Review
Jin Gong, Shaoqi Li, Xiaodong Han, Pin Wang, Wenxian Sun, Chang Xu, Heya Luan, Boye Wen, Jinxuan Guo, Cuibai Wei
Autoantibodies in Alzheimer’s disease: Multifaceted roles and therapeutic horizons
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathogenesis involving numerous factors. Recent research has highlighted the significant role of autoimmunity in the initiation and progression of AD, with autoantibodies emerging as a pivotal area of investigation. Nevertheless, the influence of autoantibodies in AD is marked by substantial heterogeneity, they may either mitigate disease progression by clearing pathogenic protein aggregates or exacerbate the pathological process through mechanisms such as the activation of inflammatory responses or the induction of neuronal damage. Objective: This review aims to synthesize the various roles of autoantibodies in AD, examine the factors that influence their functions, and assess their potential application in precision immunotherapy. Methods: PubMed and Web of Science databases were searched for English-language papers (2015–2025). Peer-reviewed human, animal and cell studies, systematic reviews and meta-analyses were screened independently by two reviewers. Results: A total of 87 studies were selected for inclusion, spanning human, animal, and cellular research. The findings indicated that certain autoantibodies, such as those targeting amyloid-β, tau, or 4-hydroxynonenal, may confer neuroprotective effects. Conversely, other autoantibodies, including those against BACE1, aquaporin-4, or HuD, may exacerbate AD pathology. Importantly, some autoantibodies were found to exhibit dual roles, contingent upon their specific modifications or the context of the disease. Conclusions: Autoantibodies constitute a double-edged immune axis in AD. Their impact hinges on antigen class, disease stage, isotype affinity and glycosylation. Precision strategies—like CAAR-T cell therapy, glycosylation modulation, and affinity optimization—offer therapeutic promise but require further validation.
Systematic Review
Yishu Yin#, Jie Deng#, Jue Liu #These authors contributed equally to this work.
The association between herpes zoster vaccination and the decreased risk of dementia: A systematic review and meta-analysis of cohort studies
Abstract: Background: Herpes zoster (HZ) infection may increase the risk of dementia, that causes a heavy socioeconomic burden. However, the epidemiological evidence between HZ vaccination and the risk of dementia remains inconclusive. Objective: This meta-analysis was conducted to investigate the effect of HZ vaccination on the onset of dementia. Methods: We searched PubMed, EMBASE, Web of Science, Science Direct, and Scopus for cohort studies assessing the association between HZ vaccination and dementia risk up to 20th January 2025. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled adopting a random-effect model. Results: Four eligible studies were included in the systematic review and five retrospective cohort studies in the meta-analysis. Among 14,493,383 dementia-free participants at baseline, 427,309 dementia cases occurred during 36-95 months of follow-up. All studies were of high quality. Pooled analysis of adjusted HRs indicated that HZ vaccination could reduce dementia risk by 29% (HR=0.71, 95% CI: 0.66-0.76, I2=97.15%). Subgroup analyses revealed heterogeneity linked to definitions of dementia, exposure measurements, vaccination doses, deprivation index, and region. The results were stable in the sensitivity analyses, and no publication bias was found. Conclusions: HZ vaccination was notably related to a reduced risk of dementia. More mechanistic studies and epidemiological studies are warranted.
Short Communication
Fabrizia D’Antonio, Massimiliano Panigutti, Alice Teghil, Marco Toccaceli Blasi, Martina Salzillo, Giusi Talarico, Micaela Sepe Monti, Giuseppe Bruno, Marco Canevelli
Exploring frailty in dementia with Lewy bodies: A pilot, cross-sectional study
Abstract: We aimed to investigate frailty in dementia with Lewy bodies (DLB) and its association with its core features. We retrospectively reviewed the clinical charts of 48 DLB outpatients. Frailty Index (FI) was generated by computing 39 age-related, multidimensional clinical deficits. FI scores varied from 0.08 to 0.54, with a median value of 0.26. FI showed a correlation with the severity of parkinsonism and visuo-spatial impairment, suggesting that some DLB features might be more influenced by frailty, whereas others, such as visual hallucinations, fluctuations, REM-behavior-disorder, seem not. Frailty may contribute to phenotypic variability in DLB; this study could inform future research aimed at clarifying the role of frailty in DLB.
Commentary
Jonathan Stone
What is frustrating the search for treatment of dementia? Fraud or ideas?
Abstract: The search for a treatment for dementia has been troubled by recent evidence of laboratory fraud. While acknowledging the seriousness of fraud, the author argues that the search for treatment has been slowed more by scientists’ failure adequately to address two questions: 1) Why is dementia delayable before diagnosis yet unstoppable after diagnosis? And 2) How did molecular markers of dementia (like the peptide Aβ) evolve? What do they do for the individual, that made their evolution possible? These questions are addressed and their implications for the delay and treatment of dementia are discussed.
Kyle J Edmunds, Alexis R Nelson, Talia L Brach, Matthew Glittenberg, Bradley T Christian, Tobey J Betthauser, Sterling C Johnson, Sanjay Asthana, Ozioma C Okonkwo
Depression modifies age-associated [11C]PiB-PET amyloid burden in a cohort enriched with risk for Alzheimer‘s disease
Abstract: Background: Depression—especially late-life onset—is associated with age-related cognitive decline and may be a key risk factor for amyloid-β (Aβ) deposition in preclinical Alzheimer’s disease (AD). Objective: This study assesses whether depressive symptoms modify the relationship between age and Aβ burden in a cohort at-risk for AD. Methods: N=238 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center (ADRC) participated in Pittsburgh Compound-B positron emission tomography (11C-PiB-PET), where distribution volume ratio (DVR) scores were used to quantify Aβ burden in nine regions of interest (ROIs) susceptible to early Aβ burden. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cross-sectional linear regression models examined interactions between age and GDS scores, adjusting for sex, apolipoprotein ε4 (APOE ε4) carriage, and age difference between PET imaging and GDS assessment. GDS-stratified analyses were performed to test within-group associations between age and 11C-PiB-PET Aβ aggregation in each ROI, and item-level analyses identified specific depressive symptoms that modified these relationships. Results: Participants had a mean age of 68.0 years (SD ± 8.4), 39.7% were APOE ε4 carriers, 64% were female, and 85.3% were White. GDS scores were largely normal (M=1.29, SD=1.61). Age × GDS interactions were significant across all ROIs, and stratified models revealed progressively stronger associations as GDS scores increased. Finally, item-level analyses identified the second and tenth GDS items as significant modifiers across six ROIs and the global composite. Conclusions: In a cohort enriched with risk for AD, emerging depressive symptoms amplified the association between age and Aβ burden.
Yiling Qiu#, Xiaole Duan#, Zhanxing Zhang, Liping Zhao, Qiong Yuan, Meijuan Wang, Shifu Xiao, Lin Sun, Alzheimer’s Disease Neuroimaging Initiative #These authors contributed equally to this work.
Sleep disturbances and language function impairment in the elderly: Evidence of limbic and prefrontal tracts involvement
Abstract: Background: Although poor sleep is widely assumed to impair cognitive function, the impact of sleep disturbances (SD) on language function and the underlying mechanisms of this relationship remains unclear. Objective: This study aimed to investigate the association between SD and language function in non-demented elderly individuals, identify potential neuroimaging correlates, and analyze risk factors for SD. Methods: We analyzed 784 non-demented elderly subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), categorized into SD (n=256) and normal sleep groups (n=528) based on self-reported sleep status. Cognitive differences were assessed, and the findings were validated using the China Longitudinal Aging Study (CLAS) and the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Diffusion tensor imaging (DTI) metrics were correlated with language function, and SD risk factors were examined. Results: In the ADNI cohort, elderly individuals with SD exhibited worse language function compared to those with normal sleep, and this finding was validated in the CLAS and CLHLS cohorts. Meanwhile, the decline in longitudinal language function among elderly individuals with SD occurred at a faster rate. Differences in DTI metrics between the two groups were primarily observed in the limbic and prefrontal regions. Finally, the risk factors for elderly with SD mainly included years of education, physical and emotional conditions, lifestyles, living environment, and parental survival status. Conclusions: SD correlates with language impairment in non-demented elderly, possibly due to limbic/prefrontal tract damage. Risk factors encompass demographic, health, lifestyle, and socio-environmental aspects. Effectively managing these factors and treating SD may improve language function.
Guoqiao Wang, Tianle Chen, John O’Gorman, Yan Li, Caiyan Li, Leonard Guizzetti, Brian Mangal, Whedy Wang, Shuang Wu, Dave Inman, Eric McDade, Randall J Bateman (Handling Associate Editor: Zhigang Li)
Harnessing greater statistical power: Comprehensive evaluation of disease modifying treatment effects across all or multiple post-baseline visits compared to the last visit for Alzheimer’s disease clinical trials
Abstract: Background: In Alzheimer's disease (AD) clinical trials, efficacy inference is traditionally based on the last visit (e.g., 18 months). However, recent studies suggest that disease-modifying treatment effects may emerge as early as 3 months post-baseline. Objective: To explore this further, our study aimed to assess the increased statistical power achieved by incorporating all or multiple post-baseline visits to estimate treatment effect, compared to relying solely on the last visit. Methods: We developed explicit formulas for the basis functions of the natural cubic spline model, ensuring compatibility with standard SAS procedures. Through simulations using disease progression trajectories from Clarity-AD and TRAILBLAZER-ALZ 2 trials, we comprehensively evaluated various models in terms of power and type I error. Additionally, we offer SAS codes that to facilitate seamless implementation of different modeling approaches. Results: Simulations based on ClarityAD and TRAILBLAZER-ALZ 2 disease trajectories demonstrated that models incorporating multiple or all post-baseline visits yield greater power than those using only the last visit, while maintaining Type I error control. Furthermore, when three post-baseline visits were included, adding more visits resulted in minimal power gains. Conclusions: Our findings support prioritizing statistical models that incorporate multiple or all post-baseline visits for treatment efficacy inference, as they offer greater efficiency than models relying solely on the last visit.
Amir Abbas Tahami Monfared, Noemi Hummel, Agnieszka Kopiec, Aastha Chandak, Artak Khachatryan, Ran Gao, Raymond Zhang, Quanwu Zhang
Integrating intangible costs into societal cost estimates of Alzheimer’s disease
Abstract: Background: Alzheimer’s disease (AD) is associated with considerable economic burden, the full extent of which can be challenging to quantify from a societal perspective. Objective: To estimate the total societal cost of AD in the United States by integrating direct costs, out-of-pocket expenses, indirect costs to caregivers, costs to business, and intangible/emotional costs to patients/caregivers across the disease continuum from mild cognitive impairment (MCI) to severe AD. Methods: Intangible costs were derived from a patient-caregiver survey. Other indirect costs were from a Health and Retirement Study (HRS) analysis; direct costs were from the literature. We estimated integrated societal cost per patient per month (PPPM) for MCI and AD (mild/moderate/severe). Negative binomial regression of indirect costs examined associations with severity, adjusting for baseline characteristics. Results: Integrated societal costs PPPM were $4,176 for MCI and $7,873 for AD ($6,634, $7,291, and $9,287 for mild, moderate, and severe, respectively); intangible costs represented 24–32% of societal costs. Indirect costs were higher with AD versus MCI (p<0.001); married status and nursing home residence were associated with lower indirect costs in AD. Conclusions: Intangible costs are a major driver, besides direct costs, of the integrated societal cost of MCI/AD. Societal costs are higher with more severe AD.
Teruyuki Matsuoka, Ayu Imai, Chikara Nakayama, Jin Narumoto (Handling Associate Editor: Madia Lozupone)
Association between pineal volume reduction and affective dysregulation in amnestic mild cognitive impairment: The role of mild behavioral impairment
Abstract: Background: Mild behavioral impairment (MBI) and pineal volume reduction are early indicators of Alzheimer’s disease (AD). Thus, the pineal volume reduction observed in early AD may be associated with MBI. Given that pineal volume reduction may be specific to AD, it might also be related to amnestic mild cognitive impairment (aMCI). Objective: In this study, we aimed to examine the relationship between MBI and pineal volume reduction in mild cognitive impairment (MCI; including aMCI and non-amnestic MCI) and normal cognition. Methods: This retrospective study included 86 patients aged ≥ 50 years with either MCI or normal cognition. Stepwise Linear regression analyses were conducted to examine the association between MBI and pineal parenchymal volume (PPV). PPV was manually measured using brain magnetic resonance imaging data. The dependent variable was the MBI Checklist (MBI-C) score. In contrast, independent variables included PPV, total intracranial volume, age, sex, Mini-Mental State Examination score, psychotropic drug use, and antidementia drug use. Results: PPV was the sole significant predictor of the MBI-C impulse dyscontrol score in the overall sample (adjusted R²: 0.058, p: 0.014, β: 0.263) and the sole significant predictor of the MBI-C affective dysregulation score in individuals with aMCI (adjusted R²: 0.117, p: 0.014, β: -0.371). Conclusions: Pineal volume reduction was associated specifically with MBI affective dysregulation symptoms in individuals with aMCI. As affective dysregulation is an early symptom of AD, these findings suggest a potential link between this symptom and pineal volume reduction, a feature potentially specific to AD.
Simone Gamm, Deborah Ummel, Nancy Vasil, Sébastien Grenier (Handling Associate Editor: Juan C. Melendez)
The need to adapt after Alzheimer's disease diagnosis: Coping strategies used to maintain identity and quality of life
Abstract: Background: Receiving a diagnosis of a major neurocognitive disorder due to Alzheimer's disease (AD) brings with it the need to adjust to a new life situation. People with AD seek to 1) maintain emotionally positive goals in their current lives, and 2) use positive experiences from the past to create continuity in their lives, with the aim of maintaining their quality of life and gaining a sense of hope. Objective: This research aims to explore the coping strategies and processes used following diagnosis. Method: An exploratory qualitative design was implemented to study the different coping strategies used by ten people with AD, via semi-structured interviews. The transcribed data was subject to an interpretative phenomenological analysis. Results: All participants experienced unpleasant emotions following their diagnosis. Their coping process following two different trajectories: 1) adaptive coping strategies to gain resilience and hope to maintain meaning in their current lives; 2) less adaptive coping strategies essentially resulting in the denial of the diagnosis and withdrawal from social life. Conclusions: This research makes it possible to identify possible intervention paths adapted to an individual’s needs to help them move towards adaptive coping strategies.
Ruohan Sun, Xiaohua Xie, Yao Meng, Jing Xu, Peiyuan Lyu, Yanhong Dong
A nomogram including serum iron metabolism-related indicator and cerebral microbleeds for predicting vascular cognitive impairment in patients
Abstract: Background: Detection of serum iron metabolism and peripheral blood ferroptosis indicators may to some extent reflect pathological changes in central nervous system iron deposition such as Alzheimer's disease and vascular cognitive impairment (VCI). Objective: The study sought to establish the first clinical prediction model related to the iron metabolism model, which helps in the early detection and prevention of VCI. Methods: The study included 255 patients at Hebei Provincial People's Hospital from January 2023 to November 2024. They were divided into two groups based on VCI diagnostic criteria, with 144 cases in the VCI group and 111 cases in the control group. The nomogram of the VCI diagnostic prediction model was built using logistic regression. The accuracy and discriminative ability of the model were confirmed in three areas: differentiation, calibration, and clinical practicability. Results: A logistic regression model identified four significant independent predictors of VCI: ferritin (odds ratio (OR)=1.003, 95% CI: 1.001~1.006), education (OR=0.929, 95% CI: 0.871~0.992), cerebral small vessel disease total load scores (OR=1.319, 95% CI: 1.039~1.673), and cerebral microbleeds (OR=2.020, 95% CI: 1.092~3.736) after adjustment for potential confounding factors (p<0.05). The predictive nomogram has good discriminatory ability, calibration ability, and clinical applicability. Conclusions: Serum ferritin was a significant predictor of VCI in middle-aged elderly people. The predictive model developed for the risk of developing VCI has good clinical applicability, calibration, and discrimination for early VCI screening.
Ella Liu, Sherri Lee Jones, Victoria Light, Charlotte Teunissen, Arabella Bouzigues, Lucy L Russell, Phoebe H Foster, Eve Ferry-Bolder, John C van Swieten, Lize C Jiskoot, Harro Seelaar, Raquel Sanchez-Valle, Robert Laforce, Caroline Graff, Daniela Galimberti, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tiraboschi, Isabel Santana, Alexander Gerhard, Johannes Levin, Sandro Sorbi, Markus Otto, Chris R Butler, Isabelle Le Ber, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, James B Rowe, Matthis Synofzik, Fermin Moreno, Barbara Borroni, Henrik Zetterberg, Jonathan D Rohrer, Simon Ducharme on behalf of the Genetic Frontotemporal Dementia Initiative (GENFI) and Banque Signature (BbS)
Accuracy of blood-based neurofilament light to different genetic frontotemporal dementia from primary psychiatric disorders
Abstract: Background: Genetic frontotemporal dementia (FTD) along with Alzheimer's disease (AD), is one of the most prevalent early-onset dementias. The differential diagnosis of FTD from primary psychiatric disorder (PPD) has been challenging due to significant symptom overlap, particular as FTD often presents with prolonged psychiatric prodromes. Objective: This study aims to evaluate whether blood-based neurofilament light chain (NfL) can differentiate genetic FTD from PPD, and to determine a global clinical cutoff to differentiate genetic FTD carriers from PPD with high specificity and sensitivity. Methods: Data (ages 40-81) were obtained from FTD mutation carriers (GENFI; n=474; n=120 C9orf72, n=114 GRN, n=50 MAPT, n=190 controls), and PPD (n=848). Blood-based NfL was measured with SIMOA HD-X (BbS) and SIMOA HD-1 (GENFI). Results: Blood-based NfL was higher in all symptomatic mutations compared to PPD. Mildly symptomatic (0 < FTLD CDR-SOB-NM < 4) C9orf72 and GRN carriers also had higher NfL. ROC curve revealed an optimal blood-based NfL cutoff of 22.1 pg/mL (J= 0.647) to distinguish symptomatic genetic FTD from PPD (78.5% sensitivity, 86.2% specificity, AUC= 0.908). For mildly symptomatic subjects, a cutoff of 16.2 pg/mL (J= 0.601) differentiated groups with 86.7% sensitivity and 73.5% specificity (AUC= 0.870). Conclusions: NfL holds potential as a blood-based biomarker for symptomatic genetic FTD carriers, with moderate accuracy to distinguish PPD from mild forms including C9orf72.
Yu-Hui Lo#, Shih-Chiang Ke#, Philip Tseng (Handling Associate Editor: Christian Sandøe Musaeus) #These authors contributed equally to this work.
Invisible multi-luminaire 40 Hz flicker does not entrain human electroencephalography
Abstract: Background: Multi-luminaire light stimulation is a novel technique based on luminance flicker with low modulation depth created by two spatially adjacent light sources aimed to deliver 40 Hz neural stimulation while reducing discomfort, offering potential non-pharmacological, noninvasive, and in-home interventions for Alzheimer’s disease and dementia. However, these cognitive effects have never been validated with electroencephalography (EEG). Objective: In this study we aim to assess the ability of multi-luminaire light stimulation to evoke a 40 Hz EEG response under two conditions: Direct viewing and indirect viewing. Methods: The M+ BrainCare light by Delta Electronics was used in this study. Participants were stimulated either directly by looking at the light (direct viewing condition), or off of the reflection from a piece of paper to mimic everyday reading (indirect viewing condition). EEG power at 40 Hz from these conditions were compared to a positive control of 40 Hz luminance flicker with 100% modulation depth (stroboscopic flicker). Results: In both multi-luminaire conditions, there was no significant 40 Hz EEG oscillations. In contrast, stroboscopic control elicited robust entrainment in all participants, propagating to frontal regions. Conclusions: Our results question the efficacy of multi-luminaire technology, specifically the Delta M+ BrainCare light, for evoking 40 Hz neural responses. Future studies involving multi-luminaire technology should pay special attention to EEG validation prior to making claims about neural oscillation and brain health.
Chhanda Bose, Ashly Hindle, Shane C Smith, Jake Strickland, Charlie Zhang, Isabel Guzman, Adam Baker, Igor Ponomarev, Maria Manczak, Andrew C Shin, Ranadip Pal, Sharda P Singh, J Josh Lawrence
Low-dose dietary vorinostat increases brain histone acetylation levels and reduces oxidative stress in an Alzheimer’s disease mouse model
Abstract: Background: Alzheimer’s disease (AD) disrupts histone acetylation/deacetylation homeostasis, blocking access of transcription factors to DNA, and compromising learning. Vorinostat (VOR), the only FDA-approved HDAC inhibitor that is orally bioavailable and brain penetrant, confers neuroprotection in AD models. We delivered VOR via diet in an AD mouse model, examining tolerability, accompanied by biochemical analyses. Objective: Our objective was to examine dietary delivery of vorinostat for tolerability, including changes to histone acetylation, amyloid-β (Aβ) production, oxidative stress (OS), mitochondrial health, and synaptic integrity. Methods: Food pellets containing control, 0.18 mg/g (low-dose) and 0.36 mg/g (high-dose) VOR were administered to hAβ-KI AD mice for 14 days. Brain acetyl-histone H3 (AH3), total H3 expression, and synaptic markers were measured via Western blot. Aβ, H2O2, antioxidant capacity, lipid peroxidation (via 4-hydroxynonenal (4-HNE)), ATP, and citrate synthase (CS) activity were measured in brain tissue. Results: VOR inhibited brain HDAC enzyme activity and increased AH3 and H3 expression at both VOR doses. Aβ and synaptic proteins were not significantly affected; however, OS markers were improved at both doses. Both doses increased CS activity, while ATP was increased only at the low dose. Finally, low-dose VOR was tolerable over 2 months. Conclusions: We established that low-dose VOR, delivered via diet, is tolerable in AD mice, successfully inhibiting brain HDAC activity while reducing OS and improving mitochondrial health. This study improves existing preclinical experimental designs by enabling noninvasive manipulation of histone acetylation through dietary intervention. This route of administration provides advantages for future preclinical animal studies.
Jillian K. Lee, Leigh Johnson, James R Hall, James R Bateman, Sid O’Bryant, Michelle M Mielke
Associations of chronic stress and social support with cognition: The role of gender and race/ethnicity in the HABS-HD Study Cohort
Abstract: Background: Few studies have examined whether chronic stress and social support are potential modifiable risk factors for Alzheimer’s disease and related dementias. Objective: To examine the associations of chronic stress and social support with domain-specific cognitive z-scores (attention, memory, executive functioning, and language) and assess whether gender or race/ethnicity modify these associations. Methods: Participants included 3,005 older adults (range: 50-92) enrolled in the Health and Aging Brain Study-Health Disparities. Social support was measured using the Interpersonal Support and Evaluations List, and chronic stress measured with the Chronic Burden Scale. Linear regression models evaluated associations of chronic stress and/or social support with domain-specific cognitive z-scores, adjusting for age, education, gender, race/ethnicity, and symptoms of anxiety. Interactions between chronic stress or social support and gender or race/ethnicity in relation to cognition were assessed. Additional analyses examined the interrelationship between chronic stress and social support in relation to cognition. Results: Higher chronic stress was associated with lower cognitive z-scores; results differed by race/ethnicity. Higher social support was associated with higher cognitive z-scores; results differed by gender and race/ethnicity. In models incorporating both chronic stress and social support, associations between social support and cognition remained, however associations between chronic stress and cognition were attenuated. A combination of high chronic stress/low social support, compared to low chronic stress/high social support, was associated with lower cognitive z-scores. Conclusions: High chronic stress and low social support is associated with worse cognition. Future studies are needed to understand the underlying mechanisms, with consideration of gender and race/ethnicity.
João Areias Saraiva, Martin Becker, Martin Dyrba, Burcu Bölükbaş, Enrico Michele Salamone, Claudio Babiloni, Michael Kölch, Harald Hampel, Stefan Teipel, Thomas Kirste, Christoph Berger (Handling Associate Editor: Daniel Ledwoń)
Electroencephalogram features support the retrogenesis hypothesis of Alzheimer’s disease: Exploratory comparison of brain changes in aging and childhood
Abstract: Background: The retrogenesis hypothesis (RH) suggests that the functional and cognitive decline observed in Alzheimer’s disease dementia mirrors in reverse order the brain development during childhood and adolescence. Objective: Equivalent electroencephalogram (EEG) patterns between older adults across different cognitive decline stages and children across different brain maturation stages were directly compared. Methods: To capture the complex patterns that allow for such a comparison, a regression model was trained on EEG data from N=510 older adults, at different stages of cognitive reserve, to identify EEG markers predictive of global cognitive status. The model was then applied on the same EEG markers of N=696 children across different ages. Results: The model predicted MMSE scores with an average error of 2.53 and R2 of 0.80. When applied to children, predictions correlated positively with age (r=0.73). Key predictors of cognitive function concordant in both populations were theta coherence (right frontal-left temporal/parietal), temporal Hjorth complexity, and beta edge frequency, supporting the RH. Conclusions: These EEG features were inversely associated between older adults and children, supporting a functional underpinning of the retrogenesis model of dementia. Clinical validation of these biomarkers could favor their use in the continuous monitoring of cognitive function.
Joshua L Paley#, Grant D Scheiffele#, Yujia Li, C Elizabeth Shaaban, Yonghui Wu, Stephen Anton, Steven DeKosky, Jiang Bian, Jingchuan Guo #These authors contributed equally to this work.
Neighborhood deprivation and mortality among people with Alzheimer’s disease and related dementia
Abstract: Background: There are limited studies quantifying the extent to which neighborhood deprivation affects mortality in individuals living with Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD). Objective: To quantify to what extent neighborhood deprivation affects adverse outcomes in individuals living with AD/ADRD. Methods: We identified individuals with AD/ADRD using a 15% random sample of national Medicare fee-for-service beneficiaries. Area deprivation index (ADI) was spatially linked to the Medicare AD/ADRD cohort using zip codes. Multivariate logistic regression was applied to examine the association between ADI and all-cause mortality among beneficiaries with AD/ADRD. Results: After adjusting for patients characteristics, compared to the lowest ADI quartile (Q1), higher ADI quartiles were associated with higher odds of all-cause mortality in individuals with AD/ADRD (Q2 = OR 1.08 [95% CI: 1.06, 1.10], Q3= OR 1.09 [95% CI: 1.07, 1.11], and Q4 OR 1.05 [95% CI: 1.03, 1.07]). Conclusions: Neighborhood deprivation is an independent risk factor for mortality in persons with AD/ADRD.
Xiao-chang Liu, Juan Zhou, Gui-rong Cheng, Meng-liu Yang, Fei-fei Hu, Dan Liu, Xin-yan Xie, Yong Ji, Yang Lv, Jian-ping Niu, Pan Cai, Bao-zhi Gang, Yong You, Xin-ling Meng, Zhao-xia Wu, Xiang-you Li, Wei Tan, Yan Zeng (Handling Associate Editor: Ling-Qiang Zhu)
Association between insomnia and its symptoms and cognitive impairment in community-dwelling older adults in China: A multicenter study
Abstract: Background: Limited evidence exists on insomnia symptoms' association with mild cognitive impairment (MCI) and dementia in older Chinese adults across rural and urban areas. Objective: To examine associations between insomnia symptoms, sleep duration, and cognitive impairment. Methods: This cross-sectional study utilized data from China’s Multicenter Dementia Survey (2019-2020), examining the association between insomnia symptoms, sleep duration, and cognitive impairment, using logistic and linear regression models. The cognitive score was obtained using the Mini-Mental State Examination (MMSE). Results: We included 10,725 participants (5964 females) aged between 65 and 100 years. Insomnia was significantly associated with an increased risk of MCI (odd ratio [OR], 1.16; 95% confidence interval [CI], 1.05 to 1.29) and lower MMSE scores (β, -0.13; 95% CI, -0.15 to -0.10). Difficulties initiating sleep (DIS; OR, 1.16; 95% CI, 1.03 to 1.31) and sleepiness during the day (SDD; OR, 1.32; 95% CI, 1.02 to 1.70) increased MCI risk, and the latter (OR, 1.79; 95% CI, 1.26 to 2.56) also increased risk of dementia. Insomnia’s negative association with MMSE scores was stronger in rural (β, -0.17; 95% CI, -0.20 to -0.14) than urban residents (β, -0.05; 95% CI, -0.08 to -0.02). Sleep duration and MMSE scores showed an inverted U-shaped relationship (peak at 7-8 hours/night). Conclusions: Insomnia symptoms, particularly DIS and SDD, are associated with higher MCI risk and poorer cognition in older adults, with amplified effects in rural China.
Natália Chermont dos Santos Moreira, Larissa de Oliveira Piassi, Jéssica Ellen Barbosa de Freitas Lima, Geraldo Aleixo Passos, Elza Tiemi Sakamoto-Hojo
PTEN inhibition induces neuronal differentiation and neuritogenesis in SH-SY5Y cells via AKT signaling pathway
Abstract: Background: PTEN is a key regulator of neuronal differentiation and neurogenesis. Its role in modulating the PI3K/AKT pathway and oxidative stress responses in neuronal models remains an area of active investigation. Objective: This study aimed to assess the effects of PTEN knockdown on neuronal differentiation, neuritic growth, and PI3K/AKT pathway activation in SH-SY5Y cells. Methods: SH-SY5Y cells were treated with PTEN siRNA to induce PTEN knockdown. The level of PTEN inhibition was confirmed, and assays were performed to evaluate neurogenesis and neuritogenesis at 3- and 7-days post-treatment. Protein expression analysis of key components in the AKT/GSK3-β/Tau pathway was conducted to assess their role in neurogenesis. Additionally, the PI3K inhibitor LY294002 was used to examine its impact on PTEN knockdown-induced neuronal differentiation. Results: PTEN knockdown significantly increased neurite lengths and reduced cytoplasmic size, indicating neuronal differentiation. Protein analysis showed that PTEN inhibition modulated the expression of components in the AKT/GSK3-β/Tau pathway. The PI3K inhibitor LY294002 prevented neuronal differentiation, confirming the involvement of the PI3K/AKT pathway in mediating the effects of PTEN knockdown. Conclusions: Our findings demonstrate that PTEN plays a crucial role in regulating neuronal differentiation in SH-SY5Y cells. The PI3K/AKT pathway mediates the effects of PTEN knockdown, suggesting PTEN as a potential therapeutic target for neurodegenerative diseases where its dysregulation may contribute to disease progression.
Gengsheng Chen, Nicole S McKay, Brian A Gordon, Nelly Joseph-Mathurin, Jingxia Liu, Suzanne E Schindler, Jason Hassenstab, Stephanie Doering, Andrew J Aschenbrenner, Qing Wang, Pamela J LaMontagne, Sarah J Keefe, Parinaz Massoumzadeh, Carlos Cruchaga, Chengjie Xiong, John C Morris, Tammie LS Benzinger
Baseline and longitudinal changes in cortical thickness and hippocampal volume predicts cognitive decline
Abstract: Background: As we transition to disease-modifying treatment for Alzheimer’s disease (AD), identifying individuals most at risk for future cognitive decline is crucial. Amyloid PET, cerebrospinal fluid and more recently blood-based biomarkers can identify the first stage of AD. However, changes detectable by PiB-PET may precede the onset of the dementia by 20-30 years. MRI is a widely available tool for detecting longitudinal changes in brain structure, such as cortical thickness and hippocampal volume and may provide additional insight into which patients are at greatest risk to develop cognitive decline. Objective: To determine how well the hippocampal volume and cortical thickness, without specific AD biomarkers, can predict cognitive decline. Methods: MRI data from 344 participants (cognitively unimpaired or mild cognitive impairment, age 50-86) were used to evaluate if changes in cortical thickness and hippocampal volume predict cognitive decline, measured by a global cognitive composite score. A random coefficient model was employed to calculate longitudinal changes in cortical thickness and hippocampal volume and assess their ability to predict cognitive decline. Results: Baseline cortical thickness as well as hippocampal volume predicted cognitive decline, regardless of baseline cognitive status. In individuals unimpaired at baseline, decreases in cortical thickness and hippocampal volume independently predicted cognitive decline. For participants with baseline mild impairment, decreases in hippocampal volume predicted further cognitive decline. Conclusions: These findings indicate that MRI could serve as an effective tool for identifying individuals at elevated risk of cognitive decline, a growing public health concern as global populations continue to age.
Zachary T Popp, Ting Fang Alvin Ang, Phillip H Hwang, Rhoda Au, Jinying Chen (Handling Associate Editor: Sean Clouston)
Association between education and rate of cognitive decline among individuals with Alzheimer’s disease: A multi-national European observational study
Abstract: Background: The cognitive reserve (CR) hypothesis presumes higher tolerance of Alzheimer’s disease (AD)-related pathology without functional decline for those with high education and more rapid decline after AD onset. Evidence supporting the second part of the hypothesis has been largely confined to U.S.-based studies. Objective: To assess the relationship between education and cognitive decline in a multi-national European cohort of older adults living with AD. Methods: We analyzed data from participants recruited into the GERAS-EU cohort study from AD clinics in the United Kingdom, Germany, and France. Linear mixed models were employed to assess the relationship between education (dichotomized using a 12-year cutoff) and cognitive decline measured by Mini-Mental State Examination (MMSE) scores during 1.5 to 3 years of follow-up, adjusting for age, sex, time from formal diagnosis, country, comorbidities, and AD treatment. Results: A total of 1,313 participants were analyzed, with mean age of 77.3 years (SD=7.6), 715 (54.5%) females, and 378 (28.8%) with high education (≥12 years). Participants with high education experienced a 0.19-point greater decline (versus low education group) in MMSE scores every 6 months during follow-up (95% Confidence Interval: 0.03-0.35, p=0.02). The secondary analyses (stratified by disease severity, sex, or country) showed a consistent direction of the association, although only significant in the severe AD group (p=0.01). Conclusions: Our findings provide partial support for the CR hypothesis. Delayed AD diagnosis in individuals with high education may contribute to faster decline after diagnosis, highlighting the importance of sensitive screening for early signs of cognitive impairment.
Peiqi Zhang, Nianwei Wu, Qingping Xue, Jingyi Li, Qingqing Ouyang, Xinyue Yu, Yunhaonan Yang, Yidan Dong, Fan Li, Tianlei Wang, Shuo Li, Xiong-Fei Pan
Plasma leptin, resistin, tumor necrosis factor-alpha, and interleukin-6 with risk of dementia: A prospective population study
Abstract: Background: Adipokines secreted from adipose tissue may contribute to dementia pathogenesis. Objective: Our study investigated the associations between plasma levels of leptin, resistin, TNF-α, and IL-6 and the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Methods: Plasma protein levels were measured using the Olink Proximity Extension Assay, and dementia was ascertained from hospital admissions and death registries in the UK Biobank. Multivariable Cox proportional hazards models with stepwise covariate adjustment were used to assess associations. Subgroup analyses were conducted to examine whether associations varied by sociodemographic characteristics, lifestyles, and major diseases. Results: Among 32002 participants, 793 developed all-cause dementia, including 260 with AD and 96 with VaD. Plasma levels of resistin and IL-6 were positively associated with risks of all-cause dementia, with hazard ratios (95% confidence intervals) of 1.10 (1.03, 1.18) and 1.10 (1.04, 1.17), respectively. Leptin (0.98; 0.86, 1.12) and TNF-α levels (1.06; 0.98, 1.13) were not significantly associated with all-cause dementia. Resistin (1.28; 1.08, 1.53) and TNF-α levels (1.21; 1.04, 1.40) were associated with VaD risk. There was a lack of evidence for the associations between four adipokines and AD. Subgroup analyses showed stronger associations between resistin and all-cause dementia in those with high body mass index, diabetes, or stroke. Conclusions: Plasma levels of resistin and IL-6 were positively associated with risks of all-cause dementia, with resistin and TNF-α strongly linked to VaD. These findings support a potential role of adipokines in dementia pathogenesis, particularly for VaD.
Danielle Jamison#, Shrinath Kadamangudi#, Batbayar Tumurbaatar, Wen-Ru Zhang, Lee Palmer, Steve Kunkel, Rakez Kayed, Agenor Limon, Giulio Taglialatela #These authors contributed equally to this work.
Comparative analysis of brain-derived tau oligomer interactomes in Alzheimer’s disease, non-demented with Alzheimer’s neuropathology, and primary age-related tauopathy: Implications for neurodegeneration and cognitive resilience
Abstract: Background: In Alzheimer’s disease (AD), soluble tau oligomers are central to neurodegeneration and cognitive decline. Resilient individuals, such as those with non-demented Alzheimer’s neuropathology (NDAN) or primary age-related tauopathy (PART), offer critical insights into protective mechanisms against tau-mediated neurodegeneration. NDAN individuals exhibit AD neuropathology without cognitive impairment or neurodegeneration, while PART, characterized by hippocampal- and entorhinal-restricted tau pathology, manifests with minimal-to-no amnestic changes. Brain-derived tau oligomers (BDTO) from these cohorts provide a unique platform to explore molecular pathways underlying both vulnerability and resilience to tau pathology. Objective: To identify vulnerability- and resilience-associated pathways by comparing BDTO interactomes across AD, NDAN, and PART. Methods: BDTO were isolated from AD (n = 4; 2M, 2F), NDAN (n = 4; 2M, 2F), and PART (n = 4; 1M, 3F) hippocampal autopsy specimens using co-immunoprecipitation. Proteins were identified via liquid chromatography-tandem mass spectrometry, and non-specific interactors were filtered using SAINTq. Interactome networks and enrichment analyses were performed using Metascape. Findings were cross-referenced with the Neuropro database and existing literature on tangle-associated proteins. Key interactors were validated through reverse co-immunoprecipitation. Results: A total of 203 proteins were identified, including eight novel interactors not previously linked to AD. All interactomes were enriched in proteins related to tau physiology and lysosomal degradation. NDAN and PART interactomes showed unique enrichment in proteins involved in cellular responses to reactive oxygen species. Conclusions: One vulnerability-associated and 18 resilience-associated pathways that may mitigate tau-mediated neurodegeneration were identified, laying the groundwork for novel diagnostic and therapeutic strategies targeting pathological tau oligomers.
William Wang, Pamela B Davis, Xin Qi, Mark Gurney, George Perry, Nora D Volkow, David C Kaelber, Rong Xu (Handling Editor: Paula Moreira)
Associations of semaglutide with Alzheimer’s disease-related dementias in patients with type 2 diabetes: A real-world target trial emulation study
Abstract: Background: Almost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia. Objective: We aim to investigate if semaglutide is associated with a decreased risk of dementia. Methods: We conducted emulation target trials based on a nationwide population-based database of patient electronic health records (EHRs) in the US among 1,710,995 eligible patients with type 2 diabetes (T2D) comparing semaglutide with other antidiabetic medications. First-time diagnosis of Alzheimer’s disease-related dementia (ADRD) including vascular dementia, frontotemporal dementia, Lewy body dementia and other dementias were examined using Cox proportional hazards and Kaplan–Meier survival analyses during a 3-year follow-up. Models were adjusted by propensity-score matching. Results: We show that semaglutide was associated with a significantly reduced risk of overall ADRD incidence with a hazard ratio ranging from 0.54 (0.49-0.59) compared with insulin, 0.67 (0.61-0.74) compared with metformin, to 0.80 (0.72-0.89) compared with older generation glucagon-like peptide-1 agonists (GLP-1RAs). The association varied for specific dementia types, with significantly reduced risk of vascular dementia and no evidence of associations with frontotemporal and Lewy body dementias. Conclusions: These findings provide evidence supporting protective effects of semaglutide on dementias in patients with T2D. Future works are needed to establish the causal relationships through randomized clinical trials and to characterize the underlying mechanisms.
Xinde Zheng#, Shuzhi Lin#, Zefeng Cai, Jilin Li (Handling Associate Editor: Masaaki Matsunaga) #These authors contributed equally to this work.
Association between cardiovascular-kidney-metabolic syndrome and risk of low cognitive function in older adults: Data from the NHANES 2011-2014
Abstract: Background: Cardiovascular-kidney-metabolic (CKM) syndrome was associated with high risk of adverse health outcomes. However, the relationship between CKM syndrome and risk of low cognitive function remains underexplored. Objective: To evaluate the association between CKM syndrome and low cognitive function risk among older adults. Methods: This study included 2,158 participants aged 60 years or older from the NHANES 2011-2014. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, Digit Symbol Substitution Test (DSST), and Animal Fluency Test. Weighted multivariable logistic regression models were used to examine the association between different stages of CKM syndrome and low cognitive function risk. Results: Among the 2,158 participants, 486 (22.5%) for the CERAD test, 492 (22.8%) for the DSST, and 456 (21.1%) for the Animal Fluency Test were diagnosed with low cognitive function. Compared with participants at CKM syndrome Stage 0, the multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for low cognitive function assessed by CERAD test in Stages 1 to 4 were 0.76 (0.23, 2.98), 1.56 (0.79, 3.72), 1.72 (1.02, 4.10), and 2.97 (1.15, 5.42), respectively. For the DSST, the OR and 95% CI in Stages 1-4 were 0.75 (0.34, 3.42), 1.21 (0.65, 2.95), 1.30 (1.04, 3.23), and 2.21 (1.05, 4.92), respectively. No significant association was found between CKM syndrome and low cognitive function for the Animal Fluency Test. Conclusions: Older adults at CKM stages 3-4 showed poorer cognitive performance, particularly in episodic memory, processing speed, and attention, compared to those at stage 0.
Suhyung Kim, Sheng-Min Wang, Dong Woo Kang, Sunghwan Kim, Jong-Hyun Jeong, Hyukjin Yoon, Hyun Kook Lim, Yoo Hyun Um (Handling Associate Editor: Tae Kim)
Impact of type 2 diabetes mellitus on differential cerebellar volume reduction in Alzheimer’s disease trajectory
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder linked to cognitive decline. Type 2 diabetes mellitus (T2DM) is a known risk factor for AD and may contribute to cerebellar atrophy, but their relationship remains unclear. Objective: This study investigated the impact of T2DM on cerebellar gray matter (GM) volume across normal cognition (NC), preclinical AD, and AD mild cognitive impairment (AD MCI) groups to explore its role in AD progression. Methods: Medical records of patients visiting St. Vincent's Hospital (September 2019–April 2024) were analyzed. Cerebellar GM volume was analyzed using voxel-based morphometry with SPM12. Group differences in cerebellar GM volume were assessed using rank analysis of covariance. Spearman’s rank correlation was used to explore associations between cerebellar GM volume and cognitive function, and HbA1c levels in patients with T2DM. Results: AD MCI patients with T2DM showed greater GM atrophy, particularly in the posterior lobe. In NC, T2DM was associated with Vermis VI volume reduction, while preclinical AD showed increased Left VIIIb volume. Amyloid-β positive (Aβ+) group has negative correlation HbA1c level and Right Crus I volume. Cerebellar GM volume correlated with cognitive scores, particularly episodic memory in AD MCI patients. Conclusions: T2DM and AD pathology contribute to cerebellar changes linked to cognitive decline. Managing T2DM may mitigate its impact on AD progression.
Jing Tian#, Sai Sreeja Meka#, Tienju Wang, Lan Guo, Heng Du #These authors contributed equally to this work.
Vulnerability of mitochondrial OXPHOS complexes in the arcuate nucleus of the hypothalamus of Alzheimer’s disease
Abstract: Background: With increasing recognition of the heterogeneity of the etiopathogenesis of Alzheimer's disease (AD), clinical and basic research has accentuated a contribution of hypothalamic dysfunction to the development of this neurodegenerative disorder. The arcuate nucleus of the hypothalamus (ARH) plays a critical role in maintaining metabolic homeostasis through its regulation of energy storage and expenditure. Although the importance of mitochondrial bioenergetics to the fitness of ARH neurons has been documented, the functional status of mitochondrial oxidative phosphorylation (OXPHOS) complexes in ARH neurons has not been comprehensively investigated in AD-related settings. Objective: This study investigated the mitochondrial OXPHOS complex enzyme activity in ARH of AD patients. Methods: We examined ARH mitochondrial OXPHOS complexes and AD-related pathological characteristics in AD patients. We also utilized transcriptome-wide association studies (TWAS) bioinformatics method to predict gene expression changes in ARH mitochondrial-related genes within the AD cohort. Results: In this study, we identified mitochondrial complex IV dysfunction in tissue homogenate and synaptosomal fractions of postmortem ARH from patients with AD. Further examination determined a reverse correlation between neuronal complex IV dysfunction and ARH amyloid-β 42. Furthermore, through hypothalamus-specific TWAS analysis we identified multiple AD susceptibility genes that encode key proteins for mitochondrial OXPHOS complex assembly and function. Conclusions: Our results suggest that ARH neuronal mitochondrial complex IV dysfunction constitutes a phenotypic change in AD that potentially contribute to ARH neuronal stress and dysmetabolism in patients with AD. These findings form a groundwork for future research to understand a hypothalamic mitochondrial pathway of AD pathogenesis.
Jingyu Zhu#, Xiao Xiao#, Xiaotong Chen, Heren Xiao, Zhengbang Tao, Haiping Zhang, Keunha Park, Linh Q Lam, Christine Thai, Brett Trouson, Bronia Glen, Kelly Pertile, Pip Pyman, Qiao-Xin Li, Colin L Masters, Christopher J Fowler, James D Doecke, Nicholas A Williamson, Jun Wang, Haiyan Gao, Wei Zhang, Bo Zhou, Qianhua Zhao, Yong Lin, Jun Xiao, Ben J Gu (Handling Associate Editor: Ana Gabriela Henriques) #These authors contributed equally to this work.
Amyloid-β protein precursor fragments in urine: Potential biomarkers for the early detection of mild cognitive impairment and dementia
Abstract: Background: Current diagnostic methods have limitations in early prediction of dementia. Objective: Develop an early screening tool to identify persons at high risk of dementia for early intervention. Methods: We examined amyloid-β protein precursor (AβPP) and its fragments in urine from cognitively normal controls (CNs) and patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD)-dementia using western blotting with different antibodies and developed a colloidal gold lateral flow-based qualitative strip. Results: Compared with CNs, the amounts of various AβPP fragments with molecular weights of approximately 14, 28, 56, and 68 kDa in patients were greater. We therefore used the strip to detect urine Aβ-containing AβPP fragments and evaluated its potential in multiple aged cohorts from 11 cities in Jiangsu Province, China (n=4418); Sichuan Provincial People’s Hospital (Chengdu, China; n=408); and the Australian Imaging, Biomarker and Lifestyle Study (AIBL; n=367). Unitizing Aβ-binding phagocytosis-promoting peptides, the strips showed increasing positivity (9.5-16.9%) with aging in the Jiangsu cohort and good clinical performance in the Chengdu cohort (κ=0.704). Significant differences between CNs and patients were found in the AIBL cohort with negative Aβ-PET, those with the slope of Aβ-PET change <1 centiloid per year, those under 75 years of age, or those with a body mass index of 25–30. Conclusions: Our data indicate the high potential of urine AβPP fragments as biomarkers for MCI and dementia at an early stage and warrant further longitudinal studies.
Qing-ning Zhang, Lan-ke Yu, Xin-yuan Zhang, You Wu, Heng Zhang, Jia-lin Wu, Zhao-hui Yao, for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Ling-Qiang Zhu)
LCN2 of cerebrospinal fluid: A potential biomarker for diagnosis and disease progression in Alzheimer’s disease
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with complex pathological features and pathogenesis, involving aspects such as amyloid-β (Aβ) deposition and neuroinflammation. AD lacks the specific biomarkers for diagnosis, which restricts diagnosis. Recent studies have indicated that Lipocalin-2 (LCN2) plays a direct or indirect role in the occurrence and development of AD. However, whether LCN2 can serve as a biomarker for AD’ diagnosis remains unclear. Objective: This study aims to investigate the role of LCN2 in AD and its potential as a biomarker for diagnosis from a clinical perspective. Methods: We analyze the participant demographic information, LCN2 and Aβ42 levels in cerebrospinal fluid (CSF), and cortex thickness from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database with Welch ANOVA, Linear regression models and other statistical methods. Results: LCN2 levels in the CSF of AD patients were significantly higher than those in individuals with mild cognitive impairment and no cognitive impairment. The LCN2 levels were closely associated with cognitive decline and pathological features of AD, including Aβ deposition, and reduced cortical thickness, but no tau protein phosphorylation. Age was an important confounding factor affecting the relationship between LCN2 and Aβ42, while gender, years of education, and APOE carrier status did not have a significant impact. Furthermore, LCN2 was linked to the upregulation of inflammatory markers, indicating its potential involvement in the neuroinflammatory processes of AD. Conclusions: LCN2 is not only a potential biomarker for the early diagnosis of AD but may also play a significant role in the neurodegenerative processes associated with the disease.
Christina Jensen-Dahm, Janet Janbek, Thomas Munk Laursen, Christiane Gasse, Gunhild Waldemar
New opioid use and mortality in older people with dementia
Abstract: Background: Opioid use is frequent among older people with dementia. Opioid use has been associated with excess mortality in the general population, but whether this also applies to older people with dementia is unknown. Objective: Investigate if new opioid use compared with no use was associated with excess mortality in older people with dementia. Methods: Matched cohort study using Danish nationwide registries including all residents (age 65+) diagnosed with dementia (including Alzheimer’s disease) between 2008-2018. Exposure was defined as first opioid prescription after dementia diagnosis (1 year washout before). Persons exposed to opioids were matched with up to two unexposed persons on age and sex. Outcome was all-cause mortality within 180 days after exposure. Cox proportional hazards models compared rates of death and adjusted for potential confounders. Results: Forty-two percent (31,619/75,471) of older people with dementia initiated a prescription for an opioid after dementia diagnosis. 31,619 exposed persons were matched to 63,235 unexposed. Among the exposed, 8540 (27%) died within 180 days after initiating their first opioid prescription compared with 3803 (6.01%) of the unexposed, yielding a 5-fold excess mortality risk (adjusted Hazard ratio: 5.06 (95% CI, 4.86-5.29)). Transdermal fentanyl use was associated with an 8-fold excess mortality risk (8.26 (7.18-9.51)). Conclusions: Opioid use was associated with excess mortality, which may be due to the opioid, the indication or both. This observation calls for further research into the links between opioid use and excess mortality in elderly with dementia as it could have important implications for patient safety.
Feilan Chen, Hainan Deng, Qingyu Zhang, Yanmei Liu, Yujie Zhang, Yan Zhang, Dan Li, Xinling Meng
Utility of machine learning algorithms in classification of progressive cognitive impairment in Alzheimer’s disease: A retrospective cohort based on China
Abstract: Background: Distinct risk factors influence Alzheimer's disease (AD) stage stratification, yet effective tools for early diagnosis and prognosis remain limited, especially in middle-aged populations. Objective: To develop machine learning models for predicting cognitive decline and identifying early markers of stage stratification in a middle-aged Chinese cohort. Methods: We conducted a retrospective study on 451 patients from 2017 to 2021 (aged 45–90 years, 47.7% male). All participants were classified into normal, mild cognitive impairment (MCI), AD. Neuropsychological scale, epidemiological and laboratory parameters were collected. Four machine learning algorithms, the Least Absolute Shrinkage and Selection Operator (LASSO) regression, Random Forest, Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost), were employed with 10-fold cross-validation. Model performance was measured using area under the receiver operating characteristics curve (ROC-AUC) and area under precision and recall curves (PR-AUC), classification confusion matrices, sensitivity, accuracy, precision, recall, F1 Score. Results: Models demonstrated high ROC-AUC and satisfactory PR-AUC, with LASSO and SVM excelling in the MCI group (recall: 85.3% and 93.1%; F1 score: 78.4% and 78.3%, respectively). Mini-Mental State Examination (MMSE) scores differed significantly across stages, except for advanced-stage items such as naming, language repetition, and language understanding. Conclusions: These multi-dimensional machine learning models show promise as effective tools for predicting AD stage stratification, enabling targeted monitoring and early intervention for at-risk patients.
Zi-ting Shang, Xue-yan Huang, Liu-lin Xiong, Zu-cai Xu, He-xu Liu, Chang-yin Yu
Methanol extract from miracle fruit seeds mitigates Alzheimer’s disease and enhance autophagy via suppressing the AKT/mTOR signal pathway
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disease. In previous study, we discovered that methanol extract of miracle fruits seeds (MFSs) had a therapeutic effect on AD model mice. Objective: In this research, we aimed to study the role of MFSs in alleviating amyloid-β (Aβ) deposition and further explore the possible mechanism of action of MFSs. Methods: We used behavioral tests and various immunolabeling techniques on two AD model (Aβ transgenic model strain CL4176 of Caenorhabditis elegans and the 3×Tg-AD mice). Results: In CL4176, MFSs (10 μg/mL) could effectively alleviate the paralysis caused by Aβ, the Aβ plaques were significantly reduced, the transcription levels of Aβ, age-1, akt-1 and mTOR genes were significantly downregulated, and the transcription of autophagy-related gene lgg-1 was enhanced. The cognitive function of mice in the MFSs group was improved, which was related to reduced synapse loss and Aβ-positive neurons in the brain. Meanwhile, the transcription levels of amyloid-β protein precursor (AβPP), Tau, Akt and mTOR were significantly reduced. The protein expressions of PSD95, SYN1, LC3II/I and Beclin-1 were significantly increased, and the value of p62/SQSTM1, p-AKT/AKT, p-mTOR/mTOR were reduced. Conclusions: MFSs significantly alleviates Aβ deposition in CL4176 and mice. The mechanism by which it improves cognitive function in AD mice may be related to enhanced autophagy regulated by the Akt/mTOR signaling pathway.
Yeting Zeng#, Xiangteng Zhao#, Shaoming Sang, Shiwen Yu, Chunjiu Zhong #These authors contributed equally to this work.
Glucose-lipid metabolic index reflects cognitive impairment of non-diabetic elderly individuals
Abstract: Background: Glucose and lipid metabolic disorders are involved in the impairment of cognitive function. However, it remains unclear the link between a new indicator of glucose-lipid metabolism index (GLMI) and cognitive impairment. Objective: This study investigates the relationship between GLMI and multidimensional cognitive function in adults aged ≥ 60 years. Methods: GLMI was derived from glucose and lipid metabolism parameters. Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning test, Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST) were used to evaluate the cognitive abilities of participants. Linear regression, subgroup analyses, multivariable adjustments, and restricted cubic spline (RCS) models were employed to evaluate GLMI-cognition associations. Results: Among 787 participants from NHANES 2011-2014, diabetic individuals exhibited higher GLMI levels and more severe cognitive impairment than non-diabetic counterparts. In non-diabetic adults, GLMI showed linear correlations with CERAD and DSST assessed cognitive deficits. Subgroup analyses confirmed high GLMI as an independent risk factor for cognitive dysfunction in CERAD and DSST assessment. Multivariable regression revealed increased GLMI significantly elevated cognitive decline risk. ROC analysis identified 581.41 as the optimal GLMI cutoff (specificity: 86.0%) for predicting DSST impairment, outperforming traditional indices (TyG/HOMA-IR). RCS models demonstrated nonlinear GLMI-cognition associations, with a dose-dependent risk curve (200–800 range) and critical threshold at 545. Conclusions: This study establishes that a high score of GLMI is associated with great severity of cognitive impairment in non-diabetic population.
