Review
Ruqaiya Jamal, Mohammad Abuzar Shaikh, Mohamad Taleuzzaman, Ziyaul Haque, Mohammed Albratty, Md Shamsher Alam, Hafiz A. Makeen, Khalid Zoghebi, Safaa Fathy Saleh
Key biomarkers in Alzheimer's disease: Insights for diagnosis and treatment strategies
Abstract: Alzheimer's disease (AD) remains a significant global health challenge, characterized by its progressive neurodegeneration and cognitive decline. The urgent need for early diagnosis and effective treatment necessitates the identification of reliable biomarkers that can illuminate the underlying pathophysiology of AD. This review provides a comprehensive overview of the latest advancements in biomarker research, focusing on their applications in diagnosis, prognosis, and therapeutic development. We delve into the multifaceted landscape of AD biomarkers, encompassing molecular, imaging, and fluid-based markers. The integration of these biomarkers, including amyloid-β and tau proteins, neuroimaging modalities, cerebrospinal fluid analysis, and genetic risk factors, offers a more nuanced understanding of AD's complex etiology. By leveraging the power of precision medicine, biomarker-driven approaches can enable personalized treatment strategies and enhance diagnostic accuracy. Moreover, this review highlights the potential of biomarker research to accelerate drug discovery and development. By identifying novel therapeutic targets and monitoring disease progression, biomarkers can facilitate the evaluation of experimental treatments and ultimately improve patient outcomes. In conclusion, this review underscores the critical role of biomarkers in advancing our comprehension of AD and driving the development of effective interventions. By providing a comprehensive overview of the current state-of-the-art, this work aims to inspire future research and contribute to the goal of conquering AD.
Systematic Review
Fei Wu, Caroline Dallaire-Théroux, Élodie Michaud, Frédéric Bergeron, Monica Lavoie, Jean-Paul Soucy, Ali Dirani, Robert Jr Laforce
Diagnosing neurodegenerative disorders using retina as an external window: A systematic review of OCT-MRI correlations
Abstract: Background: Recent studies have explored optical coherence tomography (OCT) and OCT-angiography (OCT-A) as biomarkers for Alzheimer's disease (AD). However, correlations between OCT/OCT-A and neurodegeneration metrics remain underexplored. Objective: We performed a systematic review of OCT/OCT-A and structural brain imaging using MRI across various neurodegenerative disorders. Methods: We searched Medline, Embase, and various other databases from January to June 2023 using keywords regarding neurodegenerative conditions and OCT/OCT-A. Out of 2962 citations. 93 articles were reviewed, and 28 met our inclusion criteria. Results: Layer-or-region-specific retinal metrics were the most promising for non-vascular neurodegeneration, while vascular retinal parameters had the unique capacity to reflect vascular lesions. Both types of biomarkers correlated with global brain atrophy. Microstructural brain alterations best correlated with layer-specific thinning of retina. Conclusions: A better understanding of associations between retinal and brain lesions could eventually lead to the clinical application of retinal biomarkers for the early diagnosis of neurodegenerative conditions.
Systematic Review
Rehab Emad Ashmawy, Olalekan John Okesanya, Bonaventure Michael Ukoaka, Faithful Miebaka Daniel, Sonsochukwu Godfrey Ezedigwe, Abdulmajeed Opeyemi Agboola, Mohamed Mustaf Ahmed, Jerico Bautista Ogaya, Blessing Olawunmi Amisu, Olaniyi Abideen Adigun, Olanegan Gloria Oluwakemi, Ayaat Mohamed Hamza, Marina Ramzy Mourid, MBN Kouwenhoven, Don Eliseo Lucero-Prisno III
Exploring the efficacy and safety of lecanemab in the management of early Alzheimer’s disease: A systematic review of clinical evidence
Abstract: Background: Alzheimer's disease (AD) is a growing neurodegenerative disorder causing cognitive decline, memory loss, and functional impairment. Lecanemab has shown safety and efficacy in clinical trials. Objective: This review aims to understand the clinical evidence of lecanemab's effectiveness and safety in managing early AD. Methods: A systematic search was conducted using the Scopus database and ClinicalTrials.gov. Studies from 2014 to 2024 on lecanemab’s safety, efficacy, and clinical outcomes for AD were included. Data extraction involved two independent reviewers, with synthesis using qualitative methodology. Results: Findings from 13 studies and 13 ongoing clinical trials were reported, showing that lecanemab substantially reduces amyloid plaque load in the brains of AD patients. The therapeutic regimens vary across reported studies and trials, ranging from 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg intravenously biweekly. The Clarity AD phase 3 trial, the AHEAD study, and the DIAN-TU-001 trials have reported positive study outcomes with robust efficacy and safety outcomes with minimal side effects. Completed and ongoing trials report on the onset of amyloid-related imaging abnormalities (ARIA) and the continuation of care status following the onset of ARIA in these patients. The common infusion-related reactions were observed in 26.4% of the lecanemab group compared to 7% in the placebo group. Conclusions: The management of AD has evolved over the years with the introduction of novel therapeutic agents like lecanemab. While its safety profile is generally favorable, careful monitoring is essential.
Short Communication
Hyena Kim#, Ambar Kulshreshtha#, Alvaro Alonso, Felicia C Goldstein, Erik CB Johnson, Matthew E Gold, Arshed A Quyyumi, James J Lah #These authors contributed equally to this work.
The association between pulse wave velocity and cerebrospinal fluid biomarkers for Alzheimer's disease
Abstract: We examined the association between arterial stiffness (using non-invasive pulse wave velocity (PWV)) and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers. We conducted a cross-sectional multivariate logistic regression analysis using established cut-off values for PWV and CSF biomarkers. Of the 739 participants, 69% were female, 84% White, 12% Black, and the mean age was 62. After adjustment for potential confounders, participants with high PWV had 94% (OR= 1.94, 95% CI 1.20-3.20) greater odds of AD biomarker positivity for tTau/Aβ42 and 108% (OR= 2.08, 95% Cl, 1.27-3.46) for pTau181/Aβ42. Our results suggest higher arterial stiffness is associated with AD CSF biomarker positivity.
Short Communication
Janet Malek, Ariel Levchenko, Jill O Robinson, Jamie Fong, C Roy Lin, George R Jackson, Jennifer Blumenthal-Barby, Joshua M Shulman, Amy L McGuire (Handling Associate Editor: Allyson Rosen)
Dilemmas in diagnosing Alzheimer’s disease: The peril and promise of self-fulfilling prophecies
Abstract: To date, there are limited empirical data to inform various approaches to communication with patients receiving information on Alzheimer’s disease (AD) risk or diagnosis during the pre-symptomatic or minimally symptomatic stages. This article explores the ethical implications of psychological responses known as self-fulfilling prophecies to potentially impact cognitive decline among individuals diagnosed with or at risk for AD. We describe questions these potential effects raise about the ways clinicians communicate with patients, as well as how caregivers may interact with patients. Recent advancements in biomarkers and treatment for AD underscore the urgency of understanding these phenomena and developing appropriate responses.
Short Communication
Anthony Q Briggs, Carolina Boza-Calvo, Mark A Bernard, Henry Rusinek, Rebecca A Betensky, Arjun V Masurkar (Handling Associate Editor: Jianping Jia)
The association between measures of sleepiness and subjective cognitive decline symptoms in a diverse population of cognitively normal older adults
Abstract: Subjective cognitive decline (SCD) is associated with preclinical Alzheimer’s disease (AD). Suboptimal sleep is also a risk factor for cognitive decline, but with unclear relationship to SCD. We conducted a retrospective cross-sectional study in a biracial research cohort of 148 cognitively normal older adults who underwent quantification of SCD (Cognitive Change Index; CCI), sleepiness (Epworth Sleepiness Scale; ESS), depression (Geriatric Depression Scale; GDS), and amyloid/tau PET. ESS score was associated with total, amnestic, and non-amnestic CCI scores, after adjustment for GDS, amyloid/tau burden, and race. This supports future longitudinal work on how sleepiness impacts SCD outcomes.
Short Communication
Daniele Urso, Alessandro Introna, Valentina Gnoni, Alessia Giugno, Davide Vilella, Chiara Zecca, Roberto De Blasi, Stefano Giannoni-Luza, Giancarlo Logroscino
Donanemab eligibility in early Alzheimer’s disease: A real-world study
Abstract: This study evaluates the real-world eligibility of patients with early Alzheimer's disease (AD) for donanemab, a monoclonal antibody targeting amyloid plaques. At a tertiary center in Italy, 408 patients with mild cognitive impairment (MCI) or mild AD were assessed against clinical trial criteria. While 41% were amyloid-positive, only 10.05% met eligibility for treatment, primarily due to exclusions for amyloid biomarkers, medical conditions, and MRI findings. These results highlight the gap between trial populations and real-world patients. Balancing efficacy with safety remains a key challenge in expanding access to anti-AD immunotherapy like donanemab in routine clinical practice.
Short Communication
Jairo E Martinez, Yamile Bocanegra, Ana Baena, Stephanie Langella, Averi Giudicessi, Justin S Sanchez, David Aguillon, Alice Cronin-Golomb, Yakeel T Quiroz
Religious stress coping is associated with lower entorhinal tau pathology and better memory performance in autosomal dominant Alzheimer’s disease
Abstract: Stress is a known risk factor for Alzheimer’s disease (AD), but religious stress coping practices, (e.g., prayer and attending religious services) may reduce this risk. We investigated the relation between religious stress coping and memory in cognitively-unimpaired individuals from the Colombian kindred with autosomal dominant AD. Additionally, we examined the link between religious stress coping and brain pathology. Religious coping was associated with lower entorhinal tau (p=0.02) and better memory performance (p=0.04) in Presenilin-1 E280A mutation carriers, but not in non-carriers. These findings suggest that religious coping may mitigate AD tau pathology and cognitive decline and warrant further investigation.
Commentary
Nil Saez-Calveras, Makoto Ishii
Hydrate to keep the amyloid away
Abstract: Despite older adults being more susceptible to dehydration, the relation between hydration and Alzheimer’s disease and related dementias (ADRD) remains largely unexplored. A recent study by Jee Wook Kim and colleagues examined the association between daily fluid intake and ADRD neuroimaging biomarkers in 287 cognitively normal older adults. They found that lower daily fluid intake was associated with greater brain Aβ deposition and cerebrovascular injury. Here, we discuss the strengths and limitations of this study. We further highlight the potential for reverse causality and how hydration may play a role in the clinic and future ADRD research studies.
Commentary
Claudio Zaccone#, Paraskevi Krashia#, Marcello D’Amelio #These authors contributed equally to this work.
A spit for a tip in dementia diagnosis: Evidence from saliva for dementia with Lewy bodies
Abstract: Being the second most-frequent type of age-related neurodegenerative dementia, dementia with Lewy bodies (DLB) is currently exerting a huge burden on the healthcare system. Since DLB lacks a definitive biomarker profile, a diagnostic tool becomes indispensable for effectively distinguishing DLB from other neurodegenerative diseases with overlapping neuropathological and clinical features in their early stages. In this context, saliva could serve as a viable alternative to more invasive and costly methods, providing clear advantages in terms of safety and affordability. This is a commentary serving to contextualize the findings of D’Antonio et al., featured in the Journal of Alzheimer's Disease.
David Oluwasayo Babalola#, Boluwatife Adeleye Adewale#, Kenechukwu Franklin Okwunze, Teslim Timilehin Mohammed, Ifeoluwa Oluwasegun Oduguwa, Hilda Amauche Igwe, Temitope Farombi, Rufus Olusola Akinyemi #These authors contributed equally to this work.
Knowledge and Attitudes about Dementia and Dementia Genetics in a Cohort of Geriatric Clinic Attendees in Nigeria
Abstract: Background: Population ageing in Africa will increase the burden of Alzheimer’s disease and related dementias in within the next few decades. Despite the potential for discovery of novel genetic risks in African populations, there is still a paucity of dementia genetic research among indigenous Africans. Objective: We aimed to investigate the knowledge and attitudes of elderly population in Nigeria about dementia and dementia genetics. Methods: One hundred clinic attendees (aged ≥60 years) recruited at the University College Hospital, Ibadan, Nigeria were surveyed using an interviewer-administered questionnaire consisting of the Dementia Knowledge Assessment Scale (DKAS) and other items assessing knowledge and attitudes about dementia genetics. Results: The mean age (±SD) of participants was 71.0 (±7.1) years with a mean (±SD) DKAS score was 8.87 (±10.84). Only 10% were considered to have good knowledge of dementia (i.e., DKAS score ≥26). Attempts by participants to translate “dementia” in their local languages revealed misleading themes in their perception of the condition. Of the 42 participants who claimed to know what dementia is, 32 (76.2%) of them had poor knowledge (i.e., DKAS <26). Twenty-one participants were aware of the existence of genetic risk factors for dementia, but none could name a dementia risk gene. Seventy participants expressed willingness to undergo genetic testing to assess their risk of dementia. Conclusions: There is a poor level of knowledge about dementia and dementia genetics among the elderly population in Nigeria. Public health education and community engagement is important for maximizing the impact of dementia genetics studies in Africa.
Shuoshi Wang, Jingnian Ni, Mingqing Wei, Ting Li, Jing Shi, Jinzhou Tian, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Teruyuki Matsuoka)
Impact of obesity on neuropsychiatric symptoms in Alzheimer’s disease: Insights from the ADNI cohort
Abstract: Background: Obesity is a major global health issue linked to increased risks of dementia, including Alzheimer's disease (AD). While the association between obesity and neuropsychiatric symptoms (NPS) in AD remains underexplored, identifying these links could aid in weight management in AD patients. Objective: This study investigates the relationship between body mass index (BMI) and NPS in AD dementia patients, focusing on the potential mediating role of systemic inflammation. Methods: We employed Generalized Additive Models (GAMs) to explore the relationship between BMI and NPS, as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q). Participants were classified into ideal, overweight, and obese groups based on WHO criteria. Longitudinal analyses assessed the trajectory of NPI-Q scores in different groups over a one-year follow-up. Results: BMI significantly affects NPI-Q total scores and specific symptoms, including delusions, hallucinations, agitation/aggression, elation/euphoria, disinhibition, irritability/lability, aberrant motor behavior, nighttime disturbances, and appetite/eating disturbances. Obese patients exhibited higher NPI-Q total scores and greater severity in symptoms such as hallucinations, agitation/aggression, elation/euphoria, apathy/indifference, disinhibition, aberrant motor behavior, and nighttime disturbances. Additionally, CRP and complement C3 were identified as mediators in the relationship between obesity and NPS, highlighting the role of systemic inflammation. Conclusions: This study demonstrates that obesity is associated with a heightened burden of NPS in AD dementia patients. The identification of CRP and complement C3 as mediators suggests inflammation plays a crucial role in the association between obesity and NPS. These findings underscore the importance of addressing obesity and its inflammatory consequences in managing NPS among this vulnerable population.
Tohmi Osaki, Yutaro Oki, Ryoko Kumagai, Rei Ono, Hisafumi Yasuda, Yoji Nagai, Hisatomo Kowa (Handling Associate Editor: Robert Rissman)
Longitudinal deterioration of subjective cognitive decline in apolipoprotein ε4 carriers and improvement of subjective cognitive decline by multi-domain intervention for prevention of dementia: The Cognitive Function Instrument Assessment
Abstract: Background: Subjective cognitive decline represents an early stage of mild cognitive impairment, with the Cognitive Function Instrument (CFI) serving to subjectively evaluate the decline in daily living activities associated with this minor cognitive decline. Objective: To examine how CFI scores change with apolipoprotein E ε4 (ApoE4) carriage, objective cognitive decline, and dementia prevention intervention. We aimed to assess CFI’s usefulness in the early dementia risk identification. Methods: This study involved 196 older adults with normal cognition in a randomized controlled intervention trial. CFI was assessed every six months from baseline to 18 months, using the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC) to measure cognitive decline. We employed a mixed model for repeated measures to compare the CFI scores at 18 months in the ApoE4, ADCS-PACC, and allocation groups. Results: CFI scores increased in ApoE4 carriers and decreased in the intervention group, with significant differences observed in the CFI score changes at 18 months between carriers and non-carriers and among the allocation groups (p=0.002, p=0.026, respectively). However, there was no significant difference in the CFI score change among ADCS-PACC groups (p=0101). Conclusions: We observed CFI scores worsening over time in individuals with ApoE4 and showing a tendency to deteriorate over time in those with objective cognitive decline. These findings suggest that the CFI may be able to identify high-risk individuals for dementia at an early stage. Furthermore, the improvement in the CFI score is considered a significant finding when considering future measures for subjective cognitive decline.
Miguel Ramos-Henderson, Marcelo Avalos-Tejeda, Claudia Carvallo
Picture Free and Cued Selective Reminding Test (P-FCSRT): A normative study for Chilean middle-aged and older adults
Abstract: Background: The Picture Free and Cued Selective Reminding Test (P-FCSRT) has proven useful in assessing episodic memory while controlling for interference from attentional processes. In Chile, studies have supported its diagnostic utility in detecting dementia in older adults, however, it lacks both normative data that account for the influence of age and educational level from mid-adulthood onwards, and the quantification of intrusive errors which have significant clinical value. Objective: The aim of this study is to determine normative scores and intrusive errors for the P-FCSRT, controlling for sociodemographic factors (age and educational level) in the Chilean population. Methods: A total sample of 185 healthy participants from the Aging Mets cohort were recruited from three regions in Chile (Antofagasta, Santiago, and Puerto Montt). The P-FCSRT was administered to all participants. A multivariate regression-based normative approach was used to generate normative data, considering the effects of age, years of schooling, and sex. Results: Significant effects of age and years of schooling were found on P-FCSRT free recall, total recall, delayed recall, intrusions, and sensitivity to cues. Age had a distinct effect on each P-FCSRT dimension, whereas years of schooling had a consistent effect across them. Sex did not influence any P-FCSRT dimension. Conclusions: This study is the first to provide normative data for the Chilean version of the P-FCSRT and will be beneficial for clinical neuropsychologists in improving the procedures for a more accurate assessment of episodic memory and related impairments.
Sarah M Bannon, Sydney McCage, Kristin Walker, Julie Brewer, Nina Ahmad, Talea Cornelius, Robert A Parker, Kristen Dams-O’Connor, Bradford Dickerson, Christine S Ritchie, Ana-Maria Vranceanu
Resilient Together for Dementia: A qualitative study of couples’ treatment preferences to address distress early after diagnosis
Abstract: Background: Despite technological advances and earlier and more confident diagnoses, there is a lack of post-diagnosis support for couples navigating the challenges of early dementia. Clinically elevated emotional distress is common for both partners after diagnosis, and interferes with the health, relationships, and adjustment of both partners if not addressed. Objective: Our objective was to gather in-depth information on couples’ preferences to inform the development of a proposed dyadic intervention addressing emotional distress early (within 6 months) after one partners’ receipt of a dementia diagnosis. Methods: We recruited couples after a recent dementia diagnosis (N=16 dyads; 32 participants) from a large academic medical center via direct provider referrals for 60-minute virtual dyadic interviews. Data were analyzed using a hybrid inductive-deductive approach to thematic analysis. Results: We identified themes within 3 a-priori determined domains. For dyadic intervention format (domain 1), couples preferred to participate in sessions together and to have flexible options for telehealth and in-person participation. Preferences for intervention content (domain 2) included information on dementia, skills to reduce distress and promote resiliency, and support to communicate about the diagnosis and related stress. Barriers and facilitators (domain 3) included denial or hesitation, resource constraints, and interests in learning skills and connecting to others. Conclusions: We gathered comprehensive information that could be used to adapt existing dyadic interventions and to tailor support to match couples’ preferences early after dementia diagnoses. Early interventions should prioritize flexible delivery of information and skills to couples to support adaptive coping following dementia diagnoses.
Clara Berridge, Natalie R Turner, William B Lober, George Demiris, Jeffrey Kaye
Sharing patient technology preferences with care networks: Stakeholders’ views of the “Let’s Talk Tech” decision aid for dementia care
Abstract: Background: Let’s Talk Tech (LTT) is a self-administered web intervention for people with memory loss and their care partners that supports decision-making about digital health technologies. In past work, dyads wanted to share LTT preference reports with their larger care networks. Objective: This study aims to understand with whom care dyads want to share their technology preference reports and why, and if and how clinicians want to receive them. Methods: Together, fifteen dyads of people living with mild cognitive impairment (MCI) or early-stage dementia (n=15) and a care partner (n=15) completed LTT and two survey questions. Care partners completed independent follow-up interviews, and 32 clinicians at four Alzheimer’s Disease Research Center-affiliated clinics viewed an LTT report and completed a 10-question survey. We used descriptive statistics for survey responses and thematic analysis for interviews. Results: Two-thirds of care partners (n=10) wanted to share the report with family members. Half (n=8) wanted to share it with clinicians to keep them informed about the dyad’s planning and facilitate conversations about technology options. 30 of 32 clinicians reported they would want their patients’ technology preferences reports, with 25 wanting to access it via the EHR. Conclusions: Findings demonstrate potential value to both family dyads and providers of sharing technology preferences beyond the care dyad. Clinicians were highly receptive to accessing technology preference reports in EHRs and to having discussions about technology be a part of advance care planning. Future research should test integration in the EHR and the potential of sharing technology preferences to support person-centered technology choices.
Hyejin Ahn, Woo-jin Cha, Do Hyeon Woo, Seunghyuk Ha, Kyungtae Kim, Hyeji Choi, Min Soo Byun, Gijung Jung, Dahyun Yi, Dong Young Lee
Performance on the Rey-Osterrieth Complex Figure Test in Non-Demented Middle-Aged and Elderly Koreans
Abstract: Background: Existing studies on Rey-Osterrieth Complex Figure (ROCF) performance in South Korea have not fully accounted for key demographic factors and often include limited sample sizes. This study examines ROCF performance in a non-demented aging sample to explore cognitive variability and provide comparative data for future research. Objective: This study investigates the effects of age, education, and gender on performance on the ROCF test copy, immediate recall, and delayed recall trials for middle-aged and elderly Koreans. Methods: The ROCF was administered to 461 community-dwelling, non-demented adults aged 50 to 90 years (M = 70.1, SD = 8.4), with 0 to 25 years of education (M = 11.4, SD = 4.7). We analyzed cognitive performance across age groups (50-59, 60-69, 70-79, and 80-90 years), education levels (0-8, 9-12, ≥13 years), and gender to characterize cognitive variability in a non-demented aging sample. Analysis of variance and stepwise multiple regression analyses were conducted to assess the relative contributions of the demographic variables. Results: Lower education levels, advanced age, and female gender were associated with poorer performance. Education accounted for the greatest variation in the copy trials, whereas age accounted for the largest portion of the variance in the recall trials. Conclusions: The findings highlight the necessity of accounting for age, education, and gender when interpreting ROCF test scores in aging populations, especially in South Korea where educational attainment among older adults varies widely. Based on these findings, we established reference values stratified by these demographic variables for middle-aged and older Korean adults.
Jiahao Li, Feng Zhang, Ulrich LM Eisel
Adverse events associated with lecanemab: A disproportionality analysis of data from the FDA Adverse Event Reporting System
Abstract: Background: Lecanemab, a monoclonal antibody targeting amyloid-β plaques, is FDA-approved for early Alzheimer's disease (AD) treatment. However, safety data from daily clinical practice is limited. Objective: This study aims to assess the adverse events (AEs) linked to lecanemab using the FDA Adverse Event Reporting System (FAERS) to inform better safety management. Methods: A retrospective pharmacovigilance study was conducted using FAERS data from Q1 2023 to Q2 2024. Disproportionality analysis, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), was applied to evaluate AEs where lecanemab was the primary suspect drug. Results: From Q1 2023 to Q2 2024, 917 AEs related to lecanemab were recorded in the FAERS database, with 67.2% of patients aged between 65 and 85 years and 54.5% involving women. Disproportionality analysis identified significant AEs across 22 organ systems, particularly nervous system and psychiatric disorders. Common AEs included headache, amyloid-related imaging abnormalities, and infusion-related reactions, while sleep-related issues like somnolence, abnormal dreams, and poor-quality sleep were notable. Median onset time was 48 days, with serious outcomes in 14.3% of cases, including 70 hospitalizations and 15 deaths. Conclusions: This pharmacovigilance analysis confirms known AEs of lecanemab and highlights new safety concerns, particularly its impact on sleep. These findings underscore the importance of ongoing monitoring and research to enhance lecanemab's safety profile in AD treatment. However, due to the limitations of FAERS, our analysis is imperfect in terms of important AEs such as therapy-related brain loss and death.
Min-Chien Tu, Ya-Kuei Yu, Hsiao-Wen Chung, Yen-Hsuan Hsu, Jir-Jei Yang, Wen-Chau Wu
Quantitatively assessing daily functional impairment in dementia by imaging cerebrovascular correlates
Abstract: Background: Impaired daily functioning can change day-to-day activities at the early stage of dementia, in varied association with cognitive decline and/or affective symptoms. Current clinical practice uses scales to assess daily functioning and can be prone to subject/proxy-related bias. Objective: To investigate the yet unclear cerebrovascular correlate of daily activities and the usefulness of cerebral blood flow (CBF) as a quantitative marker of functional impairment. Methods: Ninety patients with clinically diagnosed dementia and 30 healthy controls were prospectively recruited. Regional CBF within the frontotemporal-subcortical circuits was quantified by magnetic resonance imaging, compared between control and CBF-stratified patient groups, and then correlated with basic and instrumental activities of daily living. Results: Lower CBF was found to associate with impaired daily activities in most of the regions investigated after adjusted for the effect of age and Mini-Mental State Examination score. Analyses of partial correlation and receiver operating characteristic further revealed that impaired basic activities of daily living was best detected by the baseline CBF in the right middle temporal gyrus, with the area under the curve (AUC) = 0.860 (p < 0.001). Impaired instrumental activities of daily living was best detected by the CBF in the right superior temporal gyrus (AUC = 0.695, p < 0.001). The CBF in the two regions showed no significant detecting ability for anxiety and depression. Conclusions: We identified the radiological cerebrovascular correlates of daily functioning in line with the previously conceptualized role of frontotemporal-subcortical circuits, allowing quantitative assessment of daily activities with minimal confounding from affective symptoms.
Xinyi Yang#, Lei Chi#, Meizhao Qiao#, Anxing Huang, Huimin Wu, Shanshan Chen, Jia Fan, Xingjian Lin, Jiu Chen for the Alzheimer’s Disease Neuroimaging Initiative #These authors contributed equally to this work.
The effect of C-reactive protein and interleukin-3 on mild cognitive impairment with APOE ɛ4
Abstract: Background: The apolipoprotein E ε4 allele (APOE ε4) and inflammation are associated with Alzheimer’s disease (AD) pathology. Mild cognitive impairment (MCI) is considered the preclinical and early stage of AD. However, the comprehensive effects of APOE ε4 and inflammatory mediators on MCI patients with specific APOE ε4 genotypes remain poorly understood. Objective: Our study aimed to explore how different numbers of the APOE ε4 alleles affect plasma C-reactive protein (CRP) and interleukin-3 (IL-3) levels and their associations with brain structure. Methods: A total of 339 MCI patients from the Alzheimer’s Disease Neuroimaging Initiative study were enrolled. We compared their plasma concentrations of CRP and IL-3, cognitive performance, and cerebrospinal fluid (CSF) AD biomarkers levels across different APOE ε4 genotypes. Structural magnetic resonance imaging was utilized to measure gray matter volume outcomes. Pearson correlation analysis was used to explore the associations between the above indicators. Results: Plasma CRP levels increased in the APOE ε4 carriers, but IL-3 expression notably decreased, and the homozygous state is the most significant. A negative correlation between CRP and several cognitive abilities was observed only in APOE ε4 homozygotes. Additionally, a positive correlation between IL-3, cognitive scores, and CSF biomarker levels was confirmed only in APOE ε4 homozygotes. Imaging data demonstrated that the gray matter volume of the right middle frontal gyrus was associated with CRP only in APOE ε4 non-carriers. Conclusions: Our study demonstrated that peripheral inflammatory mediators’ effect on cognitive function and brain structure in MCI patients differs based on their APOE ε4 allele carrier status.
Hui Min Chen, Kuo Shen, Ling Ji, Colman McGrath, Hui Chen
Patterns and trends in the burden of Alzheimer’s disease and related dementias in China (1990-2021) and predictions to 2040
Abstract: Background: The epidemiology of Alzheimer’s disease and related dementias (ADRD) in China is understudied as compared to global levels. Objective: The aim of this study was to examine the trend of dementia epidemiology in China from 1990 to 2021 and provide predictions for the next two decades. Methods: The Global Burden of Disease study (GBD) 2021 were used to analyze the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) rates due to ADRD in China and globally. Joinpoint regression analysis was used to analyze the epidemiological trends from 1990 to 2021. A forecast of ADRD prevalence trends was conducted utilizing Autoregressive Integrated Moving Average (ARIMA) models. Results: China was experiencing a growing burden of ADRD. As of 2021, the number of people with dementia in China had risen to 56.85 million (95%CI:49.38, 64.98), up from 21.80 (95%CI:19.07, 24.84) million in 1990. The prevalence, incidence, mortality, and DALY rates all indicated a greater disease burden among the Chinese population compared to global levels, with a significantly higher burden in the female group. The projected prevalence rate was expected to increase by 60% compared to the current prevalence rate. Conclusions: As the population in China continues to age, ADRD presents an undeniable challenge. To mitigate the growing burden of ADRD and improve the overall health of the population, it is essential to establish a comprehensive plan that focuses on increasing public awareness and enhancing the quality of life for all, with special attention given to women.
Tianyi Zhang#, Xiao Luo#, Qingze Zeng#, Kaicheng Li, Yi Chen, Yan Sun, Lumin Leng, Guoping Peng, Minming Zhang, Zhirong Liu, on behalf of Alzheimer's Disease Neuroimaging Initiative #These authors contributed equally to this work.
Smoking alters effective connectivity of resting-state brain networks in mild cognitive impairment
Abstract: Background: Smoking, a modifiable risk factor for Alzheimer's disease (AD), is associated with impaired functional connectivity in resting-state networks (RSNs). This study investigates how smoking affects brain effective connectivity (EC). Objective: Investigate smoking-associated EC alterations. Methods: We identified 129 cognitively unimpaired (CU: 85 non-smokers, 44 smokers) and 84 mild cognitive impairment (MCI: 55 non-smokers, 29 smokers) participants. Granger causality analysis was used to calculate the directed interactions of information flows based on the seed areas of the default mode network, executive control network, and salience network. Mixed-effect analyses were performed to explore the interactive effects of smoking × cognitive status. Linear mixed-effects models evaluated correlations between EC values and longitudinal cognitive decline. Results: Mixed-effect analyses revealed significant interactive EC differences among 4 groups: (1) Smoking MCI individuals showed reduced EC from the left putamen to the frontoinsular cortex (FIC) compared to the smoking CU and non-smoking MCI group; (2) Non-smoking MCI subjects had lower EC from the dorsolateral prefrontal cortex (DLPFC) to the right inferior occipital gyrus (IOG) than non-smoking CU; (3) Smoking CU subjects exhibited increased EC from the DLPFC to the left middle cingulate cortex compared to the with the non-smoking CU and smoking MCI individuals. Additionally, EC Posterior cingulate cortex-to-IOG and EC Putamen-to-FIC significantly predicted MMSE and ADNI_EF scores over time, respectively. Conclusions: Smoking distinctly impacts EC within RSNs and overall brain function in both MCI and CU individuals, potentially reducing functional compensation in MCI. These results support smoking cessation as part of AD management strategies.
Borna Bonakdarpour, Rhiana Schafer, Clara Takarabe, Elena Barbieri, Jonathan Miller, Sandra Siegel Miller (Handling Associate Editor: Amy Clements-Cortes)
Virtual group singing programs for well-being in healthy older adults and persons with neurocognitive disorders during early COVID-19 pandemic: A perspective from ChicagoAbstract: Background: During the COVID-19 pandemic, older adults experienced health declines due to isolation. Group singing is known to enhance social, emotional, and physical well-being, but its feasibility in virtual formats was unclear. Objective: To assess the feasibility of virtual group singing for cognitively healthy (CH) adults and individuals with neurocognitive disorders (NcD) during the pandemic. Methods: Two teleconferencing programs were conducted for participants aged >55: (1) a sing-along series with 52 weekly sessions of familiar music and (2) a choir program with structured weekly rehearsals culminating in a virtual concert. Retrospective surveys assessed anxiety reduction, social connection, and physical well-being using Likert scales and participants provided open-ended responses. Quantitative data were analyzed with ordinal regression and probability modeling, while qualitative themes were explored with Fisher’s exact test. Results: Participants reported high levels of satisfaction across all measures. Sing-along programs provided greater satisfaction, particularly through reminiscence (p=0.003). Choir participants noted enhanced intellectual well-being (p=0.017). NcD participants were less satisfied with social connection but showed similar overall satisfaction levels compared to CH participants. Conclusions: Virtual group singing was feasible during periods of isolation as supported by satisfaction of the participants with pertaining to anxiety reduction, social connection and physical well-being. Sing-along programs provided emotional satisfaction through reminiscence (connection to past), while choir programs offered intellectual stimulation through multiple rehearsals. These findings highlight the potential of virtual singing to promote stability, connection, and well-being for older adults during times of disruption.
Neha Singh-Reilly, Jonathan Graff-Radford, Danni Li, Michelle M Mielke, Mary M Machulda, Christopher G Schwarz, Matthew L Senjem, Clifford R Jack, Jr, Val J Lowe, Keith A Josephs, Jennifer L Whitwell
Aβ42/40 and p-tau 181 as disease biomarkers in Atypical Alzheimer’s disease
Abstract: Background: Studies suggest that plasma Alzheimer’s disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown. Objective: The main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity. Methods: We assessed whether plasma p-tau 181 and Aβ42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD. Results: Plasma Aβ42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity. Conclusion: Plasma Aβ42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.
Petros Stamatelos, Ion N Beratis, Panagiota Hatzaki, Alexandra Economou, Nikolaos Andronas, Dimosthenis Pavlou, Styliani P Fragkiadaki, Dionysia Kontaxopoulou, Anastasios Bonakis, Leonidas Stefanis, George Yannis, Sokratis G Papageorgiou
Mild cognitive impairment, Alzheimer’s disease dementia, and predictors of driving cessation: A 7-year longitudinal prospective study
Abstract: Background: Patients with dementia face driving difficulties and, at some point, cease driving. Objective: We sought to identify predictors of driving cessation among patients with mild cognitive impairment (MCI) or mild Alzheimer’s disease dementia (AD). Methods: We enrolled in this longitudinal study patients with MCI, AD (Clinical Dementia Rating<2) and cognitively normal (NC) individuals. At baseline evaluation, participants underwent a neurological, neuropsychological and driving simulator assessment. Re-evaluations after 48 and 84 months included a structured interview with the patients and their caregiver. Primary endpoints were driving cessation, death and progression to dementia. Results: 109 individuals were included (32 NC, mean age 65.8 years/47 MCI, mean age 69.1 years/30 AD, mean age 72.8 years). Dangerous driving events during follow-up were referred for 45% and 59% of MCI and AD patients, respectively. 18 MCI (38%, mean time to cease 35 months) and 25 AD (83%, mean time to cease 15 months) patients ceased driving during follow-up. 36% of MCI patients progressed to dementia during follow-up. Cox Regression multivariate analysis revealed age (Hazard Ratio-HR 1.080), semantic verbal fluency-SVF (HR 0.822) and Tandem Walking Test modified with simultaneous reverse number counting-mTWT (HR 1.099) as significant predictors of driving cessation. Simulator accident probability reached statistical significance only in the univariate model (HR 1.040). Conclusions: Age, SVF and mTWT are significant predictors of driving cessation among MCI and AD patients. Driving simulator may be a promising component of driving evaluation. Large-scale studies are prerequisite for the implementation of a multi-disciplinary driving fitness evaluation protocol.
Grace Derboghossian, Keenan Pituch, Mia Anthony, Dereck Salisbury, Feng Vankee Leen, Fang Yu
Relationships among cardiorespiratory fitness, brain age, and neurodegeneration in older adults with amnestic mild cognitive impairment
Abstract: Background: There is growing evidence that cardiorespiratory fitness (CRF) mitigates the likelihood of dementia caused by Alzheimer's disease and may underlie the cognitive benefits observed from aerobic exercise. Previous evidence demonstrates neurodegeneration is the biological substrate for cognition deterioration and brain age may protect the brain from the deleterious effects of neurodegeneration. However, little is known about the relationships between CRF, brain age, and neurodegeneration in older adults with amnestic mild cognitive impairment (aMCI). Objective: The aim of this cross-sectional study was to examine associations between CRF, brain age, and neurodegeneration among individuals with aMCI, using baseline data from the Aerobic exercise and Cognitive Training (ACT) trial, which examined the cognitive effects and underlying mechanisms of a 6-month ACT in older adults with aMCI. Methods: CRF was measured with peak oxygen uptake (VO2peak), from a symptom-limited peak cycle-ergometer test. Brain age and hippocampal volume were obtained from structural magnetic resonance imaging. Brain age was estimated using brainageR. Descriptive statistics and bivariate correlations were assessed. Linear regression models were used to analyze the relationships between CRF, brain age, and hippocampal volume, while adjusting for covariates. All analyses were conducted using R (version 4.3.2). Results: The sample (N = 141) averaged 73.66±5.78 years of age, 16.91±2.89 years of education, 27.46±5.15 in BMI, and 23.49±2.16 on Montreal Cognitive Assessment, with 53% male and 92.2% White. The mean brain age was 72.37±7.89 years with 3157.31±449.35mm3 hippocampal volume. No association was found between CRF, brain age, and hippocampal volume. Conclusions: Future studies need to explore other brain indicators related to CRF.
Hyeonseok Jeong, Doyu Kim, Seunghee Na, Byungseok Kim, Jin Kyoung Oh, Eun Kyoung Choi, Sujung Yoon, Marom Bikson, Yong-An Chung#, In-Uk Song# #These authors equally contributed to this work.
Repeated neuromodulation with low-intensity focused ultrasound in patients with Alzheimer's disease
Abstract: Background: Low-intensity focused ultrasound (LIFU), a non-invasive targeted brain stimulation technology, has shown promise for therapeutic applications in Alzheimer’s disease (AD) patients. Despite its potential, the implications of repeated LIFU neuromodulation in AD patients remain to be investigated. Objective: This pilot study evaluated the safety and potential to improve cognition and functional connectivity following repeated LIFU treatment in AD patients. Methods: Ten early-stage AD patients underwent six sessions of neuronavigation-guided LIFU targeting the left dorsolateral prefrontal cortex (DLPFC) within 2–3 weeks, alongside ongoing standard pharmacotherapy. Neuropsychological assessments and resting-state functional magnetic resonance imaging were performed at baseline and eight weeks post-treatment. Results: Memory performance (p = 0.02) and functional connectivity between the left DLPFC and both the left perirhinal cortex and left dorsomedial prefrontal cortex (corrected p < 0.05) significantly improved from baseline. Additionally, enhancements in memory performance were positively correlated with increases in functional connectivity of the left DLPFC with the left perirhinal cortex (Kendall’s tau = 0.56, p = 0.03). No adverse events were reported during the LIFU treatments or at the subsequent follow-up. Conclusions: LIFU may have the therapeutic potential to enhance both brain network connectivity and memory functions in AD patients. Our results provide a basis for further research, including randomized sham-controlled trials and optimization of stimulation protocols, on LIFU as a supplementary or alternative treatment option for AD.
Freida Blostein, Kelly M Bakulski, Mingzhou Fu, Herong Wang, Matthew Zawistowski, Erin B Ware
DNA methylation age acceleration is associated with incident cognitive impairment in the Health and Retirement Study
Abstract: Background: DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the association between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity. Objective: Our study aimed to investigate associations between DNA methylation clocks and incident cognitive impairment using a larger and US nationally-representative sample from the Health and Retirement Study. Methods: We measured DNA methylation age acceleration in 2016 by regressing the DNA methylation clocks, including GrimAge, against chronological age. Cognitive change over time was determined by Langa-Weir cognition status from 2016 to 2018. Multivariable logistic regression evaluated the association between DNA methylation age acceleration and cognitive change, adjusting for cell-type proportions, demographic, and health factors. We also applied inverse probability weighting to address potential selection bias from varying loss-to-follow-up rates. Results: The analytic sample (N=2,713) was 54% female, 8.4% Black/African American, 86% White, 7.5% Hispanic, and 68 years old at baseline. During the two years of follow-up, 12% experienced cognitive change and had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those maintaining normal cognition (mean = -0.8 years). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive change during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11). Conclusions: Our study offers insights into DNA methylation age acceleration associated with cognitive change over time, suggesting avenues for improved prevention, diagnosis, and treatment.
Tom Heinze, Max Tuchtenhagen, Sven Knüppel, Daniela Weber, Gabriele Pohl, Franziska Jannasch, Catarina Schiborn, Matthias B Schulze, Tilman Grune, Tanja Schwerdtle
EPIC-Potsdam sub-cohort study: The early role of trace elements, oxidative stress, and anthropometrics in Alzheimer's disease and dementia onset
Abstract: Background: Serum trace elements, anthropometric data, and oxidative stress markers are often altered in patients diagnosed with Alzheimer's disease (AD) or other types of dementia (OTD). However, these parameters are rarely examined together before disease onset in a single study population. Objective: This nested case-control study aims to investigate anthropometric data, serum trace elements, exchangeable copper (CuEXC), and oxidative stress markers to identify early associations with the risk of AD or OTD. Methods: From the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort (DRKS-ID: DRKS00020593), the High Fat Diet, Microbiota, and Neuroinflammation in the Progression of Alzheimer study was generated. One hundred twenty-eight individuals who developed AD or OTD were identified, approximately 15.7 years after baseline data collection, and matched for age, sex, fasting status, and season of blood sampling with 512 controls. Serum levels of manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), selenium (Se), iodine (I), CuEXC, and plasma malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) were analyzed. Results: Cases and non-cases did not differ in anthropometric data or oxidative stress markers. Female cases exhibited a trend of elevated serum Cu and CuEXC levels compared to female non-cases. A higher Se/Cu ratio suggested an inverse association (OR = 0.72, 95% CI: 0.56-0.92), while an increased Cu/Zn ratio was positively associated (OR = 2.1, 95% CI: 1.1–4.1) with AD or OTD incidence. Conclusions: Ratios of serum trace elements, rather than individual levels, show early associations with the risk of AD or OTD while anthropometric and oxidative stress markers did not.
Zhongxuan Wang, Qi Wang, Chunying Fu, Xiang Li, Luyi Zhang, Xiaoyu Zhang, Dongshan Zhu
The fall-dementia connection: Synergistic effects of falls with genetic and health risk factors
Abstract: Background: Few studies have examined the inverse relationship between dementia and falls, i.e., whether falls before dementia are a herald of dementia. Objective: We aimed to explore the relationship between fall experiences and risk of dementia, assessing how factors like APOE ε4 allele, family history of dementia, comorbidities, traumatic brain injury (TBI), and frailty modify this association. Methods: We used data from the UK Biobank. We used Cox proportional hazards models to estimate the HRs and 95% CIs for the association between falls and all-cause dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and non-Alzheimer/non-vascular dementia (NAVD). The synergistic effects of fall experiences and APOE, dementia family history, cardiovascular disease (CVD), diabetes, TBI, frailty on dementia were also investigated. Results: Totally, 403,502 participants were included. 99,832 people experienced at least one fall, and 4143 dementia cases were observed. People who experienced falls had a higher risk of all-cause dementia, AD, VaD, and NAVD, with HRs (95% CIs) of 1.71(1.61, 1.83), 1.33 (1.20, 1.47), 2.00 (1.74, 2.29), and 2.03 (1.84, 2.24), respectively. The risk of dementia increased with the number of falls and with falls occurring later in life (after age 60). Fall experiences had a synergistic effect with dementia risk factors (APOE ε4 allele, family history of dementia and comorbidities), TBI, and frailty, collectively increasing the risk of dementia. Conclusions: Falls before dementia were linked to a higher risk of dementia. The risk escalated with more falls and falls after age 60. Combining falls with risk factors further amplified dementia risk.
Sölve Elmståhl, Katarina Ellström, Tomas Månsson, Rani Basna, Arkadiusz Siennicki-Lantz, Kasim Abul-Kasim
Associations between cerebral small vessel disease and reduced forced vital capacity and expiratory volume in a general healthy Swedish elder population study–Good Aging in Skåne
Abstract: Background: Cerebral small vessel disease (CSVD) is one of the most important causes of cognitive decline. Only a few previous studies have evaluated lung function measures in relation to brain neuropathological changes, and even less studies on specific lesions and areas that could shed light on mechanisms of CSVD. Objective: The aim was to study the association between lung function and CSVD in the general elder population. Methods: 379 participants, aged 72-87 years from the general population study ‘Good Aging in Skåne study (GÅS)’were investigated with a 3T MRI brain examination and spirometry. Z-scores of FEV1 and FVC were calculated using the GLI 2012 equations. Age-adjusted associations between white matter hyperintensities (WMH), medial temporal lobe atrophy (MTA), lacunar infarction, cerebral atrophies and cerebral microbleeds and lung function were calculated and stratified for sex. Results: Decreased FEV1 and FVC z-scores below < -1.0 were both associated with increased risk of WMI and global cortical atrophy. Decreased FVC z-scores were also associated with MTA and lacunar infarction in women and precuneus atrophy in men. The associations for WMH, MTA and lacunar infarctions and higher STRIVE score were noted among women, but not among men. FEV1 z scores were not related to diabetes, coronary artery disease or stroke. Conclusions: Lower lung function was associated to MRI markers of CSVD in this general healthy population, particularly with WMH, especially for women. Although possible shared risk factors exist between lung and heart disease, lung function should be recognized in future studies on CSVD.
Akisato Nishigaki, Hidehiro Ishikawa, Yamato Nishiguchi, Kei Tachibana, Natsuko Kato, Kana Matsuda, Yurie Mori, Hirofumi Matsuyama, Keita Matsuura, Yuichiro Ii, Hideaki Wakita, Shinji Oikawa, Hidekazu Tomimoto, Akihiro Shindo (Handling Associate Editor: Zhigang Wang)
Alpha-1-acid glycoprotein as a potential serum biomarker for cerebral amyloid angiopathy
Abstract: Background: Cerebral amyloid angiopathy (CAA) is a form of cerebral small vessel disease (SVD) associated with Alzheimer’s disease, intracerebral hemorrhage, and cognitive decline. Despite its clinical significance, no reliable serum biomarker exists for early diagnosis or monitoring of disease progression. Objective: This study hypothesizes that α1-acid glycoprotein (α1-AGP) and other serum biomarkers can aid CAA diagnosis and assessment using gel-based mass spectrometry. A comparative analysis was performed to investigate associations between serum biomarkers and radiological scores. Methods: Serum proteins from individuals with probable or possible CAA (n = 10), classified using the modified Boston criteria, and age-matched controls (n = 10) were analyzed via two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS). Candidate proteins were validated using enzyme-linked immunosorbent assay (ELISA). Outcome measures included biomarker diagnostic accuracy, assessed by receiver operating characteristic (ROC) curve analysis, and correlations between α1-AGP levels and CAA-SVD scores. Results: Four proteins—hemopexin, complement C3, complement C9, and α1-AGP—were significantly elevated, while apolipoprotein A-1 was reduced in the CAA group. ELISA confirmed higher α1-AGP levels in individuals with CAA (p < 0.0001). ROC analysis demonstrated that α1-AGP could indicate the presence of CAA with a sensitivity and specificity of 1.00 (95%CI: 1.000, 1.000). Additionally, α1-AGP levels correlated with the CAA-SVD score (R² = 0.783). Conclusions: α1-AGP may serve as a novel serum biomarker for CAA. Larger cohorts and external validation are required to substantiate these findings and determine their clinical relevance.
Wei Bao, Haidi Bi, Lishuo Chao, Yaqing Jiang, Xiaoping Yu, Fei Ruan, Di Wu, Zhaoyan Chen, Kai Le (Handling Associate Editor: Zhifang Dong)
Identifying the mediating role of brain atrophy on the relationship between DNA damage repair pathway and Alzheimer’s disease: A Mendelian randomization analysis and mediation analysis
Abstract: Background: DNA damage and repair (DDR) and structural atrophies in different brain regions were recognized as critical factors in the onset of Alzheimer's disease (AD). Objective: We utilized Mendelian randomization (MR) to examine the causal effects of the DDR-related molecular traits on AD and the potential mediating roles of different brain region volumes. Methods: In primary analysis, we utilized public genome-wide association studies of AD and summary data from existing molecular traits datasets, including gene expression, DNA methylation, and protein levels quantitative trait loci (eQTL, mQTL, and pQTL) in both blood and brain to examine their causal associations by summary-data-based MR analysis and additional five two-sample MR methods. Subsequently, mediation analysis explored the potential mediate roles of 13 imaging-derived brain volume phenotypes in the associations between the DDR pathways and AD through a network MR design. Results: We found that the volumes of the right thalamus proper and global cerebral white matter mediated the causal pathways from EGFR to AD and relatively weak mediation effects of the right lateral ventricle volume in the causal pathways involving CHRNE, DNTT, and AD. Conclusions: We identified causal relationships among DDR pathways, specific brain region volumes, and AD. Monitoring the molecular traits of these DDR-related genes and developing targeted drugs may help detect and interrupt the early progression of AD.
