Pages 705-713
Review
Tracy Butler, Sin-Ruow Tey, James E. Galvin, George Perry, Richard L. Bowen, Craig S. Atwood
Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer’s Disease
Abstract: The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer’s disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.
Pages 715-729
Systematic Review
Evie Margaret Connolly, Ríona Mc Ardle, Kweku Andrew Ampadu Bimpong, Sarah Slight
What Impact Does the Diagnosis of Mild Cognitive Impairment Have on the Wellbeing, Everyday Behavior, and Healthcare Utilization of People and Their Carers? A Systematic Review
Abstract: Background: Dementia is a major cause of disability and dependency globally. Mild cognitive impairment (MCI) is considered an early indicator of developing dementia. There are growing efforts to detect and diagnose MCI earlier; consequently, we need to understand the perspectives of individuals and carers regarding the implications of an MCI diagnosis. Objective: To systematically review qualitative literature to understand the impact of a MCI diagnosis on both the individual and their carers, focusing on wellbeing, everyday behaviors, and healthcare utilization. Methods: Key search terms were input into five databases. Studies were included if they were peer-reviewed qualitative research published in English that obtained perspectives of community-dwellers with MCI or carers and focused on either their wellbeing, everyday behaviors and/or healthcare utilization. The protocol was pre-registered on PROSPERO (CRD42021291995). Data was synthesized narratively. Results: Key findings from 15 eligible articles highlighted the negative impact of an MCI diagnosis on the wellbeing of both individuals and carers, due to stigma and limited understanding regarding diagnosis/prognosis. Changes in everyday behavior varied, particularly regarding motivation to engage with physical activity, hobbies and social opportunities. Both individuals and carers were sometimes dissatisfied with healthcare services; ineffective communication during clinical consolations highlighted as a reason for lack of trust in clinicians. Conclusions: Results indicate that an MCI diagnosis impacts both people with MCI and their carers across key facets of life. There is a critical need to effectively communicate the diagnosis and prognosis of MCI to support wellbeing and everyday activities and ensure trust in healthcare services.
Pages 731-734
Commentary
Remy Cardoso, Charlotte E. Teunissen, Catarina Resende Oliveira
Enhancing Alzheimer's Disease Diagnosis and Care by Focusing on Plasma Biomarkers for Identifying Mild Cognitive ImpairmentAbstract: Biomarkers that accurately identify mild cognitive impairment (MCI) are of greater importance for Alzheimer’s disease (AD) management and treatment. On the other hand, blood-based biomarkers are not only more practical but also less invasive than the common cerebrospinal fluid biomarkers. In their report in the Journal of Alzheimer’s Disease, Wang and collaborators identified 67 upregulated and 220 downregulated long noncoding RNAs (lncRNAs). They further demonstrated that 4 of these lncRNAs could discriminate MCI from cognitively healthy individuals. Apart from their significance as potential biomarkers for MCI diagnosis, these lncRNAs can offer additional information on the cellular mechanisms of AD pathology.
Pages 735-736
Editorial
Ricardo Benjamín Maccioni, Raul Prieto
Understanding the Human Being from a Quantum Perspective: Lessons to Elucidate Alzheimer’s Disease Pathogenesis
Pages 737-749
Andrew Liem Hieu Huynh, Yihan Wang, Liwei Ma, Yi Ling Clare Low, Weisi Chen, Christopher Fowler, Edwin C.K. Tan, Colin L. Masters, Liang Jin, Yijun Pan, and the AIBL Research Group
A Comparison of an Australian Observational Longitudinal Alzheimer’s Disease Cohort to Community-Based Australian Data
Abstract: Background: Observational Alzheimer’s disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied. Objective: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia. Methods: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities. Results: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation - AIBL 79±7 years, PBS/census 81±7, p<0.001, dementia/census 83±8, p<0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, p=0.020, dementia/census 29%, p<0.001; CALD - AIBL 3%, PBS/census 20%, p<0.001, dementia/census 22%, p<0.001). Conclusions: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD.
Pages 751-760
Kazuo Kitagawa, Sono Toi, Megumi Hosoya, Misa Seki, Sae Yamagishi, Takao Hoshino, Hiroshi Yoshizawa
Small Vessel Disease Burden Predicts Incident Dementia and Poor Functional Outcome in Independent Outpatients
Abstract: Background: Total small vessel disease (SVD) score is used to measure the burden of SVD. Objective: This study aimed to clarify the predictive value of total SVD score for incident dementia and functional outcomes in independent outpatients with vascular risk factors. Methods: We derived data from a Japanese cohort in which patients underwent magnetic resonance imaging and cognitive examinations. They were followed up until March 2023. The primary outcomes was dementia. Secondary outcome was functional outcomes. We measured a modified Rankin scale (mRS) score at the last visit and defined poor functional outcomes as mRS score ≥3. Results: After excluding those with a mRS score ≥2, Mini-Mental State Examination score in Japanese version <24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, dementia occurred in 31 patients. In multivariate analysis, the score 4 group showed a significantly higher risk of incident dementia than the score 0-3 groups (adjusted hazard ratio, 6.25; 95% CI, 1.83-21.40, p=0.003). The total SVD score was also independently related to poor functional outcome. Conclusions: The total SVD score of 4, and ≥1 could predict dementia and poor functional outcomes, respectively. Our results suggest intensive management of patients with SVD to prevent dementia and to maintain independent activities of daily living.
Pages 761-771
Jing Wang, Gong Zhang, Hao Lai, Zengbin Li, Mingwang Shen, Chao Li, Patrick Kwan, Terence J. O’Brien, Ting Wu, Siyu Yang, Xueli Zhang, Lei Zhang
Characterizing Gut Microbiota in Older Chinese Adults with Cognitive Impairment: A Cross-Sectional Study
Abstract: Background: Cognitive impairment is a clinical manifestation that occurs in the course of dementia like Alzheimer's disease. The association between cognitive impairment and gut microbiota is unclear. Objective: We aimed to identify gut microbiota characteristics and key gut microbiota biomarkers associated with cognitive impairment in a relatively large cohort of older adults in China. Methods: A total of 229 adults aged ≥60 years from Shenzhen, China were recruited into this cross-sectional study. Participants were divided into cognitive impairment (CI) and no cognitive impairment (NCI) groups according to the results of the Mini-Mental State Examination. Diversity analysis and network analysis were used to characterize the gut microbiota between the two groups. The linear discriminant analysis effect size method and machine learning approaches were sequentially performed to identify gut microbiota biomarkers. The relationship between biomarkers and lifestyle factors was explored using Transformation-based redundancy analysis (tb-RDA). Results: A total of 74 CI participants and 131 NCI participants were included in the analysis. The CI group demonstrated lower α-diversity compared to the NCI group (Shannon: 2.798 versus 3.152, p < 0.001). The density of the gut microbiota interaction network was lower in the CI group (0.074) compared to the NCI group (0.081). Megamonas, Blautia, Pseudomonas, Stenotrophomonas, and Veillonella were key biomarkers for CI. The tb-RDA revealed that increased fruit intake and exercise contribute to a higher abundance of Megamonas, Blautia, and Veillonella. Conclusions: We identified a significantly reduced abundance of certain beneficial gut microbiota in older Chinese adults with cognitive impairment.
Pages 773-785
Raul dos Reis Ururahy, Marina Scott do Val, Aline Maria Macagnan Ciciliati, Renata Elaine Paraizo Leite, Vitor Ribeiro Paes, Roberta Diehl Rodrigues, Lea Tenenholz Grinberg, Carlos Augusto Pasqualucci, Wilson Jacob Filho, Claudia Kimie Suemoto
The Association Between Neuropathological Lesions and Body Mass Index Is Independent of Cognitive Abilities
Abstract: Background: The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy studies are key to detecting preclinical neurodegenerative and cerebrovascular diseases that could be underlying weight changes. Objective: We investigated the association between dementia-related brain lesions and BMI and evaluated whether the cognitive function was a mediator of this association. Methods: In 1,170 participants, sociodemographic data, clinical history, and cognitive post-mortem evaluation were assessed with an informant. Neuropathological evaluation was performed in all cases. Linear regression models were used to investigate the association between neuropathological lesions (exposure variable) and BMI (outcome) adjusted for demographic, clinical, and cognitive variables in the whole sample, and in only those with normal cognition. Corrections for multiple comparisons were performed. In addition, a mediation analysis was performed to investigate the direct and indirect effects of cognitive abilities on the association between neuropathology and BMI. Results: Individuals with lower BMI had a higher burden of neuropathological lesions and poorer cognitive abilities. Only neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI, while other neurodegenerative and cerebrovascular lesions were not. NFT were indirectly associated with BMI through cognitive abilities, and also directly, even in participants with normal cognition. Conclusions: Neurofibrillary tangles were directly associated with low BMI even in individuals with preclinical Alzheimer's disease.
Pages 787-796
Sho Oasa, Gefei Chen, Marianne Schultzberg, Lars Terenius
Small Molecule Decoy of Amyloid-β Aggregation Blocks Activation of Microglia-Like Cells
Abstract: Background: Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer’s disease (AD). Aggregates are also recognized by microglia, which in early phases maybe protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic. Objective: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide. Methods: The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed. Results: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40- and Aβ42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys. Conclusions: Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously.
Pages 797-811
Anna Kostenko, Orazio Prezzavento, Gioacchino de Leo, David D’arco, Rosario Gulino, Antonella Caccamo, Giampiero Leanza
Cognitive and Histopathological Alterations in Rat Models of Early- and Late-Phase Memory Dysfunction: Effects of Sigma-1 Receptor Activation
Abstract: Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session. Results: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer’s disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases.
Pages 813-822
Bruce Seligmann, Salvatore Camiolo, Monica Hernandez, Joanne M. Yeakley, Gregory Sahagian, Joel McComb (Handling Associate Editor: Junichi Iga)
Molecular Gene Expression Testing to Identify Alzheimer's Disease with High Accuracy from Fingerstick Blood
Abstract: Background: There is no molecular test for Alzheimer’s disease (AD) using self-collected samples, nor is there a definitive molecular test for AD. We demonstrate an accurate and potentially definitive TempO-Seq® gene expression test for AD using fingerstick blood spotted and dried on filter paper, a sample that can be collected in any doctor’s office or can be self-collected. Objective: Demonstrate the feasibility of developing an accurate test for the classification of persons with AD from a minimally invasive sample of fingerstick blood spotted on filter paper which can be obtained in any doctor’s office or self-collected to address health disparities. Methods: Fingerstick blood samples from patients clinically diagnosed with AD, Parkinson’s disease (PD), or asymptomatic controls were spotted onto filter paper in the doctor’s office, dried, and shipped to BioSpyder for testing. Three independent patient cohorts were used for training/retraining and testing/retesting AD and PD classification algorithms. Results: After initially identifying a 770 gene classification signature, a minimum set of 68 genes was identified providing classification test areas under the ROC curve of 0.9 for classifying patients as having AD, and 0.94 for classifying patients as having PD. Conclusions: These data demonstrate the potential to develop a screening and/or definitive, minimally invasive, molecular diagnostic test for AD and PD using dried fingerstick blood spot samples that are collected in a doctor’s office or clinic, or self-collected, and thus, can address health disparities. Whether the test can classify patients with AD earlier then possible with cognitive testing remains to be determined.
Pages 923-834
Olga Utyro*, Olga Włoczkowska-Łapińska*, Hieronim Jakubowski *These authors contributed equally to this work.
Association of GLOD4 with Alzheimer’s Disease in Humans and Mice
Abstract: Background: Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer’s disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4’s association with AD was unknown. Objective: To assess GLOD4’s role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh-/-5xFAD mouse AD model of AD. Methods: GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4 protein/mRNA, Aβ precursor protein (Aβpp)/mRNA, Atg5, p62, and Lc3 mRNAs were quantified. Results: GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh-/-5xFAD mice compared to Blmh+/+5xFAD sibling controls, but not in Blmh-/- mice without the 5xFAD transgene compared to Blmh+/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh-/- mice of both sexes and in Blmh+/+ males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh-/-5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5, p62, and Lc3 genes. Conclusions: These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits.
Pages 835-845
Huimin Zhao*, Changlin Yang*, Fangkai Xing *These authors contributed equally to this work.
Correlation of the Serum Fatty Acids with Cognitive Function: An NHANES 2011-2014 and Multivariate Mendelian Randomization Analysis
Abstract: Background: The relationship between serum fatty acids and cognitive function has been the subject of extensive study. Objective: To analyze the relationship between serum fatty acids composition and cognitive function by NHANES database and multivariate Mendelian randomization (MR) analysis. Methods: A sub-cohort of 1,339 individuals with serum fatty acids and Digit Symbol Substitution Test (DSST) examinations from the 2011–2014 wave of the NHANES were analyzed using fully adjusted multiple linear regression models for associations between serum hydrolyzed fatty acid levels and cognitive function. Univariable and multivariable MR was used to analyze the correlation between 98 exposures related to serum fatty acids and cognitive function. Results from different database sources were combined using meta-analysis. Results: The fully adjusted regression analysis showed that linoleic acid (LA), Omega 6, fatty acids (FAs), and LA/FAs were positively correlated with DSST. 27 exposures were included for univariate MR analysis. Ultimately, only 2 traits had IVW test p-values ranging between 0.0019 and 0.05, both of which were LA/FAs. The meta-analysis of univariate MR revealed that LA/FAs was positively associated with cognitive function (β: 0.040, 95% CI=0.013-0.067, p=0.0041). In multivariate MR analysis, after adjusting for education, ischemic stroke, and age, LA/FAs was positively independently associated with cognitive function (IVW β: 0.049, 95% CI=0.021-0.077, p=0.0006). The results of MVMR are well in line with the univariate results. Conclusions: Both the Cross-sectional observational analyses and MR-based studies supported a suggestive causal relationship between the serum ratio of Linoleic acid in fatty acids and cognitive function.
Pages 847-876
Xian-Zheng Sang*, Wen Chen*, Xiao-Xiang Hou*, Chun-Hui Wang, Dan-Feng Zhang, Li-Jun Hou *These authors contributed equally to this work.
Association Between Statin Use and Dementia, and Related Mechanisms: A Bibliometric Analysis from 2007 to 2023
Abstract: Background: Emerging evidence suggests the potential of hydroxymethylglutaryl-coenzyme A (HMG-CoA, statins) as a therapeutic option for dementia. Objective: The primary objective of this study is to assess the current state of research on statins use in dementia, with a focus on identifying pivotal questions within the field. Methods: A systemic search for publications on statin use in dementia between 2007 and 2023 was conducted, utilizing the Web of Science Core Collection. The scientific output was analyzed from various perspectives through VOSviewer, CiteSpace, and the bibliometrics website (https://bibliometric.com/). Results: 560 articles authored by 2,977 individuals and 999 institutions across 58 countries were included, which were published in 295 periodicals and cited 21,176 references from 16,424 authors. The annual publication output remained steady, while the number of citations increased consistently. The U.S. and Mayo Clinic emerged as the most significant country and institution, respectively. B. McGuinness and D.L. Sparks were the most eminent authors. Journal of Alzheimer’s Disease was the most influential journal. Three sets of keywords and the top 10 references were identified, suggesting pivotal questions within the field. Conclusions: While statins show promising potential as a treatment option for dementia, their use remains uncertain due to the reported short-term cognitive impairment events and questionable long-term protective effects against dementia. The pivotal question is to ascertain the association between statins and cognition. The mechanisms underlying the effects of statins on cognition are multifaceted. This study provides insights into the current status within the field of statin use in dementia.
Pages 877-887
Carlota Méndez-Barrio, Manuel Medina-Rodríguez, Gonzalo Mendoza-Vázquez, Ernesto García-Roldán, Silvia Rodrigo-Herrero, Andrea Luque-Tirado, Ángela Almodóvar-Sierra, Emilio Franco-Macías
Prodromal Alzheimer’s Disease: Global Cognition, Cue Efficiency, and Cerebrospinal Fluid Neurofilament Light Values Predict Short-Term Conversion to Dementia
Abstract: Background: Predicting which patients with prodromal AD (pAD) will imminently convert to dementia may be paramount in a memory clinical setting, especially with potential disease-modifying therapies on the horizon. Objective: To explore a practical tool for this prediction, combining cognitive tests and cerebrospinal fluid (CSF) biomarkers. Methods: We designed a longitudinal prospective, observational, and multicenter study, enrolling patients with pAD. Inclusion criteria comprised memory complaints, Mini-Mental State Examination (MMSE) score of ≥22, memory impairment as indicated by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT+IR) and/or TMA-93, Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, and positive CSF Aβ42/Aβ40 ratio (<0.095, Euroimmun). The primary outcome was the conversion to dementia (CDR-GS≥1) within the first year of follow-up, referred to as "short-term conversion". A multiple regression logistic model was adopted to design the “Predict Short-Term Conversion” (PSTC) score. Results: Between 2020 and 2022, 83 patients were recruited. The median age was 74, with 49.4% being women. Twenty-five (30.1%) patients were classified as short-term converters. The PSTC score incorporated baseline scores on MMSE (≤24=3, >24=0) and FCSRT+IR Total Recall (≤14=4, >14=0), and CSF neurofilament light chains (NfLs) concentrations (β=0.001299). The PSTC score demonstrated an area under the curve of 0.79 (95% CI: 0.71-0.91, p<0.0001), with a cutoff value of 5.14 presenting 76% sensitivity and 80% specificity. Conclusions: The PSTC score, comprising two relatively brief cognitive test scores and NfLs CSF concentrations, could be useful for predicting short-term converters among patients diagnosed with pAD.
Pages 889-899
Shu Liu, Paul Maruff, Victor Fedyashov, Colin L. Masters, Benjamin Goudey
A Data-Driven Cognitive Composite Sensitive to Amyloid-β for Preclinical Alzheimer’s Disease
Abstract: Background: Integrating scores from multiple cognitive tests into a single cognitive composite has been shown to improve sensitivity to detect AD-related cognitive impairment. However, existing composites have little sensitivity to amyloid-β status (Aβ +/-) in preclinical AD. Objective: Evaluate whether a data-driven approach for deriving cognitive composites can improve the sensitivity to detect Aβ status among cognitively unimpaired (CU) individuals compared to existing cognitive composites. Methods: Based on the data from the Anti-Amyloid Treatment in the Asymptomatic Alzheimer's Disease (A4) study, a novel composite, the Data-driven Preclinical Alzheimer’s Cognitive Composite (D-PACC), was developed based on test scores and response durations selected using a machine learning algorithm from the Cogstate Brief Battery (CBB). The D-PACC was then compared with conventional composites in the follow-up A4 visits and in individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Result: The D-PACC showed a comparable or significantly higher ability to discriminate Aβ status [median Cohen’s d = 0.172] than existing composites at the A4 baseline visit, with similar results at the second visit. The D-PACC demonstrated the most consistent sensitivity to Aβ status in both A4 and ADNI datasets. Conclusions: The D-PACC showed similar or improved sensitivity when screening for Aβ+ in CU populations compared to existing composites but with higher consistency across studies.
Pages 901-912
Tao Wang*, Shaozhen Yan*, Yi Shan, Yi Xing, Sheng Bi, Zhigeng Chen, Hanyu Xi, Hanxiao Xue, Zhigang Qi, Yi Tang, Jie Lu *These authors contributed equally to this work.
Altered Neuronal Activity Patterns of the Prefrontal Cortex in Alzheimer’s Disease After Transcranial Alternating Current Stimulation: A Resting-State fMRI Study
Abstract: Background: Transcranial alternating current stimulation (tACS) could improve cognition in patients with Alzheimer’s disease (AD). However, the effects of tACS on brain activity remain unclear. Objective: The purpose is to investigate the change in regional neuronal activity after tACS in AD patients employing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: A total of 46 patients with mild AD were enrolled. Each patient received 30 one-hour sessions of real or sham tACS for three weeks (clinical trial: NCT03920826). The fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) measured by rs-fMRI were calculated to evaluate the regional brain activity. Results: Compared to baseline, AD patients in the real group exhibited increased fALFF in the left middle frontal gyrus-orbital part and right inferior frontal gyrus-orbital part, as well as increased ReHo in the left precentral gyrus and right middle frontal gyrus at the end of intervention. At the 3-month follow-up, fALFF increased in the left superior parietal lobule and right inferior temporal gyrus, as well as ReHo, in the left middle frontal gyrus and right superior medial frontal gyrus. A higher fALFF in the right lingual gyrus and ReHo in the right parahippocampal gyrus were observed in the response group than in the nonresponse group. Conclusions: The findings demonstrated the beneficial effects of tACS on the neuronal activity of the prefrontal cortex and even more extensive regions and provided a neuroimaging biomarker of treatment response in AD patients.
Pages 913-921
Anoop Manakkadan, Dolly Krishnan, Sheila Rui Xia Ang, Sreedharan Sajikumar
Slow Release of Hydrogen Sulfide in CA1 Hippocampal Neurons Rescues Long-Term Synaptic Plasticity and Associativity in an Amyloid-β Induced Model of Alzheimer’s Disease
Abstract: Background: Impairment of synaptic plasticity along with the formation of amyloid-β (Aβ) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer’s disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2S in AD conditions using rat hippocampal slices and the organic molecule GYY4137, a slow releasing H2S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aβ42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aβ42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro. Conclusions: GYY4137, with its slow release of H2S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD.
Pages 923-936
Hongxiu Guo, Shangqi Sun, Yang Yang, Rong Ma, Cailin Wang, Siyi Zheng, Xiufeng Wang, Gang Li, the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer’s Disease Metabolomics Consortium
A Novel Score to Predict Individual Risk for Future Alzheimer’s Disease: A Longitudinal Study of the ADNI Cohort
Abstract: Background: Identifying high-risk individuals with mild cognitive impairment (MCI) who are likely to progress to Alzheimer's disease (AD) is crucial for early intervention. Objective: This study aimed to develop and validate a novel clinical score for personalized estimation of MCI-to-AD conversion. Methods: The data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Two-thirds of the MCI patients were randomly assigned to a training cohort (n=478), and the remaining one-third formed the validation cohort (n=239). Multivariable logistic regression was performed to identify factors associated with MCI-to-AD progression within 4 years. A prediction score was developed based on the regression coefficients derived from the logistic model and tested in the validation cohort. Results: A lipidomics-signature was obtained that showed a significant association with disease progression. The MCI conversion scoring system (ranged from 0 to 14 points), consisting of the lipidomics-signature and five other significant variables (Apolipoprotein ε4, Rey Auditory Verbal Learning Test immediate and delayed recall, Alzheimer's Disease Assessment Scale delayed recall test, Functional Activities Questionnaire, and cortical thickness of the AD signature), was constructed. Higher conversion scores were associated with a higher proportion of patients converting to AD. The scoring system demonstrated good discrimination and calibration in both the training cohort (AUC=0.879, p of Hosmer-Lemeshow test=0.597) and the validation cohort (AUC=0.915, p of Hosmer-Lemeshow test=0.991). The risk classification achieved excellent sensitivity (0.84) and specificity (0.75). Conclusions: The MCI-to-AD conversion score is a reliable tool for predicting the risk of disease progression in individuals with MCI.
Pages 937-950
Xiaohong Zhang, Mingzhen Wang, Kaiyue Chen, Na Shi, Xia Cui, Zhicheng Yang, Feifei Chen, Xingfeng Lin
Understanding Family Caregivers’ Needs in Coping with the Behavioral and Psychological Symptoms of People with Dementia: A Hermeneutic–Phenomenological Study
Abstract: Background: Alzheimer’s disease and related dementias (ADRD) are progressive conditions. Family caregivers of patients, especially those caring for patients with ADRD exhibiting behavioral and psychological symptoms of dementia (BPSD), undergo significant physical and mental changes during long-term care. While most researchers have focused on the specific needs of family caregivers, the comprehensive understanding of these needs is limited. In this study, Alderfer’s existence, relatedness, and growth theory was used to develop an interview framework to systematically and comprehensively understand the needs of family caregivers of individuals with ADRD. Objective: The objective of this study was to understand family caregivers’ needs in coping with BPSD in individuals with ADRD, aiming to alleviate caregivers’ stress and promote their overall well-being. Methods: This study used a hermeneutic–phenomenological interview research design. Data were collected via remote conferences involving interviews with 17 participants selected via maximum variation sampling. The Colaizzi seven-step method was utilized, and the interview contents were analyzed using NVivo 12.0 software. Results: The needs of family caregivers in coping with the BPSD of individuals with ADRD could be summarized into three themes, namely existence needs, relatedness needs, and growth needs, and 10 sub-themes. Conclusions: The study findings provide new insights into the needs of family caregivers in coping with patients exhibiting BPSD. Family caregivers experience significant negative emotions, poor caregiving experiences, heavy caregiving burdens, and a desire for professional assistance and policy support.
Pages 951-959
Shu Liu*, Jiarui Li*, Li Wang, Yi Zhang, Baojian Wei, Yushang Li *These authors contributed equally to this work.
Association Between Ethylene Oxide Exposure and Cognitive Function in US Older Adults: NHANES 2013-2014
Abstract: Background: Ethylene oxide (EO) is a common organic compound associated with many adverse health outcomes. However, studies exploring the association between EO exposure and cognitive function are limited. Objective: This study aims to examine this relationship between EO exposure and cognition in older adults. Methods: This study enrolled 438 older adults from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle. EO exposure was quantified by the measurements of blood hemoglobin adducts of ethylene oxide (HbEO) concentrations. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer's Disease battery (CREAD), the Animal Fluency test (AFT), and the Digit Symbol Substitution Test (DSST). Linear regression model, generalized additive model, and smooth curve fitting were applied to examine the linear and nonlinear relationship between EO exposure and cognitive function. We used a two-piecewise linear regression model to detect the threshold effect of EO exposure on cognitive function. Results: Participants with higher HbEO levels had lower AFT and DSST scores than those with lower HbEO levels. After adjusting for all confounding factors, log2-transformed HbEO levels were negatively associated with AFT score. The smooth curve fitting demonstrated the nonlinear relationship between EO exposure and DSST scores. When log-2 transformed HbEO levels > 4.34 pmol/g Hb, EO exposure was negatively associated with DSST score. Conclusions: This study indicated that high levels of HbEO were associated with cognitive decline in US older adults. Future cohort studies are needed to verify our findings.
Pages 961-969
Mélissa C. Allé, Christelle Joseph, Pascal Antoine (Handling Associate Editor: Teresa Liu-Ambrose)
Involuntary Autobiographical Memory in Alzheimer’s Disease: A Double-Edged Way of Remembering the Past?
Abstract: Background: Alzheimer’s disease (AD) is characterized by severe memory alterations, affecting especially memories of personal past events. Until now, autobiographical memory impairments have been characterized using formal memory assessments, requiring patients to strategically and deliberately recall past events. However, contrary to this highly cognitively demanding mode of memory recall, autobiographical memories frequently come to mind unexpectedly based on automatic associative processes. The involuntary recall of personal memories is effortless and possibly represents a preserved way for AD patients to remember past events. Objective: This study aimed to investigate involuntary autobiographical memory in AD patients and compare the characteristics of these memories with those of healthy controls. Methods: Involuntary autobiographical memory was measured in 24 AD patients and 24 matched control participants using self-report measures. Participants were asked to report the frequency with which involuntary autobiographical memories were experienced in their daily life and to describe and self-assess one example of an involuntary memory. Results: We showed that AD patients and control participants did not differ in terms of the frequency or subjective characteristics of their involuntary autobiographical memories in daily life, except for feelings of intrusiveness. Compared to control participants, AD patients reported their involuntary autobiographical memories as being more intrusive. In addition, more negative and vague involuntary autobiographical memories were associated with greater depressive symptoms. Conclusions: These findings open up a new avenue for research to better understand the extent to which involuntary autobiographical memory might be preserved in AD patients and why these memories may in turn become intrusive to patients.
Pages 971-986
Michael Walsh, Madeline Uretsky, Yorghos Tripodis, Christopher J. Nowinski, Abigail Rasch, Hannah Bruce, Megan Ryder, Brett M. Martin, Joseph N. Palmisano, Douglas I. Katz, Brigid Dwyer, Daniel H. Daneshvar, Alexander Y. Walley, Theresa W. Kim, Lee E. Goldstein, Robert A. Stern, Victor E. Alvarez, Bertrand Russell Huber, Ann C. McKee, Thor D. Stein, Jesse Mez, Michael L. Alosco
Clinical and Neuropathological Correlates of Substance Use in American Football Players
Abstract: Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer’s disease and related tauopathies pathologically and clinically. Objective: To examine the association between substance use and clinical and neuropathological endpoints of CTE. Methods: Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes. Results: Of the 429 football players (mean age=62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p-values<0.05, ΔR2=0.04-0.18) and depression (FDR-p-values<0.05, ΔR2=0.02-0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p-values<0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p-values>0.05). Conclusions: Among deceased football players, substance use was common and associated with clinical symptoms.
Pages 987-999
Joseph Nowell, Sanara Raza, Nicholas R. Livingston, Shayndhan Sivanathan, Steve Gentleman, Paul Edison
Do Tau Deposition and Glucose Metabolism Dissociate in Alzheimer’s Disease Trajectory?
Abstract: Background: Tau aggregation demonstrates close associations with hypometabolism in Alzheimer’s disease (AD), although differing pathophysiological processes may underlie their development. Objective: To establish whether tau deposition and glucose metabolism have different trajectories in AD progression and evaluate the utility of global measures of these pathological hallmarks in predicting cognitive deficits. Methods: 279 participants with amyloid-β (Aβ) status, and T1-weighted MRI scans, were selected from the Alzheimer’s Disease Neuroimaging Initiative (http://adni.loni.usc.edu). We created the standard uptake value ratio images using Statistical Parametric Mapping 12 for [18F]AV1451-PET (tau) and [18F]FDG-PET (glucose metabolism) scans. Voxel-wise group and single-subject level SPM analysis evaluated the relationship between global [18F]FDG-PET and [18F]AV1451-PET depending on the Aβ status. Linear models assessed whether tau deposition or glucose metabolism better predicted clinical progression. Results: There was a dissociation between global cerebral glucose hypometabolism and global tau load in amyloid-positive AD and amyloid-negative mild cognitive impairment (MCI) (p>0.05). Global hypometabolism was only associated with global cortical tau in amyloid-positive MCI. Voxel-level single subject tau load better predicted neuropsychological performance, Alzheimer’s disease assessment scale-cognitive (ADAS-Cog) 13 score, and one-year change compared with regional and global hypometabolism. Conclusions: A dissociation between tau pathology and glucose metabolism at a global level in AD could imply that other pathological processes influence glucose metabolism. Furthermore, as tau is a better predictor of clinical progression, these processes may have independent trajectories and require independent consideration in the context of therapeutic interventions.
Pages 1001-1013
Sara A.J. van de Schraaf, Hanneke F.M. Rhodius-Meester, Lindsey M. Rijnsent, Meyrina D. Natawidjaja, Esther van den Berg, Frank J. Wolters, J.M. Anne Visser-Meily, Geert Jan Biessels, Marjolein de Vugt, Majon Muller, Cees M.P.M. Hertogh, Eefje M. Sizoo
Healthcare Professionals’ Perspectives on Post-Diagnostic Care for People with Vascular Cognitive Impairment: When Help Is Needed in a “No-Man’s Land”
Abstract: Background: Post-diagnostic care for people with vascular cognitive impairment (VCI) typically involves multiple professions and disjointed care pathways not specifically designed to aid VCI needs. Objective: Exploring perspectives of healthcare professionals on post-diagnostic care for people with VCI. Methods: We conducted a qualitative focus group study. We used purposive sampling to include healthcare professionals in different compositions of primary and secondary care professionals per focus group. Thematic saturation was reached after seven focus groups. Transcripts were iteratively coded and analyzed using inductive thematic analysis. Results: Forty participants were included in seven focus groups (4-8 participants). Results showed knowledge and awareness of VCI as prerequisites for adequate post-diagnostic care, and for pre-diagnostic detection of people with VCI (theme 1). In light of perceived lack of differentiation between cognitive disorders, participants shared specific advice regarding post-diagnostic care for people with VCI and informal caregivers (theme 2). Participants thought current care for VCI was fragmented and recommended further integration of care and collaboration across settings (theme 3). Conclusions: People with VCI and their caregivers risk getting stuck in a “no man’s land” between post-diagnostic care pathways; challenges lie in acknowledgement of VCI and associated symptoms, and alignment between healthcare professionals. Education about the symptoms and consequences of VCI, to healthcare professionals, people with VCI and caregivers, may increase awareness of VCI and thereby better target care. Specific attention for symptoms common in VCI could further tailor care and reduce caregiver burden. Integration could be enhanced by combining expertise of dementia and stroke/rehabilitation pathways.
Pages 1015-1025
Yongbin Zhu, Yueping Wu, Liping Shi, Yue Yang, Yanrong Wang, Degong Pan, Shulan He, Liqun Wang, Jiangping Li
Association of Plastic Exposure with Cognitive Function Among Chinese Older Adults
Abstract: Background: The widespread exposure to plastic products and the increasing number of individuals with cognitive impairments have imposed a heavy burden on society. Objective: This study aims to investigate the relationship between plastic product exposure in daily life and cognitive function in older Chinese individuals. Methods: Data were obtained from the 2023 Ningxia Older Psychological Health Cohort, comprising 4045 participants aged 60 and above. Cognitive function was assessed using the Mini-Mental State Examination scale. A population-based plastic exposure questionnaire was used to calculate plastic exposure scores (PES). Binary logistic regression was employed to analyze the relationship between PES and cognitive function, while restricted cubic splines were used to examine the dose-response relationship between PES and cognitive function. Latent profile analysis (LPA) was employed to explore the potential patterns of plastic exposure, and logistic regression was used to investigate the relationship between different exposure patterns and cognitive function. A linear regression model was utilized to investigate the relationship between PES and different dimensions of cognitive function. Results: Among the 4045 participants, 1915 individuals were assessed with mild cognitive impairment (MCI). After adjusting for all covariates, PES (OR=1.04, 95% CI 1.02-1.06) was significantly associated with the risk of MCI and exhibited a dose-response relationship. LPA identified two potential categories of plastic exposure, with a higher risk of MCI observed in the group using plastic utensils. Conclusions: This study indicates a positive correlation between plastic exposure levels and MCI risk, particularly among individuals who frequently use plastic tableware.
