Review
Tianyi Wang#, Haochen Jiang#, Ruwen Zheng, Chuchu Zhang, Xiumei Ma, Yi Liu #These authors contributed equally to this work.
Trends and research focus on autophagy in Alzheimer’s disease (2003–2023): A bibliometric study
Abstract: Background: Alzheimer's disease (AD) is characterized by amyloid-β plaques and tau aggregates, with autophagy dysfunction playing a key pathogenic role. While autophagy modulation shows therapeutic promise, comprehensive bibliometric analyses are lacking. Objective: This study aims to map the research landscape of autophagy in AD through bibliometric analysis, identifying key trends, contributors, and emerging focus areas. Methods: We analyzed 4,018 publications (2003–2023) from Web of Science using VOSviewer and CiteSpace. Publication trends, influential authors, countries, institutions, and research hotspots were examined through co-occurrence, burst detection, and clustering analyses. Results: Annual publications have steadily increased, peaking in 2022. The US led in output and citations, with major contributions from the University of California and New York University. Ralph A. Nixon emerged as the most influential author. Early research (2003–2013) primarily focused on protein degradation mechanisms, whereas recent studies (2014–2023) emphasize mitochondrial dysfunction, apoptosis, and related pathways. Key evolving topics include endoplasmic reticulum stress and chaperone-mediated autophagy, with significant implications for therapeutic innovation. Conclusions: Autophagy plays a critical role in AD pathogenesis and represents a promising therapeutic target. Despite mechanistic advances, clinical translation remains challenging. Future research should prioritize multi-omics integration, drug delivery optimization, and managing risks associated with excessive autophagy activation. These findings provide valuable insights for developing novel AD therapies targeting autophagy.
Systematic Review
Alessandro von Gal#, Dario Papa#, Marco D’Auria, Laura Piccardi #These authors contributed equally to this work.
Disruptive resting state networks characterizing depressive comorbidity in Alzheimer’s disease and mild cognitive impairment
Abstract: Background: Depressive comorbidity in neurodegeneration has been shown to predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). However, its pathophysiology is not completely understood. Objective: Here, we characterize aberrant functional resting state networks (RSNs) characterizing depressive comorbidity in both AD and MCI. Methods: We conducted a systematic literature review on Scopus, PubMed, and Web of Science to extract experiments that compared resting state scans of depressed and non-depressed MCI or AD patients. We employed Activation Likelihood Estimation (ALE) meta-analysis on eligible studies resulting from the search, to describe regions of significant co-activation across studies. Results: The systematic search resulted in 17 experiments, with 303 participants in total. The ALE yielded 10 clusters of significant co-activation distributed in the five major RSNs and across cortico-basal ganglia-thalamic circuits. Conclusions: Depressive comorbidity in neurodegeneration presents signature aberrant resting-state fluctuations. Understanding these within- and between-network alterations may be useful for future diagnostic and therapeutic applications.
Short Communication
Moira Marizzoni, Luigi Coppola, Cristina Festari, Delia Luongo, Dominic Salamone, Daniele Naviglio, Andrea Soricelli, Peppino Mirabelli, Marco Salvatore, Annamaria Cattaneo, Giovanni B Frisoni
Circulating short chain fatty acids in Alzheimer’s disease: A cross-sectional observational study
Abstract: Short chain fatty acids (SCFAs), produced mainly by gut microbes, might play a role in the pathophysiology of Alzheimer’s disease (AD). We examined the SCFAs profile in 28 individuals with cognitive impairment due to AD (CI-AD), 29 with cognitive impairment not due to AD (CI-NAD), and 10 cognitively unimpaired (CU). CI-AD showed higher levels of acetate and valerate and lower levels of butyrate than CU and CI-NAD (p<0.018). Acetate separated CI-AD from CI-NAD with AUC=0.95 while the best neurodegeneration-related biomarker GFAP with AUC= 0.79. SCFAs use for diagnosis and as treatment target in AD deserve further studies.
Commentary
Joshua L Gills, Omonigho M Bubu
A critical examination of the relationship between cardiovascular health, cognition, and dementia risk
Abstract: Poor cardiovascular health is strongly linked to increased risk of cognitive impairment and Alzheimer’s disease and related dementias. This commentary discusses Yang and associates' work on the associations between cardiovascular health in middle age, as defined by Life Essential 8 scores, and later digital cognitive performance and incident Alzheimer's disease. We examine the strengths and weaknesses of their study within the broader research context. We emphasize the potential significance of sleep and stress the need for longitudinal studies incorporating robust neuropsychiatric methodologies, advanced neuroimaging techniques, and diverse participant samples to enhance the reliability and generalizability of results.
Commentary
Yorito Hattori
The emerging role of the circadian rhythm in the blood-brain barrier dysfunction associated with cerebral small vessel disease
Abstract: The relationship between circadian rhythm and cerebrovascular disease has recently emerged as a fascinating area of research. It has been found that the circadian rhythm could affect the development and exacerbation of cerebral small vessel disease (CSVD). Dysfunction of the blood-brain barrier (BBB) is one of the key players in the mechanisms of CSVD. This is thought to be regulated by circadian oscillations of clock genes, which control transporter function, regulating the permeability of the BBB endothelial cells, tight junction proteins, and pericytes. Understanding the interaction between circadian genes and BBB components may contribute to the development of promising treatments for CSVD.
Commentary
Carolin AM Koriath, Robert Perneczky
Obesity and Alzheimer’s disease dementia: Examining inflammatory links to cognitive decline and neuropsychiatric symptoms
Abstract: Obesity is recognized as a risk factor for cardiovascular disease, vascular dementia, and Alzheimer’s disease dementia (AD dementia). Emerging evidence indicates that obesity in AD patients is associated with heightened neuropsychiatric symptoms, as reflected by inflammatory biomarkers such as C-reactive protein and complement C3. Neuroinflammation, particularly through certain aspects of microglial activation, plays a significant role in AD development and cognitive decline. While further research into these underexplored neuroinflammatory pathways as potential therapeutic targets is warranted proactive weight management starting in middle age may help mitigate both cognitive decline and neuropsychiatric symptoms.
Eric T Klopack, Mateo P Farina, Bharat Thyagarajan, Jessica D Faul, Eileen M Crimmins
How much can biomarkers explain sociodemographic inequalities in cognitive dysfunction and cognitive impairment? Results from a machine learning model in the Health and Retirement Study
Abstract: Background: Biomarkers may be pathways by which social adversity affects cognitive aging and Alzheimer's disease and related dementias (ADRD) risk. Objective: How much variance in cognitive dysfunction and cognitive impairment onset do blood-based and physiological biomarkers provide above and beyond easily attainable sociodemographic variables, and how much can biomarkers explain differences in cognitive functioning and ADRD by sociodemographic variables? Methods: We utilize machine learning to generate measures of predicted cognitive dysfunction and cognitive impairment incidence based on 91 biomarkers, identify the relative importance of each biomarker, and examine how much these biomarkers mediate sociodemographic differences. Results: Markers related to cellular aging, neurodegeneration, diet and nutrition, immune functioning, and lung function were identified as important. Biomarkers mediated 47.2-77.3% of the variance associated with age, 22.7-35.2% of racial/ethnic differences in cognitive dysfunction, and 12.5-17.6% of educational differences. Conclusions: Biomarkers provide the potential to understand pathways linking sociodemographic characteristics to cognitive functioning and health. Future research should consider additional biomarkers and evaluate the specific systems that put people at risk for cognitive impairment.
Roshanak Mehdipanah, Emily M Briceño, Madelyn Malvitz, Wen Chang, Steven G Heeringa, Darin B Zahuranec, Deborah A Levine, Kenneth M Langa, Xavier F Gonzales, Nelda Garcia, Noreen Khan, Lewis B Morgenstern
Ethnic disparities in care needs among individuals with cognitive impairment
Abstract: Background: As more individuals with cognitive impairment and dementia (CID) remain at home, greater needs arise, necessitating additional support. Objective: To examine ethnic differences in the needs of individuals with CID among Mexican American (MA) and non-Hispanic White (NHW) participants. Methods: Adults 65+ with possible cognitive impairment (Montreal Cognitive Assessment score<26), and their caregivers living in Nueces County, Texas, were included. We used the Camberwell Assessment of Need for the Elderly (CANE) tool to study the needs (accommodations, self-care, continence, physical health, emotional well-being, social relationships, and availability of support networks) and their domains of individuals with CID including environmental, physical, psychological and social needs. Using negative binomial and Poisson regressions, ethnic differences were examined within each domain. Results: A total of 473 participants were included. NHW participants (N=150) were slightly older (75.5 versus 72.7 years) and had higher rates of MCI and dementia (55% versus 47%) compared to MA participants (N=323). All participants reported high levels of needs (met or unmet). Furthermore, although NHW participants reported having fewer social needs (met or unmet) compared to MA participants (Incident Rate Ratio [IRR]=-0.79; 97.5%CI:0.63-0.98), NHW participants had a greater level of unmet needs when it came to social needs compared to MA participants (IRR=1.85; 97.5%CI:1.33-2.57). Conclusions: Findings indicate high levels of needs among individuals with CID. There also exist ethnic differences, with NHW participants having greater unmet needs in social areas. Enhancing access to resources and support systems is essential for equitable support for individuals with CID across various ethnic backgrounds.
Aaron Lam, Dexiao Kong, Angela L D’Rozario, Catriona Ireland, Rebekah M Ahmed, Zoe Menczel Schrire, Loren Mowszowski, Johannes Michaelian, Ron R Grunstein, Sharon L Naismith (Handling Associate Editor: Ashleigh Smith)
Sleep disturbances and disorders in the memory clinic: Self-report, actigraphy, and polysomnography
Abstract: Background: Sleep disturbances are common in dementia but rarely studied in memory clinics. Objective: In a memory clinic setting we aimed to (1) identify rates of obstructive sleep apnea (OSA), abnormal sleep duration, circadian phase shift, insomnia, poor sleep quality, and REM sleep behavior disorder (RBD); (2) assess concordance between self-reported and actigraphy-derived measures; investigate associations between sleep disturbances; and (3) neuropsychological performance and (4) cognitive status. Methods: Adults over 50 at a memory clinic between 2009-2024 were included. OSA was assessed via polysomnography and prior history. Sleep duration and circadian phase were measured by self-report and actigraphy. Self-report questionnaires evaluated insomnia, sleep quality, and RBD. Global cognition, processing speed, memory, and executive function were assessed. Analysis of Covariance and multinomial logistic regression examined the impact of OSA, sleep duration, insomnia, and sleep quality on cognition and cognitive status. Results: 1,234 participants (Mage 67.2, 46%M) were included. 75.3% had OSA, while 12.7% were previously diagnosed. Insomnia affected 12.0%, 54.3% had poor sleep quality, and 14.2% endorsed RBD symptoms. Self-reported short (30.5%) and long (10.2%) sleep exceeded actigraphy rates (8.5% and 5.1%) with poor concordance between measures. OSA was linked to impaired global cognition and memory (p<0.05). Prolonged sleep predicted deficits in global cognition, processing speed, memory, and executive function and a higher risk of aMCI (all p<0.05). Poor sleep quality was linked to better memory (p<0.05). Conclusions: Despite discrepancies between self-reported and objective prevalence rates, sleep disturbances are highly prevalent in memory clinics and impact cognition, necessitating further examination.
Alexandra Sandberg#, Srivalli Puttagunta#, Nathan Duval#, Holly Fleming, Lilia Koza, Kade Hieber, Jessica Holsopple, Michael Reyna, Daniel Paredes, Daniel A Linseman #These authors contributed equally to this work.
Immunocal®, a cysteine-rich whey protein, rescues reelin and reduces amyloid plaque burden in a transgenic amyloid-β protein precursor (hAβPPSweInd) mouse model of Alzheimer’s disease
Abstract: Background: Deficits in Reelin expression play a significant role in the pathogenesis of various neurological disorders, including schizophrenia and Alzheimer’s disease (AD). Notably, Reelin-expressing neurons of the entorhinal cortex layer II are among the first to be affected in AD. Objective: Strategies aimed at correcting deficits in Reelin might provide a novel therapeutic approach for AD. Methods: Here, we examined the effects of the whey protein supplement and glutathione (GSH) precursor, Immunocal®, on Reelin expression both in vitro in hippocampal-entorhinal cortex slices from rat brain and in vivo in the hAβPPSweInd (J20) mouse model of AD. Results: Incubation of brain slices with Immunocal® increased Reelin expression at the mRNA and protein levels. Oral treatment with Immunocal®, given ad libitum in drinking water beginning at 3 months of age, corrected a deficit in cortical GSH levels observed in untreated mice and preserved Reelin expression in the hippocampal-entorhinal cortex sub-region of 5-month-old J20 mice. We also assessed the long-term effects of Immunocal® by treating J20 mice from 3 months old to 12 months old. Long-term Immunocal® treatment preserved brain GSH and rescued Reelin mRNA and protein expression, while significantly reducing amyloid plaque formation in the entorhinal cortex and hippocampus of AD mice. Conclusions: These findings suggest that Immunocal® promotes Reelin expression in vitro and sustains brain GSH and Reelin expression while diminishing amyloid plaque load in the entorhinal cortex and hippocampus of J20 mice. Thus, Immunocal® offers a promising therapeutic approach to enhance Reelin expression and curtail amyloid deposition in AD.
Laura Storm Næsborg Andersen, Anja Hviid Simonsen, Asmus Vogel, Oskar McWilliam, Steen Gregers Hasselbalch, Kristian Steen Frederiksen (Handling Associate Editor: Sofia Toniolo)
Isolated elevation of 181p-tau in the cerebrospinal fluid is associated with distinct clinical features: Findings from a Danish memory clinic cohort
Abstract: Background: Deposition of amyloid-β and tau are key pathological events in Alzheimer’s disease and may be assessed by cerebrospinal fluid (CSF) biomarkers. It remains uncertain whether patients who display abnormal phosphorylated tau in isolation differ from patients with other biomarker profiles. Objective: The primary objective was to investigate differences in demographics, comorbidities, and cognitive performance in amyloid-β negative phosphorylated tau positive patients. Further, the aim was also to investigate the relationship between cognitive function and phosphorylated tau level. Methods: A total of 1049 consecutive patients from the Copenhagen Memory Clinic Cohort from 2018 to August 2022 were included and divided into four groups based on the CSF biomarkers amyloid-β42 (A) and phosphorylated tau (T). Data on co-morbidities, abuse, and neuropsychological tests were recorded, and retrospective data analyses were performed across all groups Results: A total of 2.8% participants had an A-T+ biomarker profile and were younger (Mean: 65.1 years, SD: 14.2), comprised of more men (65.5%) than the A+T- group and exhibited both more psychiatric illness (p=0.027) and alcohol and/or drug abuse (p=0.004) than the A+T+ group. The A-T+ group performed better on both Addenbrooke’s Cognitive Examination (p=0.002) and Mini-Mental State Examination (p=0.001) as well as immediate (p=0.026) and delayed recall (p=0.009) compared to the A+T+ group but showed no difference compared to the A-T- group on all cognitive scores. Further, higher p-tau levels were associated with worse cognitive performance although effects were small. Conclusions: The findings indicate that patients with the A-T+ biomarker profile have different clinical characteristic that may indicate a non-neurodegenerative background.
Cynthia A Nyongesa, Mike Hogarth, Judy Pa (Handling Associate Editor: Teresa Wu)
Artificial intelligence-driven natural language processing for identifying linguistic patterns in Alzheimer's disease and mild cognitive impairment: A study of lexical, syntactic, and cohesive features of speech through picture description tasks
Abstract: Background: Language deficits often occur early in the neurodegenerative process, yet traditional methods frequently fail to detect subtle changes. Natural language processing (NLP) offers a novel approach to identifying linguistic patterns associated with cognitive impairment. Objective: We aimed to analyze linguistic features that differentiate cognitively unimpaired (CU), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) groups. Methods: Data was extracted from picture description tasks performed by 336 participants in the DementiaBank datasets. 53 linguistic features aggregated into 4 categories: lexical, structural, syntactic, and discourse domains, were identified using NLP toolkits. With normal diagnostic cutoffs, cognitive function was evaluated with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Results: With age and education as covariates, ANOVA and post-hoc Tukey’s HSD tests revealed that linguistic features such as pronoun usage, syntactic complexity, and lexical sophistication showed significant differences between CU, MCI, and AD groups (p < 0.05). Notably, past tense and personal references were higher in AD than both CU and MCI (p < 0.001), while pronoun usage differed between AD and CU (p < 0.0001). Correlations indicated that higher pronoun rates and lower syntactic complexity were associated with lower MMSE scores and although some features like conjunctions and determiners approached significance, they lacked consistent differentiation. Conclusions: With the growing adoption of artificial intelligence (AI)-based scribing, these results emphasize the potential of targeted linguistic analysis as a digital biomarker to enable continuous screening for cognitive impairment.
Hao Liu#, Yunfei Li#, Zheng Sun, Xiaoyu Xu, Bicong Yan, Yuehua Li, Xiaohu Zhao, for the Alzheimer's Disease Neuroimaging Initiative #These authors contributed equally to this work.
Altered hemispheres lateralization of brain functional gradients in Alzheimer's disease
Abstract: Background: The human brain demonstrates intrinsic hemispheric asymmetry across structural, functional, and biochemical domains. While cortical gradients provide a multiscale framework for understanding brain network organization, their hemispheric divergence in Alzheimer's disease (AD) remains unexplored. Objective: To characterize interhemispheric gradient lateralization patterns across the AD continuum and evaluate their clinical correlates. Methods: Resting-state fMRI data of 45 normal controls (NC), 45 patients with mild cognitive impairment (MCI), and 45 patients with AD underwent gradient networks processing. Interhemispheric comparisons of mean gradient values were conducted across these groups. A lateralization index (L value) was defined for 17 networks, and differences among the three groups were analyzed using one-way ANOVA. Additionally, correlations between network L values and cognitive scores were examined. Results: NC and MCI participants exhibited left lateralization of gradient values in the second gradient. In contrast, AD patients showed a loss of interhemispheric lateralization. Notably, AD patients demonstrated reduced lateralization in default mode network (DMN) and control network. The degree of lateralization in DMN was significantly positively correlated with cognitive function. Conclusions: Our findings indicated that patients with AD demonstrated a diminished lateralization in gradient networks. Quantifying gradient laterality may serve as a multimodal biomarker for early AD detection and therapeutic monitoring.
Ming-Jie Li, Meng-Ning Lan, Yao-Xuan Du, Yue Liu, Hua-Yue Zhang, Min Guo, Shi-Wei Liu, Hai-Yang Xia, Zheng-Jun Wu, Hua-Jun Zheng
EPRCN exerts neuroprotective function by regulating gut microbiota and restoring gut immune homeostasis in Alzheimer’s disease model mice
Abstract: Background: No effective drug treatment is currently available for Alzheimer’s disease (AD), highlighting the urgent need to develop efficient therapeutic options. We have developed a formula based on medicine and food homology (MFH) consisting of egg yolk oil, perilla seed oil, raphani seed oil, cinnamon oil, and noni puree (EPRCN), and demonstrated that it can treat AD by alleviating neuroinflammation and oxidative stress. However, whether EPRCN can improve AD by regulating gut microbiota remains unknown. Objective: The current study aimed to evaluate the effect of EPRCN on regulating gut microbiota and neuroprotection. Methods: 16S rRNA sequencing was used to assess the structure of gut microbiota. Hematoxylin-eosin (HE) staining, qRT-PCR, and ELISA were used to evaluate gut inflammation. Detected indexes associated with cholinergic dysfunction and neuronal damage to investigate the neuroprotective effects of EPRCN. Results: 16S rRNA gene analysis revealed that EPRCN remodeled the gut microbiota, inhibited gut metabolic disorders, and promoted CoA biosynthesis in scopolamine-induced mice. EPRCN can ameliorates gut inflammation by activating the cholinergic anti-inflammatory pathway. The results further indicated that EPRCN improved cholinergic dysfunction by inhibiting the activity of acetylcholinesterase and restoring cholinergic receptors. Additionally, EPRCN administration suppressed the neuronal loss and elevated brain derived neurotrophic factor expression in hippocampus. Correlation analysis found that alteration of several gut microbes was associated with indexes improved by EPRCN. Conclusions: These findings suggest that EPRCN may serve as a promising dietary intervention for treating AD by regulating the microbiota-gut-brain axis and exerting neuroprotective function.
Junshi Zhang#, Tingting Liu#, Haojie Wu, Jianshe Wei, Qiumin Qu #These authors contributed to this work equally.
Identification of NDUFV2, NDUFS7, OPA1, and NDUFA1 as biomarkers for Alzheimer's disease: Insights from oxidative stress and mitochondrial dysfunction in the hippocampus
Abstract: Background: Alzheimer's disease (AD) is characterized by amyloid-β deposits, neurofibrillary tangles, and hippocampal neurodegeneration, with oxidative stress and mitochondrial dysfunction playing critical roles in its pathogenesis. Identifying hub genes associated with these processes could advance biomarker discovery and therapeutic strategies. Objective: This study aimed to identify key oxidative stress- and mitochondrial dysfunction-related genes in the AD hippocampus, evaluate their diagnostic potential, and explore therapeutic agents targeting these genes. Methods: We analyzed datasets GSE48350 and GSE5281, encompassing 56 controls and 29 AD patients. Weighted gene co-expression network analysis (WGCNA) selected genes with significance (adjusted p-value < 0.05 and |logFC| ≥ 0.5). Further studies involved immune cell infiltration, Gene set enrichment analysis (GSEA), and intersecting differentially expressed genes (DEGs) with oxidative stress-related genes (ORGs) and mitochondrial dysfunction-related genes (MDRGs). Functional enrichment and Protein-protein interaction (PPI) analyses were conducted. Experimental validation was done in AD mouse models, and diagnostic potential was tested using datasets GSE28146 and GSE29652. Therapeutic drugs were predicted based on hub genes. Results: AD showed altered immune cell expression. GSEA linked DEGs to nervous system processes and neurotransmitters. 194 oxidative stress-related DEGs were enriched in neuronal death and mitochondrial processes. PPI analysis identified 24 DEGs related to both oxidative stress and mitochondrial dysfunction (DEO-MDRGs), with diagnostic potential (AUC > 0.5). LASSO regression selected four DEO-MDRGs: NDUFV2, NDUFS7, OPA1, and NDUFA1. Their protein levels were reduced in AD mice with decreased mitochondrial function. These genes showed good diagnostic performance. Potential drugs, like ME-344 and metformin hydrochloride, may be useful in AD treatment. Conclusions: NDUFV2, NDUFS7, OPA1, and NDUFA1 can serve as biomarkers for AD diagnosis.
Yuan-Han Yang, Hsi-Wen Chang, Ching‑Fang Chien, Tzyh‑Chyuan Hour
Investigating the effects of 40 Hz sound stimulation on Alzheimer’s disease pathways: Modulation of amyloid-β42 secretion, tau phosphorylation, phagocytosis, and autophagy
Abstract: Background: Alzheimer’s disease (AD) is the main cause of dementia in an aging society. Previous studies have demonstrated that non-invasive light flicker and sound with gamma frequency oscillations can modulate AD-related pathology in AD mice, potentially improving patient outcomes. However, the molecular mechanism by which sound with gamma frequency oscillations inhibits the expression of amyloid-β1-42 (Aβ42) and the phosphorylation of tau, and modulating cell autophagy in nerve cells are still unclear. Objective: This study aimed to explore the molecular effects of 40 Hz sound stimulation on AD-related pathways in a cellular model. Methods: We designed a 40 Hz stimulating sound (H+ multi-frequency audio) for this study, and cells were exposed to H+ multi-frequency audio. The concentration of Aβ42 was quantified by enzyme-linked immunosorbent assay. Protein levels were examined by western blotting. Phagocytosis was examined by confocal microscopy and phagocytic analysis. Results: First, we found that exposure to the 40 Hz stimulating sound inhibited the secretion of Aβ42 by activating the AβPP/ADAM10 pathway and suppressing the AβPP/BACE1 pathway. Second, 40 Hz stimulating sound inhibited tau phosphorylation at Thr181 through the inactivation of the Akt/mTOR pathway. Third, 40 Hz stimulating sound enhanced the phagocytosis and autophagy of Aβ42 through the AMPK/ULK/LC3B pathway in cells. Conclusions: Our study showed that 40 Hz stimulating sound is involved in the inhibition of Aβ42 secretion, p-Tau protein expression, and the promotion of phagocytosis and Aβ42 autophagy in cells. We suggest that 40 Hz stimulating sound could be a potential intervention to attenuate AD progression in the future.
Jie Lin, Yan Li, Hao Li
Association between atherogenic index of plasma and dementia: a longitudinal observational study
Abstract: Background: Atherogenic index of plasma (AIP) is a novel biomarker for status of lipid metabolism, but the association between AIP and dementia remains unclear. Objective: We aimed to investigate the association between AIP and dementia among people with different glycemic status. Methods: From the China Health and Retirement Longitudinal Study, 5,195 dementia-free adults aged ≥45 (mean age 62.15±7.00 years; 2668 [51.36%] female) at baseline (2011-2012) were followed up until 2018 to detect incident dementia. Dementia was ascertained based on cognitive batteries and the Activity of Daily Living scale. AIP was calculated by the formula: log [triglyceride (mg/dL) / high-density lipoprotein cholesterol (mg/dL)] and tertiled as low, moderate, and high. Data were analyzed using logistic regression. Results: During the follow-up, 716 (13.3%) participants developed dementia. In basic-adjusted model, higher AIP was dose-dependently associated with an increased risk of dementia (per 1-SD increment in AIP, odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.02, 1.20, p=0.020), whereas the association was not significant in fully-adjusted model (OR: 1.07 [0.97, 1.18]; p=0.158). Compared with low AIP group, the OR (95% CI) of dementia was 1.27 (1.01, 1.60) for high AIP. After stratification, the association between high AIP and dementia was significant among people with diabetes (OR: 1.97, 95% CI: 1.11, 3.49) and a significant multiplicative interaction between high AIP and glycemic status was found (p for interaction=0.029). Conclusions: High AIP is associated with higher risk of dementia, particularly among people with diabetes. Our findings suggested that AIP could serve as an early indicator of dementia.
Robert W Levenson, Jennifer Merrilees, Maya L Henry, Nina F Dronkers
Associations between dementia symptoms and caregiver and relationship health: A prominent role for speech and language
Abstract: Background: Dementia is a significant public health issue globally. People with dementia (PWD) exhibit symptoms in multiple domains (e.g., cognition, emotion, motor, speech/language) that can vary in their impact on the caregiver and the PWD-caregiver relationship. Objective: We assessed the relative impact of various dementia symptoms on caregiver health and well-being and on the PWD-caregiver relationship using a broad sampling of PWD symptoms and caregiver/relationship outcome measures. Methods: Data were analyzed from 54 primary caregivers of PWDs who completed seven questionnaires assessing caregiver health and well-being and PWD-caregiver relationship quality. An exploratory factor analysis of these questionnaires revealed two primary factors: (a) General Distress (anxiety, burden, depression, general health, loneliness), and (b) Relationship Quality (interpersonal closeness, relationship satisfaction). Caregivers also rated nine categories of PWD symptoms (memory, executive functions, speech/language, visual/spatial, motor, changes in behavior, sleep, medical/sensory, activities of daily living). Results: Greater caregiver General Distress was associated with greater PWD speech/language and sleep symptoms. Lower caregiver Relationship Quality was associated (at trend, p < 0.10, levels) with greater PWD speech/language and activities of daily living symptoms. Correlations with the seven individual caregiver outcome measures revealed that speech/language symptoms were the most robust predictors (correlated with five measures), followed by sleep and activities of daily living symptoms (correlated with two measures), and memory, visual/spatial, and motor symptoms (correlated with one measure). Conclusions: Findings highlight the profound adverse effects that PWD speech and language deficits may have on caregivers and underscore the importance of addressing these deficits in dementia care.
Jiahui Liu, Chatrawee Duangjan, Nguyen M Phan, Sean P Curran
Loss of WDR23 slows the rate of age-related cognitive decline with elevated amyloid burden
Abstract: Background: WDR23 is a regulator of cellular proteostasis and oxidative stress response processes that are critically involved in the pathogenesis of Alzheimer's disease (AD). Dysregulation of these pathways can contribute to amyloid-β (Aβ) and tau pathologies, ultimately leading to cognitive impairment. Objective: We explored the effects of Wdr23 knockout on key AD-related pathologies, including transcriptomic changes, Aβ and tau pathology, and cognitive function in the 3xTg-AD mouse model of early onset familial AD. Methods: Transcriptomic analysis of hippocampal tissue was performed to identify Wdr23-dependent gene expression changes across age groups. Aβ and tau pathology was assessed via immunohistochemistry. Behavioral assays were conducted to determine cognitive function and locomotor activity. Results: Transcriptomic data revealed an age-dependent effect of Wdr23 knockout on gene expression, with enrichment of pathways related to cognition and synaptic plasticity, especially middle-age and aged mice. Interestingly, while Wdr23 knockout exacerbated amyloid plaque accumulation in older mice, it did not impact tau pathology. Behaviorally, Wdr23 knockout mice exhibited improved cognitive function and enhanced activity levels compared to wild-type counterparts, suggesting a dissociation between Aβ pathology and cognitive performance. Additionally, we observed age-related changes in NRF2 target gene activation but declined in Wdr23 knockout mice over time. Conclusions: Our findings highlight a complex relationship between proteostasis, amyloid pathology, and cognitive outcomes in AD, warranting further investigation into the specific mechanisms by which Wdr23 modulates these processes. This study suggests that targeting proteostasis pathways could offer potential therapeutic benefits, particularly in preserving cognitive function, even in the presence of amyloid pathology.
Sima Toopchiani, Shireen Sindi, Neil Poulter, Sujin Kang, Chi Udeh-Momoh, Geraint Price, Miia Kivipelto, Lefkos Middleton, Oliver Robinson (Handling Associate Editor: Arnold Eiser)
Sex differences in cognitive trajectories and practice effects in a cohort of older Londoners: The role of risk factors
Abstract: Background: Sex differences in cognitive abilities have been reported; however, the underlying reasons remain unclear. Objective: To i) investigate sex differences in cognitive performance, ii) evaluate the contributions of established dementia risk factors to these differences, and iii) examine the role of non-modifiable risk factors on sex differences in cognitive performance. Methods: Among 964 cognitively unimpaired participants (aged 60-85) of the UK CHARIOT-PRO Main Study, we assessed cross-sectional and longitudinal associations, over up to 3 years of follow-up, between sex and cognitive performance, using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results: Sex differences, mostly favoring women were observed at baseline across almost all RBANS indices including the total scale (Cohen’s d = 0.3, adjusted mean difference in score= -5.4, p<0.001). Sex differences were observed in Practice effects (PEs), with men showing less PE in almost all cognitive domains including the total scale (adjusted mean difference= -1.3, p=0.002). Greater sex differences in PEs, were documented among the ‘older’ participants in two out of five cognitive domains including the immediate memory index (mean difference: older (69-85 years) group= -3.2, p=0.002); younger (60-68 years) group= -0.8, p=0.4). Sex differences were more pronounced among ‘Apolipoprotein-Ꜫ4 -carriers’ in three out of five domains including the total scale (mean difference in carriers= -2.6, p=0.002); non-carriers= -0.7, p=0.3). Conclusions: Sex differences in cognition and PE were observed after adjusting for risk factors associated with Alzheimer’s disease. Future studies should also consider the effects of sex on non-modifiable risk factors and PEs to identify potential ‘masked’ neuropathology.
Ilaria Ricchi, Alessandra Griffa, Ricardo Corredor-Jerez, Jonas Richiardi, Jean-François Démonet, Gilles Allali, Bénédicte Maréchal#, Olivier Rouaud#, for the Alzheimer’s Disease Neuroimaging Initiative #These authors contributed equally to this work.
The complementary role of automated brain volumetry to stratify ADNI participants within the ATN framework
Abstract: Background: The amyloid, tau, neurodegeneration (ATN) framework provides a biological staging model of Alzheimer’s disease (AD) using magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), or positron emission tomography (PET) biomarkers. MRI, being non-invasive, accessible, and cost-effective, holds promise as a biomarker. Objective: To evaluate the utility of MRI-based automated brain volumetry in classifying cognitive impairment severity—cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia—as well as ATN profiles, independently. Methods: We analyzed 394 subjects from the Alzheimer’s Disease Neuroimaging Initiative. First, we assessed how well MRI volumetry stratifies cognitive stages. Next, we tested its ability to distinguish A+T+N+ from A-T-N- individuals while classifying clinical stages. Finally, we evaluated its predictive power for cognitive severity in A+T+ and A-T- subgroups, irrespective of neurodegeneration (N), to examine the added value of volumetry across AT profiles. Results: MRI volumetry showed comparable performance to established biomarkers in identifying CU, MCI, and dementia, and offered complementary value when combined with phosphorylated tau. Hippocampal and temporal gray matter volumes distinguished A+T+N+ from A-T-N- classes with accuracies of 0.81 and 0.78, respectively. In A+T+ versus A-T- comparisons, the highest classification performance for cognitive severity was observed in the A-T- group. Conclusions: MRI-based brain volumetry can effectively classify cognitive stages and distinguish biological subtypes in AD. It is a promising tool for clinical staging and predicting impairment severity, especially when used alongside phosphorylated tau.
Aoqiang Zhai, Ruiqi Zou, Tianrun Lv, Siqi Yang, Yanjie Zhong, Yang Xiong, Fuyu Li, Haijie Hu
Genetic association of social participation with cognitive function: A bidirectional Mendelian randomization study
Abstract: Background: Cognitive decline poses a significant challenge in aging societies. While some studies suggest that active social participation mitigates cognitive decline, others present conflicting findings. Objective: This bidirectional two-sample Mendelian randomization (MR) study aimed to elucidate the causal relationship between social participation and cognitive function. Methods: The cognitive performance dataset (n = 257,841) was used as the discovery sample, while cognitive function (n = 22,593) and Alzheimer’s disease (AD) datasets (n = 394,705) served as replication samples and proxies for severe cognitive decline. Inverse variance weighting was the primary analytical method, supplemented by weighted median, MR-Egger, MR.RAPS, MR-PRESSO, and maximum likelihood methods for sensitivity analyses. Results: Social participation in sports club or gym (β = 0.09, 95% CI: 0.05 to 0.14, p < 0.001), religious group (β = 0.11, 95% CI: 0.08 to 0.14, p < 0.001) and other group activity (β = 0.06, 95% CI: 0.03 to 0.09, p < 0.001) reduced the risk of cognitive decline, while pub or social club (β = -0.06, 95% CI: -0.1 to -0.02, p = 0.005) and social inactivity (β = -0.05, 95% CI: -0.09 to -0.01, p = 0.017) accelerated cognitive decline. Improved cognitive performance promoted participation in beneficial activities and reduced pub or social club participation. Additionally, AD motivated visits to pub or social club (OR = 1.01, 95% CI: 1.00 to 1.03, p = 0.011). Conclusions: Specific types of social participation may protect against cognitive decline, offering evidence for targeted interventions to prompt cognitive health in aging populations.
Eduardo Cumbo, Daniela Migliore (Handling Associate Editor: Luis Agüera-Ortiz)
Differential effects of antidepressants on cognition in Alzheimer’s disease with depression: A sub-group analysis of an open-label, observational study
Abstract: Background: Depressive symptoms are common in Alzheimer’s disease (AD), leading to an increasing use of antidepressants. Objective: To compare the effects of vortioxetine with other conventional antidepressants on cognition in AD patients with depressive symptoms. Methods: This analysis is a subgroup of a 12-month, prospective, randomized, open-label, parallel-group study involving 108 outpatients receiving either vortioxetine or escitalopram, paroxetine, or bupropion as part of routine care. Data were collected at baseline, 6 and 12 months. Cognitive symptoms were assessed using the Mini-Mental State Examination (MMSE), Attentive Matrices (AM), Coloured Progressive Matrices (CPR), and Digit Span; depressive symptoms using the Hamilton Depression Scale (HAM-D) and the Cornell Scale for Depression in Dementia (CSDD). Results for patients on vortioxetine were compared to those on other antidepressants. Results: Total scores on cognitive measures improved in all groups. Improvements versus baseline in MMSE, AM, and CPM were statistically significant in the vortioxetine group (p<0.001), but not in the other antidepressant groups. Digit Span scores did not differ significantly from baseline. The between-group differences in MMSE, AM, and CPM changes were statistically significant in favor of vortioxetine (p<0.05), while the Digit Span change showed a trend towards superiority with vortioxetine, but did not reach statistical significance. The between-group differences in HAM-D and CSDD changes were also statistically significant for vortioxetine (p<0.05). Conclusions: Vortioxetine was superior in improving both cognitive and depressive symptoms compared to other antidepressants. Larger studies which may also help to understand whether the beneficial effect observed with vortioxetine was a direct effect or mediated by its specific antidepressant efficacy are required.
Hyukjun Lee, Ji Won Han, Seung Wan Suh, Hee Won Yang, Dae Jong Oh, Eunji Lim, Jin Shin, Bong Jo Kim, Dong Woo Lee, Jeong Lan Kim, Jin Hyeong Jhoo, Joon Hyuk Park, Jung Jae Lee, Kyung Phil Kwak, Seok Bum Lee, Seok Woo Moon, Seung-Ho Ryu, Shin Gyeom Kim, Ki Woong Kim (Handling Associate Editor: Tae Kim)
A sleep-based risk model for predicting dementia: Development and validation in a Korean cohort
Abstract: Background: Dementia is a major public health challenge, yet existing prediction models often overlook sleep-related symptoms, despite their known links to cognitive decline. Objective: To develop and validate a four-year Dementia Risk Score (DRS) incorporating self-reported sleep-related symptoms with demographic and clinical factors to predict all-cause dementia, including Alzheimer’s disease. Methods: Data from 3,082 Korean adults aged 60–79 years were analyzed. Predictors were selected using LASSO regression and included in a multivariate logistic regression model. A point-based scoring system, the DRS, was constructed from the model coefficients. Internal validation was conducted using bootstrapping and a separate dataset. Results: The DRS achieved robust predictive performance, with AUC values of 0.824 in the training set and 0.826 in the validation set. Key predictors included sleep disturbance, use of sleep medications, daytime dysfunction, leg discomfort, and urge to move legs. Conclusions: The DRS provides a practical, scalable tool for predicting dementia risk, supporting community-based screening and early intervention. External validation is needed to confirm its broader applicability.
Kengo Ito, Yukihiko Washimi, Takashi Kato, Keisuke Suzuki, Yasuomi Ouchi, Chigusa Watanabe, Yoshihide Sunada, Yumiko Kutoku, Kazunari Ishii, Kenji Ishii, Michio Kitayama, Etsuro Matsubara, Noriyuki Kimura, Harumasa Takano, Hiroaki Adachi, Kazuhiro Hara, Takeshi Kawarabayashi, Mikio Shoji, Norio Sugimoto, SDAF-PET study group (Handling Associate Editor: Jose Antonio Lojo Ramírez)
18F-FDG PET for the differential diagnosis of Alzheimer's disease and frontotemporal lobar degeneration: A multicenter prospective study in Japan
Abstract: Background: 18F-fluoro-2-deoxy-2-D-glucose positron emission tomography (18F-FDG PET) is a biomarker of neuronal injury, according to the revised National Institute on Aging-Alzheimer's Association criteria. Objective: This multicenter prospective cohort study aimed to evaluate the value of 18F-FDG PET for differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) in comparison with phosphorylated tau protein (p-tau181) in cerebrospinal fluid (CSF). Methods: In total, 138 patients (AD, 119; FTLD, 19) from 11 participating institutions underwent clinical and neuropsychological examinations, magnetic resonance imaging (MRI), CSF examination, and 18F-FDG PET at baseline. The cases were visually classified into predefined dementia patterns using 18F-FDG PET by three experts. A region-of-interest (ROI)-based automated analysis of 18F-FDG PET was also performed. The participants were followed up for 12 months, and the clinical diagnosis of dementia was re-evaluated. Results: The sensitivity, specificity, and accuracy of the visual reading of 18F-FDG PET for differentiating AD from FTLD were 94%, 78%, and 92%, respectively. In contrast, those of p-tau181 in CSF were 62%, 79%, and 65%, respectively. The sensitivity, the primary endpoint, was 32% higher for 18F-FDG PET than for p-tau181 in CSF. Additionally, the accuracy, the secondary endpoint, was 27% higher for 18F-FDG PET than for p-tau181 in CSF. In addition to the visual reading of 18F-FDG PET, the ROI-based automated analysis showed sensitivity, specificity, and accuracy of 81%, 79%, and 81%, respectively. Conclusions: This study showed that the diagnostic performance of 18F-FDG PET in differential diagnosis of AD and FTLD was higher than that of p-tau181 in CSF.
Jose Antonio Lojo-Ramírez, Paula Fernández-Rodríguez, Miriam Guerra-Gómez, Alba Marta Marín-Cabañas, Emilio Franco-Macías, Jose Manuel Jiménez-Hoyuela-García, David García-Solís (Handling Associate Editor: Marcel Daamen)
Evaluation of early-phase 18F-Florbetaben PET as a surrogate biomarker of neurodegeneration: In-depth comparison with 18F-FDG PET at group and single patient level
Abstract: Background: Imaging biomarkers are essential in Alzheimer’s disease (AD) diagnosis, particularly since the introduction of the ATN criteria by the NIA-AA. These criteria include amyloid-β plaques (amyloid PET), fibrillar tau (tau PET), and neurodegeneration (FDG PET or MRI). Early-phase amyloid PET imaging has shown a strong correlation with FDG PET at the group level. Objective: This study evaluates the comparability of early-phase FBB PET (eFBB) perfusion imaging and FDG PET metabolic imaging at both group and individual levels. Methods: A retrospective study included 103 patients with mild cognitive impairment (MCI) or mild dementia suspected of AD who underwent FDG PET and dual-phase 18F-Florbetaben PET (including a 5-minute eFBB scan) between 2019 and 2023, along with 33 healthy controls. Imaging analyses included qualitative, semi-quantitative, and voxel-wise techniques to compare eFBB and FDG PET scans. Results: eFBB and FDG PET SUVR values showed a strong correlation across all brain regions (rho=0.879). Visual assessments of eFBB and FDG PET by two raters achieved intra-observer agreement rates of 87.5% and 86.4%, respectively. Voxel-wise analysis revealed moderate to good overlap, as indicated by Dice-Sørensen coefficients, in the MCI and mild dementia groups. Discriminative performance between eFBB and FDG PET was comparable, with no significant differences as eFBB reliably reflected brain metabolic patterns observed on FDG PET, supporting its diagnostic utility. Conclusions: eFBB PET could serve as a surrogate biomarker for FDG PET in the diagnostic evaluation of neurodegenerative dementias. Dual-phase amyloid PET enables simultaneous assessment of neurodegeneration and amyloid burden, offering a streamlined and resource-efficient approach for clinical practice.
Yuanqin Cai#, Xi Wang#, Yang Xiang, Zhenning Wang, Qinghua Long, Chuhua Zeng #These authors contributed equally to this work.
Codonopsis pilosula polysaccharides alleviate neuronal apoptosis induced by endoplasmic reticulum stress-activated PERK-ATF4-CHOP signaling in APP/PS1 mice
Abstract: Background: Codonopsis polysaccharides (CPPs) shows neuroprotective potential in Alzheimer's disease (AD) and may reduce neuronal apoptosis by modulating endoplasmic reticulum stress (ERS). Objective: To investigate the protective mechanisms of CPPs against neuronal apoptosis in APP/PS1 mice, focusing on the ERS response and the PERK-ATF4-CHOP signaling pathway. Methods: APP/PS1 mice were orally administered CPPs at different doses. Their learning and memory abilities were evaluated using the Morris water maze (MWM). The integrity of hippocampal neurons and senile plaque deposition were assessed using histopathology, immunohistochemistry, and immunofluorescence. The expression of amyloid-β (Aβ) plaques secretase protein, ERS markers, and apoptosis-related proteins was assessed using western blot analyses. The affinity of the PERK-ATF4-CHOP pathway and CPPs was analyzed and assessed using molecular docking. Results: MWM testing revealed that CPPs improved the learning and memory abilities of APP/PS1 mice. Histopathological examination confirmed that CPPs reduced hippocampal neuronal apoptosis. Immunohistochemistry and immunofluorescence analysis showed that CPPs decreased Aβ protein expression and ERS. Western blot analysis further confirmed that CPPs reduced the expression of proteins related to Aβ synthesis; downregulated the expression of glucose-regulated protein 78 (GRP78), PERK, ATF4, CHOP, and Bcl-2 associated X protein (Bax), while upregulating the expression of B-cell lymphoma 2 (Bcl-2). Conclusions: This study demonstrates that CPPs exert neuroprotective effects by targeting the PERK-ATF4-CHOP signaling pathway and alleviating ERS, suggesting a novel approach and potential therapeutic agent for AD treatment.
Nathaniel K Ashford#, Swati Rane#, Kristen M Farris, Jasroop Miglani, Baocheng Chu, Daniel S Hippe, Tarun Gandhi, Angela J Hanson #These authors contributed equally to this work.
Acute cerebral blood flow response to heavy cream ingestion in older adults: A non-randomized pilot study
Abstract: Background: Hypertension and the APOE4 allele are known risk factors for Alzheimer’s disease (AD) and E4 carriers show different blood pressure (BP) and cognitive responses to high fat feeding. Objective: We investigated the influence of these factors on global cerebral blood flow (CBF) and four regions of interest (ROIs) (angular gyrus, hippocampus, posterior cingulate, temporal lobe) using arterial spin labeling (ASL) MRI in fasting state and after ingestion of heavy cream in older adults. Methods: 29 adults (age in years 66.8 ± 4.1) underwent baseline and 1, 2, 3-hour ASL MRI after ingestion of 100 mL heavy cream. We used pCASL MRI with background suppression to measure CBF in ml/100g/min. Statistical analyses included mixed-effects modeling and Pearson correlation to ascertain whether CBF changed over time and how variables influenced results. Results: Global CBF decreased at 1-, 2-, and 3-hours post-heavy cream, compared to time 0 (overall change 7.11%, p<0.01); recapitulated in 3 of 4 ROIs. Mean arterial pressure emerged as a predictive variable for both baseline and post-heavy cream CBF (β=-0.25, 95% CI= -0.39, -0.10, p=0.002). Individuals with higher BP demonstrated reduced CBF, particularly in posterior cingulate and temporal lobe (β=-5.50, 95% CI= -9.9, -1.09; β=-6.28, 95% CI= -12.35, -0.21, respectively, both p<0.05). Examination of correlations with BP and change scores revealed that this relationship was driven largely by E4 carriers. Conclusions: CBF decreased after ingestion of heavy cream, globally and in regions known to be important in AD, and this finding was driven by E4 carriers with higher BP.
Tomoyuki Nagata, Shinichiro Nakajima, Shinsuke Kito, Shunichiro Shinagawa
Correlations between agitation and other neuropsychiatric symptoms in each stage of Alzheimer’s disease: A re-analysis of CATIE-AD
Abstract: Background: Among neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), agitation has been shown to occur commonly in the course of AD, overlapping or comorbid with other NPSs. Objective: The proportion of patients with agitation and the severity of agitation appear to differ depending on the neurocognitive stage of AD, and knowledge about the characteristic comorbid symptom pattern may help in elucidation of the underlying mechanism. Methods: Among 421 clinic-based patients with AD, we re-analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease (CATIE-AD) to examine the correlations between the scores for agitation and those for other Neuropsychiatric Inventory subscales in each neurocognitive stage of AD (mild, moderate, and severe) classified according to scores in Mini-Mental State Examination. Results: The scores for agitation were positively and robustly correlated with the scores for irritability in all stages of AD, and with the scores for anxiety in the moderate and severe stages. The scores for agitation were also correlated with those for sleep disorders in severe AD stage or disinhibition in the moderate AD stage. Multiple regression analysis identified irritability influencing the agitation in moderate and severe stages, and sleep disorders influencing the agitation in the severe stage. Conclusions: As comorbid NPSs with agitation, characteristic affective, impulsive, and circadian abnormalities may be relevant to generate diverse subsyndromes in AD. Irritability consistently causes agitated behaviors, including refusal to take one’s own care, and diurnal rhythm disorder in the severe AD stage may also cause poor acceptance for self-care.
Anqi Yin#, Yuran Gui#, Lu Wan#, Qinfeng Cai, Yong Luo, Jian-Zhi Wang, Rong Liu, Chenjiang Ying, Xiaochuan Wang, Fumin Yang (Handling Associate Editor: Chengxin Gong) #These authors contributed equally to this work.
p53 SUMOylation promotes neurogenesis defects in APP/PS1 mice
Abstract: Background: p53 is a transcriptional factor that regulates numerous cellular processes, the stability and activity of p53 is essential to maintain its function. Post-translational modifications (PTMs), particularly SUMOylation, play a vital role in regulating p53 activity. Objective: To investigate the neurogenesis related genes that downregulated by p53 SUMOylation in APP/PS1 mice, and the protected effect by overexpressing non-SUMOylated p53 (p53 K386R). Furthermore, to provide new clues for the mechanisms of Alzheimer’s disease (AD). Methods: Co-immunoprecipitation was used to detect the p53 SUMOylation levels in neuro2a (N2a) cells and APP/PS1 mice overexpressing wild-type p53 (p53 WT) or p53 K386R. In addition, RNA sequencing (RNA-seq) was used to detect the p53 SUMOylation regulated genes. Then we used qPCR, western blot, and immunofluorescence to measure the expression of neuroglobin (ngb) and the effect of neurogenesis defects induced by p53 SUMOylation. Results: We verified that overexpression of p53 WT promoted p53 SUMOylation and p53 K386R decreased p53 SUMOylation in N2a cells and APP/PS1 mice. Ngb was related to neurogenesis which dramatically downregulated by p53 SUMOylation. In addition, we found p53 SUMOylation caused neuron reduction and impairment of neurogenesis. Conclusions: Our data support that p53 SUMOylation may lead to neurogenesis defects by downregulating ngb in AD, suggesting that inhibition of p53 SUMOylation may be served as a therapeutic strategy for preventing AD and provide a new target for future researches and interventions.
Akinori Miyashita#, Ai Obinata#, Norikazu Hara#, Risa Mitsumori#, Daita Kaneda, Yoshio Hashizume, Terunori Sano, Masaki Takao, Ramil Gabdulkhaev, Mari Tada, Akiyoshi Kakita, Akira Arakawa, Maho Morishima, Shigeo Murayama, Yuko Saito, Hiroyuki Hatsuta, Tomoyasu Matsubara, Akio Akagi, Yuichi Riku, Hiroaki Miyahara, Jun Sone, Mari Yoshida, Haruyasu Yamaguchi, Tamao Tsukie, Mai Hasegawa, Kensaku Kasuga, Masataka Kikuchi, Hiroyasu Akatsu, Ryozo Kuwano, Takeshi Iwatsubo, Japanese Alzheimer’s Disease Neuroimaging Initiative, Shumpei Niida, Kouichi Ozaki, Takeshi Ikeuchi #These authors contributed equally to this work.
Association of rare APOE missense variants with Alzheimer’s disease in the Japanese population
Abstract: Background: Little is known about the rare missense variants (RMVs) of APOE in East Asians, including the Japanese, and their association with Alzheimer’s disease (AD) and lipid metabolism. Objective: To identify APOE RMVs in the Japanese population and investigate their association with AD and lipid metabolism, including low-density lipoprotein cholesterol levels. Methods: APOE RMVs were explored in the Niigata (NIG; 2,589 subjects) and Tohoku (ToMMo; 3,307 subjects) cohorts. A case-control study included 6,261 AD cases and 16,331 controls, all of whom were aged 65 or older. Sanger sequencing, whole-exome sequencing, or a combination of both was performed on the NIG subjects. We used the genotype data from the ToMMo cohort. APOE RMV frequencies in the Japanese population were compared with various ethnic populations. Associations between APOE RMV genotypes, AD, and lipoproteins were examined. Results: Fourteen RMVs were identified (minor allele frequency 0.02 – 0.73%), with 10 unique to East Asians. Five previously reported RMVs, such as the Christchurch RMV, were absent in Japanese individuals. Two RMVs (rs140808909 and rs190853081), which exhibit complete linkage disequilibrium, were found to have protective effects against AD: pBonferroni = 4.28E-02, OR (95% CI) = 0.70 (0.54 – 0.92). No significant differences in cholesterol levels were observed between RMV carriers and non-carriers. Conclusions: The two APOE RMVs identified in Japanese individuals may have exhibited potential protective effects against AD. Further large-scale studies are needed to confirm these findings and to explore their roles in AD and lipid metabolism.
Akira Sekikawa, Aya Higashiyama, Brian J Lopresti, Masafumi Ihara, Chendi Cui, Jiatong Li, Makoto Watanabe, Mengyi Li, Shatabdi Goon, Howard J Aizenstein, Yuefang Chang, Chikage Kakuta, Zheming Yu, Chester A Mathis, Yoshihiro Kokubo, Sarah Royse, Tetsuya Fukuda, Beth Snitz, Oscar L Lopez, Yoshihiro Miyamoto (Handling Associate Editor: Marcel Daamen)
An inverse association of cerebral amyloid-β deposition and serum docosahexaenoic acid levels in cognitively normal older adults in Japan
Abstract: Background: Alzheimer's disease (AD) is driven by amyloid-β (Aβ) plaque accumulation, but the mechanisms behind this process remain unclear. Omega-3 fatty acids, particularly docosahexaenoic acid (DHA), may offer protective effects, though their relationship with Aβ accumulation is not fully understood. Objective: This study investigated whether serum DHA and eicosapentaenoic acid (EPA) levels, measured 6–9 years before imaging, were inversely associated with cerebral Aβ deposition in cognitively normal older adults in Japan, a population known for high omega-3 intake. We focused on individuals identified as Aβ-positive based on positron emission tomography (PET) scans, as they are at higher risk for AD progression, to assess DHA’s potential in mitigating early amyloid pathology. Methods: An analytical sample of 97 older adults (75–89 years) from the Suita Study was analyzed. Serum DHA and EPA levels were assessed between 2008 and 2012, and amyloid PET was performed between 2016 and 2019. Multiple regression analyses were conducted, adjusting for age, sex, APOE4 status, and cardiometabolic disease. Results: Among 97 participants (49% males, 8.2% APOE4 carriers), 37.1% (n=36) had cardiometabolic disease, and 29.8% (n=29) were Aβ positive. In Aβ-positive individuals, higher serum DHA levels were significantly associated with lower Aβ deposition independent of age, sex and APOE4 status (standardized β = -0.423, p = 0.030). This became non-significant after additionally adjusting for cardiometabolic disease (β = -0.382, p = 0.059). No significant association was found between EPA and Aβ deposition. Conclusions: Higher long-term DHA levels may help reduce Aβ accumulation in those at risk for AD, supporting its potential role in early prevention.
