychiatric Symptoms in Patients with Alzheimer’s Disease
Abstract: Background: Current technology for exploring neuroimaging markers and neural circuits of neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) is expensive and usually invasive, limiting its use in clinical practice. Objective: To investigate the cerebral morphology and perfusion characteristics of NPS and identify the spatiotemporal perfusion circuits of NPS sub-symptoms. Methods: This nested case-control study included 102 AD patients with NPS and 51 age- and sex-matched AD patients without NPS. Gray matter volume, cerebral blood flow (CBF), and arterial transit time (ATT) were measured and generated using time-encoded 7-delay pseudo-continuous arterial spin labeling (pCASL). Multiple conditional logistic regression analysis was used to identify neuroimaging markers of NPS. The associations between the CBF or ATT of affected brain areas and NPS sub-symptoms were evaluated after adjusting for confounding factors. The neural circuits of sub-symptoms were identified based on spatiotemporal perfusion sequencing. Results: Lower Mini-Mental State Examination scores (p<0.001), higher Caregiver Burden Inventory scores (p<0.001), and higher CBF (p=0.001) and ATT values (p<0.003) of the right anteroventral thalamic nucleus (ATN) were risk factors for NPS in patients with AD. Six spatiotemporal perfusion circuits were found from 12 sub-symptoms, including the anterior cingulate gyri-temporal pole/subcortical thalamus-cerebellum circuit, insula-limbic-cortex circuit, subcortical thalamus-temporal pole-cortex circuit, subcortical thalamus-cerebellum circuit, frontal cortex-cerebellum-occipital cortex circuit, and subcortical thalamus-hippocampus-dorsal raphe nucleus circuit. Conclusions: Prolonged ATT and increased CBF of the right ATN may be neuroimaging markers for detecting NPS in patients with AD. Time-encoded pCASL could be a reliable technique to explore the neural perfusional circuits of NPS.

Morteza Abyadeh, Vijay K. Yadav, Alaattin Kaya
Common Molecular Signatures Between Coronavirus Infection and Alzheimer’s Disease Reveal Targets for Drug Development
Abstract: Background: Cognitive decline is a common consequence of COVID-19, and studies suggest a link between COVID-19 and Alzheimer’s disease (AD). However, the molecular mechanisms underlying this association remain unclear. Objective: To understand the potential molecular mechanisms underlying the association between COVID-19 and AD development, and identify the potential genetic targets for pharmaceutical approaches to reduce the risk or delay the development of COVID-19-related neurological pathologies. Methods: We analyzed transcriptome datasets of 638 brain samples using a novel Robust Rank Aggregation method, followed by functional enrichment, protein-protein, hub genes, gene-miRNA, and gene-transcription factor (TF) interaction analyses to identify molecular markers altered in AD and COVID-19 infected brains. Results: Our analyses of frontal cortex from COVID-19 and AD patients identified commonly altered genes, miRNAs and TFs. Functional enrichment and hub gene analysis of these molecular changes revealed commonly altered pathways, including downregulation of the cyclic adenosine monophosphate (cAMP) signaling and taurine and hypotaurine metabolism, alongside upregulation of neuroinflammatory pathways. Furthermore, gene-miRNA and gene-TF network analyses provided potential up- and downstream regulators of identified pathways. Conclusion: We found that downregulation of cAMP signaling pathway, taurine metabolisms, and upregulation of neuroinflammatory related pathways are commonly altered in AD and COVID-19 pathogenesis, and may make COVID-19 patients more susceptible to cognitive decline and AD. We also identified genetic targets, regulating these pathways that can be targeted pharmaceutically to reduce the risk or delay the development of COVID-19-related neurological pathologies and AD.

Marcel Daamen, Lukas Scheef, Shumei Li, Michel J. Grothe, Florian C. Gaertner, Ralph Buchert, Katharina Buerger, Laura Dobisch, Alexander Drzezga, Markus Essler, Michael Ewers, Klaus Fliessbach, Ana Lucia Herrera Melendez, Stefan Hetzer, Daniel Janowitz, Ingo Kilimann, Bernd Joachim Krause, Catharina Lange, Christoph Laske, Matthias H. Munk, Oliver Peters, Josef Priller, Alfredo Ramirez, Matthias Reimold, Axel Rominger, Ayda Rostamzadeh, Sandra Roeske, Nina Roy, Klaus Scheffler, Anja Schneider, Annika Spottke, Eike Jakob Spruth, Stefan J. Teipel, Michael Wagner, Emrah Düzel, Frank Jessen, Henning Boecker, for the DELCODE Study Group (Handling Associate Editor: Konstantinos Arfanakis)
Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline
Abstract: Background: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer’s disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. Objective: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. Methods: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N=24 amyloid-positive and N=24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Results: Group differences approached significance for BF total volume (p=0.061) and the Ch4 subregion (p=0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. Conclusions: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at “grey zone” levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings.

Joe Camarillo, Alan Villarreal Rizzo, Jose Eduardo Cabrero Castro, Brian Downer
Differences in the Cognitive Function of Mexican Adults Aged 60 and Older with Self-Reported Diabetes in 2001 and 2018
Abstract: Background: The prevalence of type 2 diabetes in Mexico has nearly doubled for adults aged ≥60. Increases in education and healthcare resources to manage chronic conditions have contributed to population-level increases in the cognitive functioning of older adults. However, research has not focused on older adults with chronic conditions such as diabetes. Objective: Our objective was to compare the cognitive functioning of Mexican adults aged ≥60 with diabetes in 2001 and 2018. Methods: Data came from Mexican Health and Aging Study. Our study used a cross-sectional design and included participants aged ≥60 with self-reported diabetes during the 2001 (n=1,052, mean age=68.4, female=59.6%) and 2018 (n=2,469, mean age=70.6, female=62.0%) observation waves. Five cognitive tests were used to create a score of global cognition. Generalized estimating equations were used to compare global cognition in 2001 to 2018. Results: Older adults in 2018 had more education and were more likely than older adults in 2001 to take oral medication for diabetes, insulin, and to check blood sugar weekly. Older adults in 2018 had higher global cognition than in 2001 when adjusting for age, gender, education, and health insurance coverage (b=0.38, SE=0.02). This statistically significant difference remained after adjusting for health conditions, health behaviors, and diabetes management behaviors. Conclusions: Older adults in Mexico with self-reported diabetes in 2018 had higher cognitive function than in 2001. Future research is needed to investigate causes of the cohort differences in cognitive functioning among Mexican older adults with self-reported diabetes.

Rabab Al-Lahham, Nicolas Mendez (Handling Associate Editor: Debomoy Lahiri)
Tau Loss of Function, by Deletion or Aggregation, Contributes to Peripheral Insulin Resistance
Abstract: Background. Several epidemiological data revealed an association between Alzheimer’s disease (AD) and type 2 diabetes. Researchers concentrated on brain insulin resistance with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of type 2 diabetes is higher in AD patients and that impairment in insulin signaling is a risk factor for AD. Objective. The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of Alzheimer’s disease by evaluating the consequences of tau loss-of-function on peripheral insulin sensitivity. Methods. Primary hepatocytes isolated from transgenic mouse models (Tau KO, P301L) and wild type mice (C57BL/6) were evaluated for their insulin sensitivity using glucose uptake assays as well as biochemical analysis of insulin signaling markers. Results. Our data show that tau deletion or loss of function promotes peripheral insulin resistance as seen in primary hepatocytes isolated from Tau KO and P301L mice, respectively. Furthermore, exposure of wild-type primary hepatocytes to sub-toxic concentrations of tau oligomers results in a dose-dependent inhibition of glucose uptake, associated with downregulation of insulin signaling. Tau oligomers-induced inactivation of insulin signaling proteins was rescued by inhibition of p38 MAPK, suggesting the involvement of p38 MAPK. Conclusions. This is the first study testing tau role in peripheral insulin resistance at the cellular level using multiple transgenic mouse models. Moreover, this study suggests that tau should be functional for insulin sensitivity, therefore, any loss of function by deletion or aggregation would result in insulin resistance.

Tommaso Costa*, Enrico Premi*, Donato Liloia, Franco Cauda, Jordi Manuello *These authors contributed equally to this work.
Unleashing the Power of Bayesian Re-Analysis: Enhancing Insights into Lecanemab (Clarity AD) Phase III Trial Through Informed t-Test
Abstract: Background: Clinical trials targeting Alzheimer's disease (AD) aim to alleviate clinical symptoms and alter the course of this complex neurodegenerative disorder. However, the conventional approach of null hypothesis significance testing (NHST) commonly employed in such trials has inherent limitations in assessing clinical significance and capturing nuanced evidence of effectiveness on a continuous scale. Objective: In this study, we conducted a re-analysis of the phase III trial of lecanemab, a recently proposed humanized IgG1 monoclonal antibody with high affinity for Aβ soluble protofibrils, using a Bayesian approach with informed t-test priors. Methods: To achieve this, we carefully selected trial data and derived effect size estimates for the primary endpoint, the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Subsequently, a series of Bayes Factor analyses were performed to compare evidence supporting the null hypothesis (no treatment effect) versus the alternative hypothesis (presence of an effect). Drawing on relevant literature and the lecanemab phase III trial, we incorporated different minimal clinically important difference (MCID) values for the primary endpoint CDR-SB as prior information. Results: Our findings, based on a standard prior, revealed anecdotal evidence favoring the null hypothesis. Additional robustness checks yielded consistent results. However, when employing informed priors, we observed varying evidence across different MCID values, ultimately indicating no support for the effectiveness of lecanemab over placebo. Conclusion: Our study underscores the value of Bayesian analysis in clinical trials while emphasizing the importance of incorporating MCID and effect size granularity to accurately assess treatment efficacy.

Claudia Di Gioia, Marco Santonico, Alessandro Zompanti, Anna Sabatini, Simone Grasso, Francesca Ursini, Claudio Pedone, Flavia Galdi, Raffaele Antonelli Incalzi, Giorgio Pennazza
Detecting Dementia by Saliva Analysis: A Fingerprinting Unobtrusive Method Based on a Fast and Cheap Sensor System
Abstract: Background: Recent studies have shown that oxidative stress plays a relevant role in Alzheimer's disease (AD), and in the pathogenesis of vascular dementia (VaD). New diagnostic methods look for biological samples with non-invasive sampling methods. Among these, saliva shows an increase in oxidative stress products, thus a corresponding reduction in antioxidant products were found in dementia cases compared to healthy controls. Compounds identified in saliva include some hydrocarbons whose production has been related to the presence of reactive oxygen species. Objective: The hypothesis is that the voltammetric analysis performed on saliva could be a useful test for diagnosing dementia, potentially discriminating between AD and VaD. Methods: A single-center observational study was conducted on patients referred to the dementia clinic in the Neurology area and healthy controls recruited in the Orthopedics area of the Campus Bio-Medico Hospital in Rome. The study was aimed at evaluating the discriminative properties of salivary voltammetric analysis between healthy subjects and patients with dementia and, as a secondary outcome, between AD and VaD. A total of 69 subjects were enrolled, including 29 healthy controls, 20 patients with AD, and 20 patients with VaD. The degree of cognitive impairment was classified on the basis of the Mini-Mental State Examination score. Results: The results obtained are promising, with an accuracy of 79.7%, a sensitivity of 82.5%, and a specificity of 75.8%, in the discrimination of dementia versus controls. Conclusions: The methods tested demonstrate to be relevant in the discrimination between dementia and controls. A confirmatory study is already running.

Jinghang Li*, Elizabeth J. Mountz*, Akiko Mizuno, Ashti M Shah, Andrea Weinstein, Ann D. Cohen, William E. Klunk, Beth E. Snitz, Howard J. Aizenstein, Helmet T. Karim *These authors contributed equally to this work.
Functional Asymmetry During Working Memory and Its Association with Markers of Alzheimer’s Disease in Cognitively Normal Older Adults
Abstract: Background: Amyloid-β (Aβ) deposits asymmetrically early in Alzheimer’s disease (AD). This process is variable and has been associated with asymmetric hypometabolism. Objective: We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults. Methods: We analyzed data from 77 cognitively healthy, older adults who completed functional magnetic resonance imaging, positron emission tomography, and cognitive testing. We identified regions of significant activation and asymmetry during the Digital Symbol Substitution Task (DSST). We examined associations between regions with significant hemispheric asymmetry (directional and absolute) and global cerebral Aβ, cerebral glucose metabolism, white matter hyperintensities, APOE ε4 allele status, DSST reaction time, age, sex, education, and cognitive function. Results: Asymmetry was not associated with several factors including cognitive function, Aβ, and white matter hyperintensities. The presence of at least one ε4 APOE allele in participants was associated with less asymmetric activation in the angular gyrus (right dominant activation). Greater education was associated with less asymmetric activation in mediodorsal thalamus (left dominant activation). Conclusions: Genetic risk of AD was associated with lower asymmetry in angular gyrus activation, while greater education was associated with lower asymmetry in mediodorsal thalamus activation. Changes in asymmetry may reflect components of compensation or cognitive reserve. Asymmetric neural recruitment during working memory may be related to maintenance of cognitive function in cognitively normal older adults.

Claudia Ramos*, Claudia Madrigal*, Daniel Camilo Aguirre-Acevedo, Margarita Giraldo-Chica, Natalia Acosta-Baena, Claudia Aponte, David Aguillón, Manuela Gómez, Alejandro Espinosa, Lucia Madrigal, Claramonika Uribe, Amanda Saldarriaga, Diana Alzate, Alejandra Ruiz, Angela Andrade, Hugo Lopez, Jessica B. Langbaum, Kaycee M. Sink, Eric M. Reiman, Pierre N. Tariot, Silvia Ríos-Romenets, Francisco Lopera *These authors contributed equally to this work.
Psychological Status of the Participants in Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Colombia
Abstract: Background: The SARS-CoV2 global pandemic impacted participants in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) the possibility of becoming infected with SARS-CoV2. Objective: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. Possibility of utilizing the mental health team services was explored, considering different risk factors, and comparing between users and non-users of these services. Methods: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics were used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. Results: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while hyperlipidemia history association was negative. Conclusions: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

Yuto Uchida, Kengo Onda, Zhipeng Hou, Juan C. Troncoso, Susumu Mori, Kenichi Oishi (Handling Associate Editor: Masahito Yamada)
Microstructural Neurodegeneration of the Entorhinal-Hippocampus Pathway along the Alzheimer’s Disease Continuum
Abstract: Background: Conventional neuroimaging biomarkers for the neurodegeneration of Alzheimer’s disease (AD) are not sensitive enough to detect neurodegenerative alterations during the preclinical stage of AD individuals. Objective: We examined whether neurodegeneration of the entorhinal-hippocampal pathway could be detected along the AD continuum using ultra-high-field diffusion tensor imaging and tractography for ex vivo brain tissues. Methods: Postmortem brain specimens from a cognitively unimpaired individual without AD pathological changes (non-AD), a cognitively unimpaired individual with AD pathological changes (preclinical AD), and a demented individual with AD pathological changes (AD dementia) were scanned with an 11.7T diffusion magnetic resonance imaging. Fractional anisotropy (FA) values of the entorhinal layer II and number of perforant path fibers counted by tractography were compared among the AD continuum. Following the imaging analyses, the status of myelinated fibers and neuronal cells were verified by subsequent serial histological examinations. Results: At 250 μm (zipped to 125 μm) isotropic resolution, the entorhinal layer II islands and the perforant path fibers could be identified in non-AD and preclinical AD, but not in AD dementia, followed by histological verification. The FA value of the entorhinal layer II was the highest among the entorhinal laminae in non-AD and preclinical AD, whereas the FA values in the entorhinal laminae were homogeneously low in AD dementia. The FA values and number of perforant path fibers decreased along the AD continuum (non-AD > preclinical AD > AD dementia). Conclusion: We successfully detected neurodegenerative alterations of the entorhinal-hippocampal pathway at the preclinical stage of the AD continuum.

Laura Serra, Sabrina Bonarota, Carlotta Di Domenico, Giulia Caruso, Giovanni Giulietti, Carlo Caltagirone, Mara Cercignani, Marco Bozzali
Preclinical Brain Network Abnormalities in Patients with Subjective Cognitive Decline
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. Objective: The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. Methods: 23 SCD and 33 healthy subjects (HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. Results: No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. Conclusions: SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term.

Oluchi Ekenze, Adlin Pinheiro, Serkalem Demissie, Hugo J. Aparicio, Andreas Charidimou, Alexa S. Beiser, Claudia L. Satizabal, Tiffany Kautz, Charles DeCarli, Steven Greenberg, Sudha Seshadri, Jose R. Romero
Association of MRI Visible Perivascular Spaces and Neurofilament Light Chain: The Framingham Heart Study
Abstract: Background: Neurofilament light chain (NfL) is a marker of neuronal injury. Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) represent cerebral small vessel disease (CSVD) but their role as markers of neuronal injury needs further clarification. Objective: To relate PVS burden according to brain topography and plasma NfL. Methods: Framingham Heart Study (FHS) participants with brain MRI and NfL measurements were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) using validated methods and categorized based on counts. A mixed region variable representing high burden PVS in either BG or CSO was assessed. Multivariable linear regression analyses were used to relate PVS burden to log-transformed NfL levels in models adjusted for age, sex, FHS cohort, time between MRI and clinic exam, and image view (model 1), vascular risk factors (model 2), and white matter hyperintensity volume, covert brain infarcts, and cerebral microbleeds (model 3). Results: Among 1,457 participants (68.1±8.5 years, 45% males), NfL levels increased with higher PVS burden. Multivariable analysis showed an association of high PVS burden strictly in BG with NfL (β=0.117, 95% CI 0.014-0.221; p=0.027), but attenuated in model 3. The associations were mainly in participants ≥65 years (β=0.122, 95% CI 0.015-0.229, p=0.026), women (β=0.156, 95% CI 0.024-0.288, p=0.021), and APOE ɛ4 non-carriers (β=0.140, 95% CI 0.017-0.263, p=0.026). Conclusions: The association of strictly BG high PVS burden with NfL suggests a role for PVS as markers of neuroaxonal injury, but our results are hypothesis generating and require further replication.

Simin Hua, Brandilyn A. Peters, Susie Lee, Kathryn Fitzgerald, Zheng Wang, Christopher C. Sollecito, Evan Grassi, Fanua Wiek, Lauren St Peter, Gypsyamber D'Souza, Kathleen M. Weber, Robert C. Kaplan, Deborah Gustafson, Anjali Sharma, Robert D. Burk, Leah H. Rubin, Qibin Qi
Gut Microbiota and Cognitive Function Among Women Living with HIV
Abstract: Background: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer's disease, but little is known among people living with HIV. Objective: To examine associations between gut microbiota and cognitive impairment among women with or without HIV. Methods: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive impairment was defined as two or more domains with T scores <1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression. Results: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus, and Gemmiger, and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways. Conclusions: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer's disease.


Marina Makri, Mara Gkioka, Despina Moraitou, Liana Fidani, Thomas Tegos, Magdalini Tsolaki
Attitudes, Motivations, and Barriers to Pre-Symptomatic Alzheimer’s Disease Screening: Development and Validation of the ‘Perceptions regarding pRE-symptomatic Alzheimer’s Disease Screening’ (PRE-ADS) Questionnaire
Abstract: Background: Pre-symptomatic screening methods for detecting a higher risk of Alzheimer’s disease (AD) are gaining popularity; thus, more people are seeking these tests. However, to date, not much is known about the attitudes toward pre-symptomatic AD screening. Objective: The goal of this study is to examine the psychometric properties of a tool for assessing the attitudes, barriers, and motivations to pre-symptomatic AD screening. Methods: This is a cross-sectional study performed on 208 Greek participants (189 students and 19 caregivers) provided with an online questionnaire. Psychometric properties were assessed through the examination of its construct validity (principal component analysis) and internal consistency. Results: Exploratory factor analysis revealed the presence of four factors. The first factor is labeled as “Perceived harms of testing” (10 items), the second “Acceptance of testing” (5 items), the third “Perceived benefits of testing” (6 items), and the fourth factor “Need for knowledge” (4 items). The reliability (internal consistency) of each factor separately was acceptable to good (0.70-0.87) while the internal consistency of the overall questionnaire (25 items) was good (Cronbach's α=0.82). Conclusion: PRE-ADS is a valid questionnaire that might help in the research of peoples’ attitudes related to the pros and cons of pre-symptomatic screening for AD, and the development of effective counseling programs and prevention strategies. However, future research is required in the target population.

Zhigang Li*, Hao Wu*, Yong Ji, Zhihong Shi, Shuai Liu, Xinran Bao, Peng Shan, Dean Hu, Meimei Li *These authors contributed equally to this work.
Toward Reagent-Free Discrimination of Alzheimer’s Disease Using Blood Plasma Spectral Digital Biomarkers and Machine Learning
Abstract: Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The detection of early-stage AD is particularly desirable because it would allow early intervention. However, a minimally invasive, low-cost, and accurate discrimination or diagnostic method for AD is especially difficult in the earliest stage of AD. Objective: The aim of this research is to discover blood plasma spectral digital biomarkers of AD, develop a novel intelligent method for the discrimination of AD and accelerate the translation of Fourier transform infrared (FTIR) spectral-based disease discrimination methods from the laboratory to clinical practice. Methods: Since vibration spectroscopy can provide the structure and chemical composition information of biological samples at the molecular level, we investigated the potential of FTIR spectral biomarkers of blood plasma to differentiate between AD patients and healthy controls. Combined with machine learning technology, we designed a hierarchical discrimination system that provides reagent-free and accurate AD discrimination based on blood plasma spectral digital biomarkers of AD. Results: Accurate segregation between AD patients and healthy controls was achieved with 89.3% sensitivity and 85.7% specificity for early-stage AD patients, 92.8% sensitivity and 87.5% specificity for middle-stage AD patients, and 100% sensitivity and 100% specificity for late-stage AD patients. Conclusions: Our results show that blood plasma spectral digital biomarkers hold great promise as discrimination markers of AD, indicating the potential for the development of an inexpensive, reagent-free, and less laborious clinical test. As a result, our research outcome will accelerate the clinical application of spectral digital biomarkers and machine learning.

Samuel Thomas Creavin, Mark Fish, Michael Lawton, Sarah Cullum, Antony Bayer, Sarah Purdy, Yoav Ben-Shlomo
A Diagnostic Test Accuracy Study Investigating General Practitioner Clinical Impression and Brief Cognitive Assessments for Dementia in Primary Care, Compared to Specialized Assessment
Abstract: Background: Many health systems are interested in increasing the number of uncomplicated and typical dementia diagnoses that are made in primary care, but the comparative accuracy of tests is unknown. Objective: Calculate diagnostic accuracy of brief cognitive tests in primary care. Methods: We did a diagnostic test accuracy study in general practice, in people over 70 years who had consulted their GP with cognitive symptoms but had no prior diagnosis of dementia. The reference standard was specialist assessment, adjudicated for difficult cases, according to ICD-10. We assessed 16 index tests at a research clinic, and additionally analyzed referring GPs clinical judgement. Results: 240 participants had a median age of 80 years, of whom 126 were men and 132 had dementia. Sensitivity of individual tests at the recommended thresholds ranged from 56% for GP judgement (specificity 89%) to 100% for MoCA (specificity 16%). Specificity of individual tests ranged from 4% for Sniffin’ sticks (sensitivity 100%) to 91% for Timed Up and Go (sensitivity 23%). The 95% centile of test duration in people with dementia ranged from 3 minutes for 6CIT and Time and Change, to 16 minutes for MoCA. Combining tests with GP judgement increased test specificity and decreased sensitivity: e.g., MoCA with GP Judgement had specificity 87% and sensitivity 55%. Conclusions: Using GP judgement to inform selection of tests was an efficient strategy. Using IQCODE in people who GPs judge as having dementia and 6CIT in people who GPs judge as having no dementia, would be a time-efficient and accurate diagnostic assessment.

Jingwen Zhang, Qing Liu, Haorui Zhang, Michelle Dai, Qianqian Song, Defu Yang, Guorong Wu, Minghan Chen
Uncovering the System Vulnerability and Criticality of Human Brain Under Dynamical Neuropathological Events in Alzheimer’s Disease
Abstract: Background: Despite the striking efforts in investigating neurobiological factors behind the acquisition of amyloid-β (A), protein tau (T), and neurodegeneration ([N]) biomarkers, the mechanistic pathways of how AT[N] biomarkers spreading throughout the brain remain elusive. Objective: To disentangle the massive heterogeneities in Alzheimer’s disease (AD) progressions and identify vulnerable/critical brain regions to AD pathology. Methods: In this work, we characterized the interaction of AT[N] biomarkers and their propagation across brain networks using a novel bistable reaction-diffusion model, which allows us to establish a new systems biology underpinning of AD progression. We applied our model to large-scale longitudinal neuroimages from the ADNI database and studied the systematic vulnerability and criticality of brains. Results: Our model yields long term prediction that is statistically significant linear correlated with temporal imaging data, produces clinically consistent risk prediction, and captures the Braak-like spreading pattern of AT[N] biomarkers in AD development. Conclusions: Our major findings include (i) tau is a stronger indicator of regional risk compared to amyloid, (ii) temporal lobe exhibits higher vulnerability to AD-related pathologies, (iii) proposed critical brain regions outperform hub nodes in transmitting disease factors across the brain, and (iv) comparing the spread of neuropathological burdens caused by amyloid-β and tau diffusions, disruption of metabolic balance is the most determinant factor contributing to the initiation and progression of AD.

Ximena Oyarzún-González, Erin L. Abner, Pablo Toro, Catterina Ferreccio
Prevalence and Factors Associated with Subjective Memory Complaint in a Semi-Rural Community in Chile
Abstract: Background: Subjective memory complaints (SMC) are commonly studied in older adults and have been identified as potentially prodromal to dementia and Alzheimer’s disease. Studies among younger adults from South America are lacking. Objective: To estimate the prevalence of SMC and the factors associated with it among Maule Cohort (MAUCO) participants. Methods: We performed a cross-sectional analysis to estimate the prevalence of SMC and investigated its associated factors from MAUCO baseline data (N=6,687). Within groups defined by age (38-59, 60-74) and global cognition (Mini-Mental State Examination: ≥26, 25-22, ≤21), multinomial logistic regression models evaluated risk factors for SMC (Yes, Sometimes, No). Results: Overall, SMC prevalence was 16.4%; 15.9% (95% CI 14.9-16.9%) among younger and 17.6% (15.8-19.4%) among older participants. Female sex, comorbidities, and bad/fair self-reported health status (SRHS) were generally associated with higher odds of SMC. Conclusion: Overall prevalence of SMC was 16%. Different factors were associated with the odds of SMC depending on age and global cognitive status. Future SMC studies should include sex-specific assessments, evaluate SRHS as a moderator of SMC reporting, and the influence of the SARS-CoV-2 pandemic on SMC reporting.


Vincent Koppelmans, Marit F.L. Ruitenberg, Sydney Y. Schaefer, Jace B. King, John M. Hoffman, Amanda F. Mejia, Tolga Tasdizen, Kevin Duff (Handling Associate Editor: Madeleine Hackney)
Delayed and More Variable Unimanual and Bimanual Finger Tapping in Alzheimer's Disease: Associations with Biomarkers and Applications for Classification
Abstract: Background: Despite reports of gross motor problems in mild cognitive impairment (MCI) and Alzheimer's disease (AD), fine motor function has been relatively understudied. Objective: We examined if finger tapping is affected in AD, related to AD biomarkers, and able to classify MCI or AD. Methods: Forty-seven cognitively normal, 27 amnestic MCI, and 26 AD subjects completed unimanual and bimanual computerized tapping tests. We tested 1) group differences in tapping with permutation models; 2) associations between tapping and biomarkers (PET amyloid-β, hippocampal volume, and APOE ε4 alleles) with linear regression; and 3) the predictive value of tapping for group classification using machine learning. Results: AD subjects had slower reaction time and larger speed variability than controls during all tapping conditions, except for dual tapping. MCI subjects performed worse than controls on reaction time and speed variability for dual and non-dominant hand tapping. Tapping speed and variability were related to hippocampal volume, but not to amyloid-β deposition or APOE ε4 alleles. Random forest classification (overall accuracy=70%) discriminated control and AD subjects, but poorly discriminated MCI from controls or AD. Conclusions: MCI and AD are linked to more variable finger tapping with slower reaction time. Associations between finger tapping and hippocampal volume, but not amyloidosis, suggest that tapping deficits are related to neuropathology that presents later during the disease. Considering that tapping performance is able to differentiate between control and AD subjects, it can offer a cost-efficient tool for augmenting existing AD biomarkers.

Amir Fazlollahi, Soohyun Lee, Felicia Coleman, Emily McCann, Martijn A. Cloos, Pierrick Bourgeat, Peter J. Nestor
Increased Resolution of Structural MRI at 3T Improves Estimation of Regional Cortical Degeneration in Individual Dementia Patients Using Surface Thickness Maps
Abstract: Background: Objective measurement of regional cortical atrophy in individual patients would be a highly desirable adjunct for diagnosis of degenerative dementias. Objective: We hypothesized that increasing the resolution of magnetic resonance scans would improve the sensitivity of cortical atrophy detection for individual patients. Methods: 46 participants including 8 semantic-variant primary progressive aphasia (svPPA), seven posterior cortical atrophy (PCA), and 31 cognitively unimpaired participants underwent clinical assessment and 3.0T brain scans. SvPPA and PCA were chosen because there is overwhelming prior knowledge of the expected atrophy pattern. Two sets of T1-weighted images with 0.8 mm3 (HighRes) and conventional 1.0 mm3 (ConvRes) resolution were acquired. The cortical ribbon was segmented using FreeSurfer software to obtain surface-based thickness maps. Inter-sequence performance was assessed in terms of cortical thickness and sub-cortical volume reproducibility, signal-to-noise and contrast-to-noise ratios. For clinical cases, diagnostic effect size (Cohen’s d) and lesion distribution (z-score and t-value maps) were compared between HighRes and ConvRes scans. Results: The HighRes scans produced higher image quality scores at 90 seconds extra scan time. The effect size of cortical thickness differences between patients and cognitively unimpaired participants was 15-20% larger for HighRes scans. HighRes scans showed more robust patterns of atrophy in expected regions in each and every individual patient. Conclusions: HighRes T1-weighted scans showed superior precision for identifying the severity of cortical atrophy in individual patients, offering a proof-of-concept for clinical translation. Studying svPPA and PCA, two syndromes with well-defined focal atrophy patterns, offers a method to clinically validate and contrast automated algorithms.

Clinical Trial Protocol
Dong-Yun Kim, Jae Sik Kim, Young-Seok Seo, Woo-Yoon Park, Byoung Hyuck Kim, Eun-Hee Hong, Ji Young Kim, Seong-Jun Cho, Hak Young Rhee, Aryun Kim, Keun You Kim, Dae Jong Oh, Weon Kuu Chung
Evaluation of Efficacy and Safety Using Low Dose Radiation Therapy with Alzheimer’s Disease: A Protocol for Multicenter Phase II Clinical Trial
Abstract: Background: Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-β (Aβ) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. Objective: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. Methods: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aβ42/Aβ40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer’s Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. Conclusions: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD.