Pages 891-896
Ethics Review
Mackenzie Graham, Martin Rossor, Brian Lawlor, Lorina Naci (Handling Editor: Allyson Rosen)
Informing cognitively healthy research participants of modifiable dementia risk factors: Ethical implications
Abstract: Research has shown that up to 40% of dementia incidence can be accounted for by 12 modifiable lifestyle risk factors. However, the predictive value of these risks factors at an individual level remains uncertain. Ethical considerations that are typically invoked with respect to the disclosure of individual research results—beneficence and non-maleficence, respect for autonomy, and justice—do not provide conclusive justification for, or against, disclosing modifiable risk factors for future dementia to cognitively unimpaired research participants. We argue for a different approach to evaluating the disclosure of individual-level modifiable risk factors for dementia. Rather than focusing on individual-level disease prediction and prevention, we suggest that disclosure should be evaluated based on the impact of behavioral and lifestyle changes on current brain health.
Pages 897-923
Review
Kalpesh Mahajan, Sanjay Sharma, Rupesh K Gautam, Rajat Goyal, Dinesh Kumar Mishra, Rajeev K Singla (Handling Associate Editor: Rekha Khandia)
Insights on therapeutic approaches of natural anti-Alzheimer's agents in the management of Alzheimer’s disease: A future perspective
Abstract: In the current scenario, Alzheimer's disease is a complex, challenging, and arduous health issue, and its prevalence, together with comorbidities, is accelerating around the universe. Alzheimer's disease is becoming a primary concern that significantly impacts an individual's status in life. The traditional treatment of Alzheimer's disease includes some synthetic drugs, which have numerous dangerous side effects, a high risk of recurrence, lower bioavailability, and limited treatment. Hence, the current article is a detailed study and review of all known information on plant-derived compounds as natural anti-Alzheimer’s agents, including their biological sources, active phytochemical ingredients, and a possible mode of action. With the help of a scientific data search engine, including the National Center for Biotechnology Information (NCBI/PubMed), Science Direct, and Google Scholar, analysis from 2001 to 2024 has been completed. This article also described clinical studies on phytoconstituents used to treat Alzheimer's disease. Plant-derived compounds offer promising alternatives to synthetic drugs in treating Alzheimer's disease, with the potential for improving cognitive function and slowing down the progression of the disease. Further research and clinical trials are needed to fully explore their therapeutic potential and develop effective strategies for managing this complex condition.
Pages 924-942
Systematic Review
Chao Ke*, Shengtao Shan*, Juli Yu, Xin Wei, Jiang Pan, Wei Zhang *These authors contributed equally to this work.
Acupuncture for patients with Alzheimer’s disease: An evidence map of randomized controlled trials, systematic reviews, and meta-analysis
Abstract: Background: Acupuncture is an effective complementary treatment for Alzheimer’s disease (AD). This review aims to summarize the available evidence provided by randomized controlled trials (RCTs) and systematic reviews (SRs) or meta-analyses (MAs) on the effect of acupuncture on AD. Objective: To systematically summarize and combine clinical research evidence on AD distribution. Methods: We conducted a comprehensive search of various databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Data, Chinese BioMedical Literature Database (CBM) and Chonqing VIP (CQVIP), from their inception to September 2023. Relevant literature about acupuncture for AD was included, and the characteristics of the evidence map were presented through charts and textual analyses. Results: In total, 117 RCTs and 17 SRs or MAs were included. The results were divided into three categories: basic characteristics of the included literature, clinical characteristics and quality assessment of the included RCTs, and clinical characteristics and quality assessment of the included SRs and MAs. Conclusions: Acupuncture as a therapeutic measure for AD has some advantages in improving cognition and quality of life; thus, it is imperative to conduct multi-center, large-scale RCTs to enhance the evidence supporting the use of acupuncture in AD. This is the first evidence map exploring acupuncture treatment for AD, providing insights into the current clinical research landscape on acupuncture treatment for AD. Furthermore, the findings of this study highlight research gaps in this field and serve as a valuable reference for guiding the planning and selection of topics for future research.
Pages 943-966
Systematic Review
Sara Martínez-López*, Mariangela Tabone*, Sara Clemente-Velasco, Maria del Rocío González-Soltero, María Bailén, Beatriz de Lucas, Carlo Bressa, Diego Domínguez-Balmaseda, Juan Marín-Muñoz, Carmen Antúnez, Beatriz G. Gálvez, Mar Larrosa *These authors contributed equally to this work.
A systematic review of lifestyle-based interventions for managing Alzheimer's disease: Insights from randomized controlled trials
Abstract: Background: Alzheimer's disease (AD) presents a significant challenge in healthcare, prompting exploration into non-pharmacological interventions to complement traditional treatments. Objective: This systematic review explores the efficacy of lifestyle-based interventions in managing AD. Methods: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus between 2018 and 2023, selecting randomized controlled trials examining factors such as exercise, diet, stress, and cognitive training in AD patients. Results: The review revealed physical exercise as the predominant non-pharmacological intervention, accompanied by dietary modifications, cognitive training, and therapies such as mindfulness and music. While exercise demonstrated improvements in quality of life, its cognitive benefits were limited. Modified diets, such as Atkins and ketogenic, displayed inconsistent effects on cognitive function but influenced other health-related parameters. Additionally, probiotic therapy and novel cognitive training technologies were explored. Conclusions: Despite some interventions showing promise in enhancing cognitive function and slowing disease progression, uncertainties remain regarding the dose-response relationship, underlying mechanisms, and potential synergistic effects. Moreover, consideration of genetic and sex-based disparities is warranted. This synthesis underscores the need for further research to elucidate the nuances of non-pharmacological interventions in managing AD effectively.
Pages 967-974
Short Communication
Ameanté Payen, James R Bateman, Sneha Dhanavanthri Muralidhara, Bonnie C Sachs, Maryjo Cleveland, Mia Yang, Samuel N Lockhart, Suzanne Craft, Jeanette M Bennett (Handling Associate Editor: Nathan D’Cunha)
Social support may buffer the effect of APOE ε4 allele on cognition in older adults
Abstract: Apolipoprotein E (APOE) ε4 is a genetic risk factor for Alzheimer’s disease (AD). Social support may confer protection against cognitive decline even in the presence of APOE ε4. We examined the relationship among APOE ε4 allele(s) carrier status, social support (overall and sub-sources), and cognition in 115 older adults (72.24±8.29 years; 71.3% female). APOE ε4 carrier status moderated social support’s effect on cognition, F(1, 106)=5.08, p=0.03, ΔR2=0.02. Among APOE ε4 carriers, as social support increased, cognitive functioning improved (β=0.19, p=0.03). This relationship was not found for APOE ε4 non-carriers, highlighting that socio-ecological influences may interact with genetic factors to influence later-life cognition.
Pages 975-980
Short Communication
Mariateresa Buongiorno*, Gonzalo Sánchez-Benavides*, Clara Marzal-Espí, Darly Milena Giraldo, Jerzy Krupinski, Natalia Cullell, Oriol Grau-Rivera, Marc Suárez-Calvet, Juan Domingo Gispert, Alex de la Sierra, for the Alzheimer’s Disease Neuroimaging Initiative and the European Prevention of Alzheimer’s Disease (EPAD) Consortium *These authors contributed equally to this work.
Blood-brain barrier permeable β-blockers association with Alzheimer’s disease cerebrospinal fluid biomarkers levels in non-demented individuals
Abstract: β-blockers that easily cross the blood-brain barrier (BBB) seem to diminish the risk of Alzheimer’s disease (AD), hypothetically facilitating waste clearance. However, their effect on AD pathophysiological markers is unknown. We compared cerebrospinal fluid (CSF) AD biomarker levels among non-demented individuals taking low, intermediate, or high BBB permeable β-blockers in two samples (ADNI: n=216; EPAD: n=79). We found that CSF amyloid-β levels were higher in individuals taking highly permeable β-blockers in the ADNI sample. This result was not replicated in EPAD, in which diminished levels of pTau181 and tTau were observed. These data suggest that β-blockers may impact AD pathophysiology.
Pages 981-986
Short Communication
Ana Sofia Costa, Lieza G Exalto, Wiesje M van der Flier, Charlotte E Teunissen, Frederik Barkhof, Hugo J Kuijf, Geert Jan Biessels, TRACE-VCI study group
Markers of amyloid-β deposition and burden of enlarged perivascular spaces in patients with cognitive impairment and small vessel disease
Abstract: MRI-visible enlarged perivascular spaces (EPVS) are common in patients with cognitive impairment and possibly linked to Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). In a study of memory clinic patients (n=450; mean age 66.5±7.45, 45.8% female), we investigated CSF amyloid-β (Aβ)1-42 (AD biomarker) and strictly lobar microbleeds (CAA marker) in relation to centrum semiovale EPVS (CSO-EPVS). Age-controlled analyses showed that severe CSO-EPVS associated with Aβ status (odds ratio [OR]=1.51, 95%CI=1.02-2.24), but not strictly lobar microbleeds (OR=1.39, 95%CI=0.92-2.11), with no significant Aβ status and microbleeds interaction. This implies that in this setting, severe CSO-EPVS is not a specific indicator of CAA.
Pages 987-993
Short Communication
Mark A Bernard, Allal Boutajangout, Ludovic Debure, Wajiha Ahmed, Anthony Q Briggs, Carolina Boza-Calvo, Alok Vedvyas, Karyn Marsh, Omonigho M Bubu, Ricardo S Osorio, Thomas Wisniewski, Arjun V Masurkar
The relationship between anxiety and levels of Alzheimer’s disease plasma biomarkers
Abstract: Anxiety is highly prevalent in Alzheimer’s disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.
Pages 994-1016
Sneh Prabha, Mohd Sajad, Farah Anjum, Md. Imtaiyaz Hassan, Anas Shamsi, Sonu Chand Thakur (Handling Associate Editor: Pankaj Gurjar)
Investigating gene expression datasets of hippocampus tissue to discover Alzheimer’s disease-associated molecular markers
Abstract: Background: Alzheimer's disease (AD) is an advancing neurodegenerative disorder distinguished by the formation of amyloid plaques and neurofibrillary tangles in the human brain. Nevertheless, the lack of peripheral biomarkers that can detect the development of AD remains a significant limitation. Objective: The main aim of this work was to discover the molecular markers associated with AD. Methods: We conducted a comprehensive microarray analysis of gene expression data from Hippocampus tissue in AD patients and control samples using three microarray datasets (GSE1297, GSE28146, and GSE29378) collected from Gene Expression Omnibus (GEO). The datasets were pre-processed and normalized, revealing 346 significant genes, 103 of which were upregulated and 243 downregulated. The PPI network of significant genes was constructed to detect the top 50 hub genes, which were then further analyzed using Gene Ontologies terms, Kyoto Encyclopedia of Genes and Genomes pathway, and GSEA, revealing 47 key genes involved in AD-related pathways. Results: The interaction of AD-associated TFs HNF4A, SPI1, EGR1, STAT3 and MYC and miRNAs hsa-miR-155-5p; hsa-miR-16-5p in the transcriptional and post-transcriptional event of 3 upregulated and 10 downregulated genes: H2AFZ, MCM3, MYO1C, AXIN1, CCND1, ETS2, MYH9, RELA, RHEB, SOCS3, TBL1X, TBP, TXNIP, and YWHAZ, respectively, has been identified. The miRNA/TF-mediated three types of the feed-forward loop (FFL) motifs, i.e., miRNA-FFL, TF-FFL, and Composite-FFL, were constructed, and seven common genes among these FFL were listed: CCND1, MYH9, SOCS3, RHEB, MYO1C, TXNIP, AXIN1, and TXNIP. Conclusions: These findings may provide insights into the development of potential molecular markers for therapeutic management of AD.
Pages 1017-1026
Si-Han Chen*, Yuan Cheng*, Yan-Jiang Wang, Yi-Fei Ji *These authors contributed equally to this work.
Interleukin-4 promotes the clearance of amyloid-β by monocyte through enhancing the recognition and intracellular processing of amyloid-β
Abstract: Background: Impaired clearance of amyloid-β protein (Aβ) in the peripheral system is a crucial event in the pathogenesis of sporadic Alzheimer’s disease (AD). Dysfunctional monocytes with deficient clearance of Aβ and increased secretion of pro-inflammatory factors in the periphery are considered to contribute to AD development. Multiple studies suggest that IL-4 can inhibit the inflammatory response and enhance the expression and activity of cathepsin protease associated with intracellular clearance of Aβ by monocytes. Objective: To investigate the effects of interleukin-4 (IL-4) on Aβ clearance and inflammatory response of monocytes in vitro. Methods: In this study, flow cytometry, confocal microscopy and ELISA techniques were used for measurement of Aβ clearance and its related mechanisms of monocytes. Results: We found that the mean intracellular content and uptake ratios of Aβ42 in total monocytes, as well as in the CD14+CD16- subset, were enhanced by IL-4, concomitant with the degradation of Aβ42 by monocytes. And IL-4 treatment also increased expression of scavenger receptor CD36 and Macrophage scavenger receptor 1 (MSR1) on monocytes. It was shown that IL-4 increased the Aβ immunoreactive area within lysosomal markers, including early endosome antigen 1 (EEA1), lysosome-associated membrane glycoprotein 1 and 2 (LAMP1 and 2) and Aβ degradative enzymes cathepsin B and S in monocytes, but reduced secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) by monocytes. Conclusions: Our study supports the role of IL-4 in regulating Aβ clearance and inflammatory response by monocytes, suggesting that IL-4 may have therapeutic potential for AD.
Pages 1027-1041
Hengming Pan, Ge Wang, Zhichao Bi, Chao Lai, Min Wang
Identification of key neutrophil extracellular trap genes in Alzheimer’s disease
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disorder that is associated with neuroinflammation. Neutrophil extracellular traps (NETs) are web-like structures that cause inflammation, but its involvement in AD pathogenesis is unclear. Objective: This study aimed to identify key NETs related genes associated with AD. Methods: A total of 180 samples from the GSE122063 and GSE36980 dataset were obtained from the GEO repository. The representative genes were obtained, and its diagnostic performance was evaluated by analyzing operating characteristic curves. Consensus clustering and principal component analysis were performed to cluster AD samples. Gene ontology, KEGG pathway enrichment, and protein interaction network were analyzed. Peripheral blood samples were collected from 5 AD patients and 5 healthy donors to determine the expression of representative proteins or genes using WB, ELISA, and RT-qPCR. Results: A total of 297 differentially expressed genes were associated with AD, 18 NETs genes showed potential diagnostic value. NETs genes expression effectively distinguished AD patients into 2 subgroups. The AD1 cluster showed higher abundance of activated dendritic cells, monocytes, and neutrophils, the AD2 cluster showed higher levels of naive B cells, eosinophils, and activated NK cells. We randomly selected and measured the levels representative genes in AD patients. The levels of NETs and CCL2, TLR2 expressions were significantly increased, whereas the level of BDNF was significantly decreased in AD patients comparing with healthy controls. Conclusions: This study identified key NET genes including BDNF, CCL2, and TLR2 to be associated with AD pathogenesis and classification.
Pages 1042-1056
Amir Mohammad Pajavand, Michel J Grothe, Michel Thiebaut De Schotten, Filippo Sean Giorgi, Andrea Vergallo, Harald Hampel, for the Alzheimer’s Disease Neuroimaging Initiative
Structural white matter connectivity differences independent of gray matter loss in mild cognitive impairment with neuropsychiatric symptoms: Early indicators of Alzheimer’s disease using network-based statistics
Abstract: Background: Depression and circadian rhythm disruption are non-cognitive neuropsychiatric symptoms (NPS) that appear at any stage of the Alzheimer’s disease (AD) continuum. Evidence suggests that NPS are linked to AD pathophysiology and hippocampal dysfunction. Objective: To examine structural white matter (WM) connectivity and its association with gray matter (GM) atrophy and to identify specific AD-related neural networks linked to NPS in individuals with mild cognitive impairment (MCI). Methods: Ninety-six elderly participants were divided into three groups based on the Global Depression Scale, Neuropsychiatric Inventory, Clinical Dementia Rating, and Mini-Mental Status Examination. Twelve individuals with MCI and NPS (MCI+) and 49 without NPS (MCI-) were classified, along with 35 age and gender-matched healthy individuals. Voxel-based morphometry and tract-based spatial statistics were used to identify structural and microstructural alterations. Network-based statistics analyzed structural WM connectivity differences between MCI groups and healthy controls. Results: Significant Structural WM connectivity and GM loss were exclusively observed in MCI+ individuals compared to controls. The hippocampus, amygdala, and sensory cortex showed GM atrophy (p<0.05), while the thalamus, pallidum, putamen, caudate, hippocampus, and sensory and frontal cortices exhibited structural WM connectivity loss (p<0.01). These data indicate early limbic system implication even without GM atrophy. Conclusions: Loss of structural WM connectivity within the Papez circuit may precede and potentially predict GM atrophy in the temporal lobe among individuals with MCI+. These findings highlight the importance of early detection of structural WM alterations in the prodromal phase of AD, which may inform diagnostic and therapeutic strategies in early AD.
Pages 1057-1073
Xiaowei Fan*, Xin Mao*, Ping Yu, Ding Han, Chuxin Chen, Hongqi Wang, Xinyi Zhang, Siyu Liu, Weijing Chen, Ziyan Chen, Xiaoqiang Du, Liangyun Jin, Yizhi Song, Hui Li, Ning Zhang, Yan Wu, Lirong Chang, Chunxue Wang *These authors contributed equally to this work.
Sleep disturbance impaired memory consolidation via lateralized disruption of metabolite in the thalamus and hippocampus: A cross-sectional proton magnetic resonance spectroscopy study
Abstract: Background: Memory consolidation in sleep-dependent individuals involves the circuitry connections of cortex, thalamus and hippocampus, regulating via neural metabolites. However, the disruption of metabolic pattern in thalamus and hippocampus remains unclear. Objective: We aim to explore the disruptive effects of insomnia on the metabolites during memory consolidation, particularly the underlying neurometabolic mechanisms in comorbidity of failed memory consolidation. Methods: This study integrates clinical research with animal experiment. In clinical research, 49 participants were divided into four groups: healthy controls (HC, n=11), insomnia with normal cognition (IS, n=14), mild cognitive impairment without insomnia (MCI, n=10), and insomnia with mild cognitive impairment (IS-MCI, n=14). Magnetic resonance spectroscopy (MRS) was used to evaluate the neural γ-aminobutyric acid (GABA) and glutamate–glutamine (Glx) in bilateral thalamus. In experimental studies, the rat model of sleep deprivation combined with amyloid-β (Aβ) injection was established, after behavior testing, the levels of Glx, choline (Cho) and N-acetyl aspartate (NAA) in the bilateral hippocampus were evaluated with MRS. Results: The patients in the IS-MCI group exhibited significantly lower GABA level than IS, MCI and HC groups. Results from rat studies showed that sleep deprivation exacerbated asymmetric alterations in Aβ-induced bilateral hippocampal metabolite abnormalities, which correlated with cognition. These neuro-metabolite disruption accompanied with synaptic loss and activation of astrocytes. Conclusions: The lateralized decrease in GABA levels of thalamus and NAA, Cho, and Glx levels of hippocampus under conditions of sleep disturbance with cognitive decline may provide evidence for the neural metabolic mechanisms underlying the disruption of memory consolidation.
Pages 1074-1083
Yanbin Xiyang, Ju Gao, Mao Ding, Xiaojia Ren, Brian S Appleby, James B Leverenz, Masaru Miyagi, Jagan A Pillai, George Perry, Xinglong Wang (Handling Editor: Paula Moreira)
Exacerbated mitochondrial dynamic abnormalities without evident tau pathology in rapidly progressive Alzheimer's disease
Abstract: Background: Rapidly progressive Alzheimer's disease (rpAD) is a clinical subtype distinguished by its rapid cognitive decline and shorter disease duration. rpAD, like typical AD (tAD), is characterized by underlying neuropathology of amyloid plaques and neurofibrillary tangles. There is early evidence that the composition of amyloid plaques could vary between the rpAD and tAD. Differences in tau pathology between rpAD and tAD are also of interest. Additionally, mitochondrial dysfunction is a key early-stage change in AD but has not yet been evaluated in rpAD. Objective: To deepen our understanding of the underlying pathophysiological processes specific to rpAD, we explore potential changes in tau pathology and mitochondrial dysfunction in rpAD compared to tAD. Methods: We performed immunohistochemical and immunoblot analyses of tau, phosphorylated tau, and key regulators of mitochondrial dynamics and bioenergetics in postmortem human temporal cortex tissues obtained from patients diagnosed with tAD or rpAD, and tissues from age-matched normal subjects. Results: tAD was characterized by significant tau phosphorylation at the PHF1 epitope. Unexpectedly, rpAD showed milder PHF1 tau phosphorylation, similar to that of age-matched controls. Despite these differences in tau pathology, both tAD and rpAD exhibited a significant decrease in the key regulators of mitochondrial dynamics and bioenergetics compared to controls. However, the decline in mitochondrial dynamics regulators was more pronounced in rpAD. Conclusions: These findings suggest divergent pathological processes between tAD and rpAD, specifically in terms of tau pathology and mitochondrial dynamic abnormalities, which underscore the necessity for different approaches to understand and potentially treat various AD subtypes.
Pages 1084-1098
Kholoud AbdElRaouf, Hussein SH Farrag, Monir A El-Ganzuri, Wael M El-Sayed
A new bithiophene inhibited amyloid-β accumulation and enhanced cognitive function in the hippocampus of aluminum-induced Alzheimer’s disease in adult rats
Abstract: Background: Alzheimer's disease (AD) is a progressive and irreversible neurological disorder that gradually deteriorates an individual's ability to carry out even the simplest tasks. Objective: This study was undertaken to investigate the potential therapeutic efficacy of a novel bithiophene in a rat model of aluminum-induced AD pathology. Methods: A total of 108 adult male albino rats weighing 160 ± 20 g, were randomly assigned to six groups: (1) a control group administered DMSO, (2) group receiving a high dose of bithiophene (1 mg/kg), (3) a model group received AlCl₃ (100 mg/kg), those rats were then treated by either (4) bithiophene low dose (0.5 mg/kg), (5) high dose (1 mg/kg), or (6) memantine (20 mg/kg). Results: Low dose bithiophene treatment was a promising strategy for mitigating oxidative stress and improving synaptic plasticity. This was demonstrated by reductions in malondialdehyde level, and increased activities of superoxide dismutase and catalase, and elevated glutathione content. Likewise, low dose bithiophene enhanced synaptic plasticity through a reduction in excitatory glutamate and norepinephrine levels, while increasing dopamine. Moreover, bithiophene significantly downregulated the expression of GSAP, GSK3-β, and p53, which are implicated in AD progression. This treatment also decreased caspase 3 and amyloid-β (Aβ1-42) accumulation in the hippocampus. Finally, behavioral assessments revealed that low dose bithiophene significantly enhanced learning abilities, as proved by Morris water maze. Conclusions: Low dose bithiophene mitigated AD through ameliorating oxidative stress, promoting synaptic plasticity, inhibiting the Aβ accumulation, and enhancing the cognitive functions in a rat model.
Pages 1099-1110
Bernhard Michalowsky, Stefan Teipel, Steffi Riedel-Heller, Karel Kostev, Jens Bohlken
Documentation of prodromal features and risk factors of dementia disease in primary care practice
Abstract: Background: Documented risk factors and prodromal features of dementia in primary care practices may support dementia prevention and early detection in routine care. Objective: To identify documented prodromal features and risk factors of dementia before the incident dementia diagnosis in German primary care practices. Methods: This case-control study used documented diagnoses (risk factors, prodromal features) and prescriptions of primary care practices for 73,717 patients with dementia disease and 73,717 matched controls (ratio 1:1). Logistic regression models were used to assess the associations between these documentations and the development of dementia diseases within 12, 12-60 (1-5 years), and 60-120 months (5-10 years) before the incident dementia diagnosis. Results: Mild cognitive impairment, depression, symptoms involving the emotional state, dizziness, and age-related physical debility were documented prodromal features associated with developing dementia diagnosis across all periods. Difficulties in gait and mobility and conduct disorders occurred significantly more often five years before the diagnosis. In terms of documented risk factors, hearing loss, visual disturbances, diabetes mellitus, and cerebrovascular diseases were associated with dementia across all periods. Mental and behavioral disorders due to the use of alcohol, intracranial injury, Parkinson's disease, chronic fatigue, intellectual disabilities, pneumonia, and epilepsy were also more often documented 60 months before the diagnosis. Conclusions: Next to mild cognitive deficits, several factors, such as disorders of conduct and emotions, gait, mobility, and mental health, can be identified and monitored in primary care practices, helping physicians focus on potential consequences for cognitive decline and subsequent dementia.</p.
Pages 1111-1120
Ziwen Gao*, Wanqiu Zhu*, Yuqing Li , Wei Ye, Xiao Chen, Shanshan Zhou, Xiaohu Li, Xiaoshu Li, Yongqiang Yu and the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Identification and cognitive function prediction of Alzheimer’s disease based on multivariate pattern analysis of hippocampal volumes
Abstract: Background: Alzheimer’s disease (AD) is strongly associated with slowly progressive hippocampal atrophy. Elucidating the relationships between local morphometric changes and disease status for early diagnosis could be aided by machine learning algorithms trained on neuroimaging datasets. Objective: This study intended to propose machine learning models for the accurate identification and cognitive function prediction across the AD severity spectrum based on structural magnetic resonance imaging (sMRI) of the bilateral hippocampi. Methods: The high-resolution sMRI data of 120 AD dementia patients, 232 amnestic mild cognitive impairment (aMCI) patients, and 206 healthy controls (HCs) were included from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The classification capacity and cognitive predict ability of hippocampal volume was evaluated by multiple pattern analysis using the support vector machine (SVM) and relevance vector regression (RVR) application of the Pattern Recognition for Neuroimaging Toolbox, separately. For validation, the analyses were performed using a biomarker-based regrouping method and another independent local dataset. Results: The SVM application produced a total accuracy of 94.17%, 80.85%, and 70.74% and area under receiver operating characteristic curves of 0.97, 0.87, and 0.72 between HC versus AD dementia, HC versus aMCI, and aMCI versus AD dementia classification, respectively. The RVR application significantly predicted the baseline and mean cognitive function at three years of follow-up. Qualitatively consistent results were obtained using different regrouping method and the local dataset. Conclusions: The machine learning methods based on the bilateral hippocampi distinguished across the AD severity spectrum and predicted the baseline and the longitudinal cognitive function with greater accuracy.
Pages 1121-1132
Deborah E Barnes*, Benjamin H Balderson*, Lisa Shulman, Dori E Rosenberg, Theresa E Matson, Kayne D Mettert, Kristin Delaney, Deborah King, Kristin Adams, Lynn Fleckenstein, Carrie B Peltz, Abisola Idu, Eric B Larson, Kristine Yaffe**, Sascha Dublin** *These individuals contributed equally as first authors. **These individuals contributed equally as senior authors.
The Systematic Multi-domain Alzheimer’s Risk Reduction Trial (SMARRT) intervention: A personalized approach to dementia risk reduction
Abstract: Background: Addressing modifiable risk factors such as physical inactivity and social isolation could reduce risk of Alzheimer’s disease and all-cause dementia, but little is known about which factors individuals are most willing to address or how they prefer to address them. Objective: To examine and describe behavior change goals set by participants during the Systematic Multi-domain Alzheimer’s Risk Reduction Trial (SMARRT). Methods: In SMARRT, older adults worked with a health coach and nurse over 2 years to set incremental, personalized goals to reduce dementia risk. We performed quantitative analyses to summarize the numbers of goals per risk factor and qualitative content analyses of health coach and nurse notes to describe types of goals and useful strategies. Results: 82 dementia-free adults (70 to 89 years) with at least two dementia risk factors participated in the SMARRT intervention arm (mean age, 76 ± 5 years; 72% women; 11% Black/African American, 4% Asian, 3% Hispanic, 7% another non-White race). Participants set a median of 12 health coach goals and 1 nurse goals. The risk factors participants chose to work on most frequently were physical activity (95%), hypertension (72%), and cognitive activity (60%). Participants reported that the most useful strategies included support and accountability from the health coach/nurse, setting small goals, and learning to manage setbacks. Conclusions: When given support, older adults at increased risk for dementia set a wide range of goals to reduce dementia risk. A flexible, personalized approach that focuses on setting feasible goals and managing setbacks provides a useful framework for dementia risk reduction.
Pages 1133-1154
Emily Mayr, Jonas Rotter, Heidrun Kuhrt, Karsten Winter, Ruth Martha Stassart, Wolfgang J. Streit, Ingo Bechmann (Handling Associate Editor: Zhou Wu)
Detection of molecular markers of ferroptosis in human Alzheimer’s disease brains
Abstract: Background: We have previously shown that droplet degeneration (DD) signifies the beginning of neuritic plaque formation during Alzheimer’s disease (AD) pathogenesis. As microglia associated with neuritic plaques exhibited strong ferritin expression and Perl’s iron staining showed iron in microglia, droplet spheres and neuritic plaque cores, we hypothesized that DD is a form of ferroptosis. Objective: Detection of molecular markers of ferroptosis in AD brains. Methods: Immunohistochemical detection of transferrin receptor (TfR) and ferritin as ferroptosis markers in prefrontal cortex of AD brains, investigation of spatial correlation of these with histopathological hallmarks of AD, visualization of ferroptotic marker genes by in situ hybridization, comparison of expression of ferroptosis genes with snRNAseq analyses and comparison of TfR and ferritin expression in different neurofibrillary tangle (NFT) stages. Results: TfR was found on neurons that appeared to be degenerating and exhibited typical features of droplet degeneration. Co-localization with hyperphosphorylated tau (p-tau) was a rare event. TfR-positive neurons increased with higher NFT stages as did ferritin expression in microglia. mRNA of genes linked to ferroptosis was detected in pretangles and p-tau negative neurons, less in DD. snRNAseq analyses support a link between AD, ferroptosis and TfR as a ferroptosis marker. Conclusions: Increased expression of TfR and ferritin in high NFT stages, demonstration of ferroptotic marker genes in Alzheimer’s lesions, as well as snRNAseq analyses strengthen our hypothesis that DD represents ferroptosis. Because of the morphological similarity between TfR-positive structures and DD, TfR might be an early ferroptosis marker expressed transiently during AD pathogenesis.
Pages 1155-1171
May A Beydoun*, Hind A Beydoun*, Michael F Georgescu, Rio Tate, Sharmin Hossain, Christian A Maino Vieytes, Alyssa A Gamaldo, Michele K Evans, Alan B Zonderman *These authors contributed equally to this work.
Sleep patterns, global mental status and mortality risk among middle-aged urban adults
Abstract: Background: Sleep, cognition, and mortality may be interdependent. Objective: We explored paths between sleep, cognition and mortality and potential interactions. Methods: The study examines the relationship among sleep, global mental status, and mortality risk using data from 1,364 participants from the Healthy Aging in Neighborhood of Diversity across the Life Span (HANDLS) study. We used Cox proportional hazards models and four-way decomposition models to analyze sleep patterns and global mental status. Results: After a median time at risk of 8.2 years, 172 deaths occurred, with rate of 16 per 1000 person-years. A 1-unit increase in the Pittsburgh Sleep Quality Index (PSQI) global score was linked to a 7% increase in mortality risk in the reduced model, but this effect was attenuated in the full model. In both reduced and fully adjusted models, the PSQI global score and sleep quality domains interacted with global mental status, with poor sleep generally associated with mortality risk in the group with better global mental status at first-visit. In four-way decomposition models, total effects (TE) of PSQI scores on mortality risk were positive and statistically significant, while being mostly controlled direct effects. However, among women, the inverse TE of global mental status on mortality risk was partially mediated by PSQI sleep latency and the PSQI global. Conclusions: Poor global mental status is associated with greater mortality risk at better sleep quality levels and vice versa. Further longitudinal studies with multiple sleep and cognitive performance repeats are needed to corroborate these findings.
Pages 1172-1182
Timothy R Juday, Ashley Holub, Soeren Mattke, Keith A Betts, Sophie A. Kitchen, Hongjiao Liu, Richard Batrla, Feride H Frech, Ara S. Khachaturian
Real-World Diagnostic, Referral, and Treatment Patterns in Early Alzheimer’s Disease Among Community-Based Practices in the United States
Abstract: Background: Over 90% of individuals with mild cognitive impairment (MCI) may not receive a timely diagnosis. Understanding community-based practice patterns, where most individuals are seen, is critical to improving patient care. Objective: To understand how patients with MCI and mild dementia due to Alzheimer’s disease (AD) are diagnosed and managed in community-based settings, including the use of clinical and cognitive assessments, referrals to dementia-related specialties, and receipt of treatment. Methods: This observational study recruited community-based primary care physicians (PCPs) (N=177) and neurologists (N=147) in August-September 2023, through a verified physician panel with broad geographic representation across the US. Physicians abstracted medical chart data from patients diagnosed with MCI or mild AD within the previous two years. Data collected included use of neurocognitive assessments, biomarker and structural imagine tests, referrals, and treatments. Descriptive statistics were used. Results: Medical records for 817 MCI and 467 mild AD patients were abstracted. The mean age was 70.2 years, 56.4% were female, and 67.2% were White. Symptoms were commonly reported by a family member (67.2%). Nearly 1 in 6 patients did not receive any neurocognitive assessments (16.1%), and nearly 1 in 4 did not receive a structural imaging or AD-specific biomarker test (23.7%). AD-specific biomarker tests were more common among patients aged ≥65 (87.1% versus 75.3%; p<0.05). Less than 1 in 4 patients were referred for cognitive/behavioral concerns. Conclusions: As the diagnostic and treatment landscape changes, education on symptom recognition, and physician training on new technologies may facilitate timely diagnoses and improve patient outcomes.
Pages 1183-1196
Jingyuan Xu, Hanneke JA Smaling, Albert Dahan, Justin Chan, Jenny T van der Steen (Handling Associate Editor: Nathan D’Cunha)
Acceptability of Bispectral Index monitoring in end-of-life care for dementia
Abstract: Background: Assessing consciousness might benefit the care for people with Alzheimer’s disease and other types of dementia at the end of life by indicating distressing symptoms and moments of awareness. This could guide symptom control and increase interaction with the person with dementia. Objective: This study aims to investigate the acceptability of a biosignal measurement of consciousness, the Bispectral Index monitoring (BIS), for persons with dementia at the end of life. Methods: Qualitative study using focus groups and interviews with demonstrations of BIS monitoring, with 17 individuals with dementia and 24 family caregivers. Qualitative content analysis was based on the theoretical framework of acceptability. Results: People with dementia did not find BIS monitoring bothersome, yet acceptability varied across participants and situations. Family caregivers considered BIS acceptable for medical situations such as palliative sedation and pain assessment. Perceived effectiveness, ethicality, and usefulness considerations underpinned reasons and concerns around acceptability. Conclusions: Potential end-users expressed diverse attitudes towards BIS monitoring in dementia end-of-life care. If BIS or similar technologies are to be implemented in the future, care must be taken to ensure that the device has sufficient added value, that the person with dementia and family are well informed, and that the technology does not replace human care. Future research should investigate its efficacy and feasibility in the situations that were deemed acceptable.
Pages 1197-1208
Stephen G Post, John Paul Ross, Rebecca Bonhag, Wei-Hsin Lu
Lucidity in deeply forgetful people: A national U.S. survey of caregivers’ reactions
Abstract: Background: Despite the prevalence and challenge of Alzheimer’s disease and related dementias, glimmers of hope arise during lucid moments. Caregivers, often burdened, play a crucial role. The study explored emotional responses to witnessed episodes of unexpected lucidity in deeply forgetful people, aiming to highlight the significance and varying reactions, especially among caregivers of this population. Objective: The aim of this study was to elucidate how moments of unexpected lucidity are experienced by those who witness them, and to examine whether caregivers and non-caregivers, as well as different types of caregivers may have different emotional reactions to the episodes. Methods: A probability-based sample representative of the United States adult population aged 40 and older with internet access was employed. 5,944 respondents completed screening questions regarding whether they knew an individual with dementia and had witnessed unexpected lucidity. Close to 2,000 individuals answered questions regarding their emotional reactions to witnessing unexpected lucidity, which we aimed to examine in more detail. Results: Both caregivers and non-caregivers showed a tendency towards positive emotions in response to lucid episodes, yet negative emotions were also mentioned. We observed group differences (caregivers versus non-caregivers, different caregiver types) in the emotional responses for some of the examined emotions. Conclusions: Caregivers can find inspiration in these fleeting moments. The research aims to guide caregivers and enhance the understanding of the enduring self-identity of deeply forgetful people, promoting compassionate care and recognizing the significance of our shared humanity.
Pages 1209-1223
Jinghuan Gan*, Yan Zeng*, Guowei Huang*, Xiao-Dan Wang*, Yang Lü*, Jianping Niu*, Xinling Meng, Pan Cai, Xia Li, Yang Li, Lu Shen, Yong You, Baozhi Gang, Yanqing Tang, Yan Lv, Zhihong Ren, Shuai Liu, Yong Ji *These authors contributed equally to this work.
The updated prevalence and risk factors of dementia in old adults in China: A cross-sectional study
Abstract: Background: The continuously increasing aging population and life expectancy have led to an inconsistent and underestimated dementia prevalence in China. An updated epidemiologic study is urgently needed. Objective: To update the prevalence rate and risk factors of dementia in China. Methods: For this national cross-sectional study, 20,438 participants aged ≥65 from 28 communities and 56 villages from 14 centers were recruited using a multistage cluster sampling design between May 2019 and December 2019. Participants were assessed with a series of clinical and neuropsychological measurements. The prevalence rates of dementia, Alzheimer’s disease (AD), and vascular dementia (VaD), as well as the risk factors, were calculated using multivariate-adjusted models. Results: The crude prevalence rates were 9.1% (95% CI, 8.7%-9.5%) for dementia, 6.0% (95% CI, 5.7%-6.3%) for AD, 1.4% (95% CI, 1.2%-1.5%) for VaD, and 1.8% (95% CI, 1.6%-2.0%) for other dementias in a population aged ≥65 years. The overall sex- and age-standardized prevalence was 8.8%. Apart from VaD, the prevalence rates of dementia and AD were higher in females than males (10.3% versus 7.7%, respectively). Moreover, the prevalence rates of dementia and AD increased significantly with age. Being unmarried and having fewer social activities increased the risks of dementia and main subtypes. Risk factors were not exactly the same for participants with AD and VaD. Conclusions: The prevalence of dementia is increased and almost comparable with that of developed countries for individuals aged ≥65 years. These findings may serve as new evidence for government interventions in aging.
Pages 1224-1238
Wenjia Liu, Sophia Chen, Xin Rao, Xiaodong Chen, Liyang Yu, Jiangtao Zhang, Jiong Chen, Bohan Cui
Exploring the role of miR-125b-5p as a pro-inflammatory factor in Alzheimer’s disease pathology
Abstract: Background: Alzheimer’s disease (AD) is a common neurodegenerative disease, where neuroinflammation significantly influences its pathophysiology by driving the disease's pathological cascade. As a pro-inflammatory regulator, miR-125b-5p contributes to AD progression, though its precise role and mechanisms remain unclear. Objective: We aims to identify mRNAs significantly regulated by pro-inflammatory miR-125b-5p in AD and uncover key neuroinflammatory pathways. Methods: Target mRNAs regulated by miR-125b-5p were predicted using online databases and analyzed with two mRNA datasets to identify differentially expressed mRNAs (DEmRNAs). Enrichment analysis was conducted to explore their biological functions and pathways. The significance of DEmRNAs expression in AD-related inflammatory pathways was verified by the Wilcoxon test, predictive accuracy was assessed via area under the curves (AUCs), and novel mRNAs were identified through positive control analysis. Results: A total of 613 miR-125b-5p target mRNAs were identified, and 44 DEmRNAs were detected to be regulated by miR-125b-5p in two datasets. The 44 target DEmRNAs associated with AD include three key pathways: insulin signaling (EXOC7, FLOT2, MKNK2), phosphatidylinositol signaling (IP6K1, MTMR3), and phospholipase D signaling (CYTH1, GAB2). Correlation analysis indicated strong correlations among 7 mRNAs, all showing significant differential expression, with AUCs above 0.5, confirming their predictive value. Three mRNAs (EXOC7, IP6K1, CYTH1) were identified as novel AD-related genes. MiR-125b-5p binding sites in the 3’-UTRs of these 7 mRNAs suggest their potential roles in AD-related inflammation and signaling pathways. Conclusions: This study investigates the pro-inflammatory miR-125b-5p’s role in the pathological processes of AD, highlighting its regulation of key target mRNAs and critical pathways.
Pages 1239-1248
Boaz Levy, Gianna D'Ambrozio
Stepwise identification of prodromal dementia: Testing a practical model for primary care
Abstract: Background: Prodromal dementia is largely underdiagnosed in primary care. Objective: To develop a clinical model for detecting prodromal dementia within the operative boundaries of primary care practice. Methods: The study employed the Functional Activities Questionnaire (FAQ) and Montreal Cognitive Assessment (MoCA) to evaluate a “functional-cognitive” step-down screening model, in which the MoCA is administered subsequent to reported symptoms on the FAQ. It classified participants from the Alzheimer’s Disease Imaging Initiative to three diagnostic categories: 1) healthy cognition (n=396), 2) mild cognitive impairment without conversion (n=430), and 3) prodromal dementia assessed 24 months before diagnosis (n=164). Results: Analyses indicated that the step-down model (Model 1) performed significantly better than an alternative model that applied the FAQ as a single measure (Model 2) and compared well with another model that administered both screening measures to all participants (Model 3). Gradient Boosting Trees classifications yielded the following estimations for Model 1/Model 2/ Model 3, respectively: Sensitivity=0.87/0.77/0.89, Specificity=0.68/0.47/0.70, PPV=0.73/0.40/0.75, NVP=0.84/0.81/0.87, F1 Score=0.79/0.52/0.81, AUC=0.78/0.67/0.79. Conclusions: These analyses support the proposed model. The study offers algorithms for validated measures, which were developed from a well characterized clinical sample. Their accuracy will likely improve further with new data from diverse clinical settings. These results can serve primary care in a timely manner in light of the recent advances in pharmacological treatment of dementia and the expected increase in demand for screening.
Pages 1249-1259
Meichun Tao, Lei Cui, Yuanyuan Du, Xiaotang Liu, Can Wang, Jing Zhao, Huimin Qiao, Zhenzhong Li，Mei Dong
Analysis of eye movement features in patients with Alzheimer's disease based on intelligent eye movement analysis and evaluation system
Abstract: Background: The early identification of Alzheimer's disease (AD) benefits patients, so creating a simple and convenient method is crucial for diagnosing early symptoms. Objective: To offer a potential approach for the early detection of both AD and mild cognitive impairment (MCI). Methods: Eye movement data from 66 patients were divided into three groups, including healthy control group (HC), MCI group, and AD group. We searched for parameters that can detect MCI at an early stage and drew receiver operating characteristic (ROC) curves. The correlation between eye movement parameters and cognitive scores was analyzed. Results: The MCI group differed from the HC group in error correction rate of antisaccade (p=0.008) and total offset degrees (>4°) (p=0.011) of lateral fixation. The AD group had different overlap prosaccade accuracy (p=0.025), latency (p=0.009) and average completion time (p=0.015), gap prosaccade latency (p=0.005) and average completion time (p=0.005), antisaccade accuracy (p=0.006), error correction rate (p<0.001) and average saccade velocity (p=0.035), and lateral fixation accuracy (p=0.018), total offset degrees (>4°) (p=0.041) compared to the HC group. The AD group differed significantly from the MCI group in accuracy (p=0.001) and error correction rate (p=0.044) of antisaccades, the latency (p=0.009) and average completion time (p=0.025) of overlap prosaccade and the latency (p=0.038) of gap prosaccade, these parameters can serve as indicators to monitor the progress of the disease. Lateral fixation combined with antisaccade was more conducive to identifying MCI patients with the area under the ROC curve of 0.837. Most eye movement parameters had a light to moderate correlation with cognitive scores. Conclusions: Eye movements can be used for early identification of MCI/AD patients and to monitor disease progression.
Pages 1260-1270
Sapna Rao, Joan Forns, Heather E Danysh, Brian Calingaert, Colleen Dempsey, Thomas Aquilina, Sanjeev Pathak, Mary S Anthony, J Bradley Layton
Natural history and clinical outcomes in patients with Alzheimer’s disease–related psychosis by antipsychotic treatment status in the United States
Abstract: Background: While some literature on clinical outcomes in persons with dementia-related psychosis exists, little is known regarding Alzheimer’s disease–related psychosis (ADP). Objective: Describe demographic/clinical characteristics of adults with ADP and estimate incidence of clinical events by antipsychotic treatment status. Methods: This cohort study identified adults ≥65 years with Alzheimer’s disease and incident psychosis (US Medicare database [2013-2018]) and no prior exposure to antipsychotics. Two nonmutually exclusive ADP subcohorts included: patients who initiated treatment with antipsychotic medications (antipsychotic users) and those who remained untreated (antipsychotic nonusers). Baseline characteristics were evaluated before psychosis diagnosis in untreated patients and before antipsychotic initiation in treated patients. Incidence rates were estimated for falls and fractures (composite and separately), seizure/epilepsy (new onset and any), and mortality. Results: 145,333 ADP antipsychotic nonusers and 49,452 antipsychotic users were identified. Both cohorts had similar baseline demographics; however, antipsychotic users versus nonusers had higher baseline skilled nursing facility use (40.3% and 27.8%), mood (72.7% and 62.1%) and anxiety (70.9% and 57.3%) disorders, falls/fractures (39.5% and 33.8%), urinary tract infections (55.1% and 47.0%), and frailty index scores (76.0% and 69.7%). Crude incidence rates (95% confidence interval)/100 person-years in antipsychotic users and nonusers were 70.0 (68.9-71.2) and 55.8 (55.4-56.1) (falls/fractures composite), 69.0 (67.9-70.1) and 54.9 (54.5-55.2) (falls), 38.6 (38.1-39.0) and 33.0 (32.7-33.2) (mortality), and 45.8 (44.9-46.7) and 54.2 (53.9-54.6) (any seizure/epilepsy). Conclusions: Antipsychotic initiators with ADP had a higher burden of some baseline comorbidities; experienced higher incidence of falls, fractures, and mortality; and had lower incidence of seizure/epilepsy than antipsychotic nonusers.
Pages 1271-1285
Hisaomi Suzuki, Kenji Tagai, Maiko Ono, Hiroshi Shimizu, Hironobu Endo, Hideki Matsumoto, Manabu Kubota, Yuko Kataoka, Sho Moriguchi, Shin Kurose, Masanori Ichihashi, Hitoshi Shinotoh, Kiwamu Matsuoka, Naomi Kokubo, Harutsugu Tatebe, Sayo Matsuura, Yasuharu Yamamoto, Yuki Momota, Kazunori Kawamura, Ming-Rong Zhang, Yuhei Takado, Hitoshi Shimada, Takahiko Tokuda, Mitsumoto Onaya, Masaru Mimura, Akiyoshi Kakita, Naruhiko Sahara, Hiroyuki Uchida, Makoto Higuchi, Keisuke Takahata
Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer’s disease patients revealed by positron emission tomography
Abstract: Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.
Pages 1286-1296
Maureen Okafor, Zhiyi Yang, Kayci L Vickers, Katherine Sanders, Najé Simama, Kelsey C Hewitt, James Lah, Allan I Levey, Felicia C Goldstein, Ihab Hajjar (Handling Associate Editor: Gabrielle Britton)
Technology literacy and access to digital resources for remote assessment among adults enrolled in Alzheimer’s disease research
Abstract: Background: The SARS-CoV-2 pandemic accelerated development of innovative methods for conducting research remotely via digital technologies. However, few studies have examined participant technological literacy skills or access as key social determinants of brain health in aging populations at risk of Alzheimer's disease and other dementias. Objective: To identify associations of sociodemographic and clinical characteristics, cognitive status and geolocation with digital technology access and skill within dementia research cohorts. Methods: A self-administered questionnaire surveyed digital access and literacy skills in persons enrolled across various studies conducted at Emory Goizueta Alzheimer’s Disease Research Center. We investigated cognitive and sociodemographic characteristics, and neighborhood disadvantage related to these digital attributes. Results: Of 1,860 participants (mean age: 65.3 years (SD:11.4)) surveyed, 71.6% were women, 87.1% Whites, 10.4% African Americans, and 46.9% had postgraduate-level education. Most participants had access to digital devices: desktop (53.7%), laptop (81.6%), tablet (71.6%), smartphone (94.6%), internet (82.0%), or videoconferencing (95.5%). Cognitively unimpaired participants had higher odds of digital access (OR:3.75; 95% CI:2.45-5.73) and skill (OR:1.22; 95% CI:1.14-1.30). Although Whites were likelier to have access (OR:1.36; 95% CI:1.01-1.82) than African Americans, no differences were found in skill between the two groups. Living in more disadvantaged neighborhoods was significantly associated with lower technology skills (OR:0.86; 95% CI:0.82-0.91). Conclusions: Cognitive impairment, race, and neighborhood socioeconomic disadvantage are significant barriers which limit digital access and skill. Improving digital knowledge, skill-building, and geographic access may encourage research participation especially in geographically remote or disadvantaged areas and help narrow sociodemographic and racial disparities existing in dementia research.
