Review
Benjamin Slade, Ben Williams, Romy Engelbrecht, Joseph Ciorciari
Improving executive functioning and reducing the risk of Alzheimer’s disease with music therapy: A narrative review of potential neural mechanisms
Abstract: The incidence of Alzheimer’s disease (AD) and the concurrent cost of healthcare will increase as the population continues to age. Pharmaceutical interventions effectively manage symptoms of AD but carry side effects and ineffectively address underlying causes and disease prevention. Non-pharmaceutical interventions for AD, such as music training and therapy do not carry these side effects and can improve symptoms, and should therefore be explored as stand-alone or co-therapy for AD. In addition, music encapsulates modifiable lifestyle factors, such as cognitive stimulation, that have been shown to delay progression of and prevent AD. However, the neural mechanisms underpinning how music improves AD symptoms are not fully understood and whether music can target compensatory processes, activate neural networks, or even slow or prevent AD needs further research. Research suggests neural mechanism may involve stimulating brain areas to promote neurogenesis, dopaminergic rewards systems, and the default mode network (DMN). Alternatively, this review proposes that music improve symptoms of AD via the fronto-parietal control network (FPCN), the salience network (SN) and DMN, and neural compensation. This review will then present evidence for how music could activate the FPCN, SN, and DMN to improve their efficiency, organization, and cognitive functions they govern, protecting the brain from damage, slowing progression, and possibly preventing AD. Establishing how music improves symptoms of AD can lead to tailored music therapy protocols that target functional neural networks responsible for impaired executive functions common in AD.
Systematic Review
Emanuela Bartolini#, Adolfo Di Crosta#, Pasquale La Malva, Anna Marin, Irene Ceccato, Giulia Prete, Nicola Mammarella, Alberto Di Domenico, Rocco Palumbo #These authors contributed equally to this work.
Gamma oscillation modulation for cognitive impairment: A systematic review
Abstract: Background: Gamma oscillation modulation has emerged as a potential non-invasive treatment to counteract cognitive impairment in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Non-invasive brain stimulation techniques like transcranial alternating current stimulation (tACS), gamma sensory stimulation (GSS), and transcranial magnetic stimulation (TMS) show promise in supporting specific cognitive functions. Objective: To review and evaluate the efficacy of gamma oscillation modulation techniques in benefiting cognitive functions among individuals with AD and MCI. Methods: A systematic review was conducted, analyzing studies from 2015 to 2023 across databases such as PubMed, Web of Science, and Scopus. Inclusion criteria focused on studies involving tACS, GSS, or TMS applied to older adults with MCI or AD. A total of 438 articles were screened, of which 10 met the eligibility criteria. Results: Findings suggest that gamma tACS, especially targeting the precuneus and dorsolateral prefrontal cortex, benefits episodic memory and cognitive performance. GSS also showed potential in supporting memory and attention, while TMS exhibited inconsistent but promising results when applied to the angular gyrus. However, heterogeneity in study designs and small sample sizes limit the generalizability of these outcomes. Conclusions: Gamma oscillation modulation offers potential cognitive benefits for patients with AD and MCI, particularly in memory support. Further studies with larger samples and well-designed protocols are needed to confirm its therapeutic efficacy and optimize intervention parameters.
Systematic Review
Yan Zhao#, Chang Tan#, Yingjing Lu, Yingling Ge, Na Zhao, Yajie Tian, Liuyang Hui, Xiaobei Feng, Zihan Liu, Sha Li, Huixian Cui (Handling Associate Editor: Carol Chan) #These authors contributed equally to this work.
The prevalence of mild behavioral impairment in older adults with mild cognitive impairment: A systematic review and meta-analysis
Abstract: Background: Mild behavioral impairment is a neurobehavioral symptom characterized by the onset of a new and persistent neuropsychiatric syndrome. Patients with co-occurring mild behavioral impairment and mild cognitive impairment have the relatively highest probability of developing dementia than sick mild behavioral impairment or mild cognitive impairment alone. Objective: This study aimed to determine the currently available best estimate of mild behavioral impairment prevalence and clarify the reasons for the difference in estimates. Methods: Data were retrieved and collected from five electronic databases. Two reviewers independently appraised the methodological quality of included studies. Heterogeneity was assessed by using the I² statistic and random effects models were employed. Sources of heterogeneity were investigated by subgroup analysis and meta-regression. All statistical analyses were conducted by Stata. Results: A total of 23 reports involving 5397 participants were included in this systematic review. The pooled effect size for the overall mild behavioral impairment was 52% (95%CI 42-62%). In the subgroup analysis and regression analysis, we found that study type, study area, assessment tools, and study subject gender could explain part of the source of heterogeneity. Conclusions: The results of this review suggest that 52% with mild cognitive impairment combined with mild behavioral impairment; there is a close relationship between the two. Future studies should pay more attention to the underlying mechanism between the two and provide a more scientific basis for early discrimination of clinical dementia and Alzheimer's disease.
Commentary
Renato Sobral Monteiro-Junior
Virtual reality-based interventions for individuals with dementia: a potential further treatment and new perspectives
Abstract: This commentary highlights issues regarding virtual reality (VR)-based interventions for individuals with Alzheimer’s disease, emphasizing their potential to improve cognitive function and delay decline. The aim of this manuscript is to present current findings and critically synthesize the practical applications of VR interventions. A recent meta-analysis demonstrates promising results, with VR interventions enhancing memory, executive functions, and overall cognition. Despite the limited number of studies and small sample sizes, findings suggest that engaging VR environments can motivate patients, fostering adherence to treatment. This commentary underscores the need for further research to validate these results and establish standardized methodologies for the effective use of VR in dementia care. Several methodological aspects and new perspectives are highlighted herein.
Commentary
James K Cooper
Differences between East and West may affect dementia studies: Thoughts from the KSA Dementia Prevalence Study
Abstract: While science is the same in the East and West, certain personal characteristics may distort scientific results. This is more likely in the East. An example may be a recent project in the East that measured the prevalence of Alzheimer’s disease dementia in a very large group. They found it to be near 1%, which seems very low. Studies that show a low prevalence of Alzheimer’s disease dementia could be due to an examination of a very healthy group with very few older people, and/or poor/inaccurate testing (none of which were in this study). Another possibility is that the person, their family or their doctor aim at ignoring or hiding a diagnosis of dementia.
Commentary
Hadrien M Lalive, Alessandra Griffa, Lorenzo Pini, Olivier Rouaud, Gilles Allali
Biomarkers do not paint the whole picture: The role of clinical expertise and advanced neuroimaging for Alzheimer’s disease diagnosis
Abstract: Accurate diagnosis of Alzheimer’s disease (AD) in Memory Clinics remains challenging due to the limited specificity of conventional clinical assessment and structural imaging. The recent commentary by Vyhnalek and colleagues advocates for the incorporation of molecular biomarkers for AD diagnosis in clinical practice. However, this approach only partially captures the complexity of disease expression due to co-pathologies such as limbic-predominant age-related TDP-43 encephalopathy, a mimic of AD. At the era of immunotherapy for AD, clinical expertise remains essential to identify AD from its mimics, especially when both entities co-exist, and may rely on advanced neuroimaging techniques such as brain connectivity.
Commentary
M Bruce MacIver, Robert A Pearce
Reduced GABAA, slow synaptic inhibition in Alzheimer’s disease
Abstract:Altered synaptic physiology clearly contributes to memory loss and other CNS symptoms in Alzheimer’s disease. A new paper in this issue of the Journal of Alzheimer’s Disease, from Zhe Jin’s group in Uppsala, Sweden, adds important new information to help us understand how. A powerful, yet largely uncharacterized form of neuronal inhibition—GABAA, slow synaptic current—was studied using whole-cell recordings in hippocampal brain slices from AD model mice (tg-APPSwe). The investigators found that GABAA, slow inhibition was significantly reduced in dentate granule neurons from aged AD mice, compared to both wild type and adult non-aged AD mice. This reduction would nicely explain the change in excitatory-inhibitory balance previously reported in this and other AD model animals, as well as impairments in pattern separation and theta-gamma cross-frequency coupling that are early manifestations of AD.
Jingna Ye, Xuelian Dai, Canwen Zhang, Zhihui Duan, Guoqing Zhou, Juan Wang
Investigating the causal relationships between mitochondrial proteins and dementia with Lewy bodies
Abstract: Background: Disruptions in mitochondrial function have been implicated in various neurodegenerative diseases. However, the specific role of mitochondrial proteins in the pathogenesis of dementia with Lewy bodies (DLB) remains poorly understood. Objective: This study aims to investigate potential causal relationships between mitochondrial proteins and DLB risk using Mendelian randomization (MR) analysis. Methods: Causal associations between 66 mitochondrial proteins (MPs) and DLB were assessed by MR analysis, utilizing data from comprehensive genome-wide association studies (GWAS), with various analytical methods, including the inverse variance weighted, MR-Egger, and weighted median. Cochran's Q statistics assessed the heterogeneity of instrumental variables. Results: Genetic predispositions to increased levels of ES1 protein homolog and apoptosis-inducing factor 1 (AIF-1) were associated with an elevated risk of DLB. Conversely, genetic predispositions to increased levels of glutaredoxin-2 (GLRX-2), complement component 1 Q subcomponent-binding protein (C1QBP), and mitochondrial glutamate carrier 2 (GC2) were found to be protective against DLB. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy among the selected instrumental variables. Conclusions: Our MR study identifies specific MPs potentially causally linked to DLB risk. These findings offer new insights into the MP-related mechanisms underlying DLB pathogenesis and highlight potential therapeutic targets.
Chaewon Suh#, Shinhye Kim#, Yoonji Joo, Eunji Ha, Youngeun Shim, Hyeonji Lee, Yejin Kim, Sujung Yoon #These authors contributed equally to this work.
The effects of Dendropanax morbiferus on cognitive function and cerebral cortical thickness: A randomized, double-blind, placebo-controlled trial
Abstract: Background: Early intervention for subjective cognitive decline (SCD) is becoming increasingly important to prevent progression to Alzheimer's disease (AD). Despite the promising results observed in animal models of AD, the neuroprotective and cognitive-enhancing effects of Dendropanax morbiferus (DM) still need to be evaluated in individuals with cognitive decline. Objective: This 12-week, randomized, double-blind, placebo-controlled trial assessed the effects of DM leaf extracts on cognitive function in 85 individuals with SCD (KCT0006329, registered on July 7, 2021). Methods: Participants were randomly assigned to either the DM (n = 43) or the placebo (n = 42) group. Cognitive functions, including attention and memory, were assessed at baseline, 8 weeks, and 12 weeks. High-resolution T1-weighted magnetic resonance imaging was performed at the beginning and end of the study to evaluate cortical thickness. Changes in cognition and cortical thickness and their associations were evaluated. Results: The results demonstrated significant improvements in attention (p = 0.014), memory (p = 0.037), and global cognitive function (p = 0.001) in the DM group compared to the placebo group, accompanied by increased cortical thickness in the left lingual gyrus/cuneus (corrected p < 0.05). Furthermore, in the DM group, increased cortical thickness in this region was correlated with both memory (r = 0.422, p = 0.016) and global cognitive functions (r = 0.471, p = 0.007). DM was well-tolerated, with no adverse events reported. Conclusions: These findings suggest that DM may possess cognitive-enhancing properties for individuals with SCD.
Aleksi Vanninen, Lauri Erkkilä, Tarja Kokkola, Tuomas Selander, Anne M Koivisto8, Merja Kokki, Tadeusz Musialowicz, Anssi Lipponen, Mikko Hiltunen, Juhana Hakumäki, Sanna-Kaisa Herukka, Tuomas Rauramaa, Ville Leinonen
Effect of ventricular volume on cerebrospinal fluid Alzheimer’s disease biomarkers in patients with idiopathic normal pressure hydrocephalus
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a common disorder in aging populations. Alzheimer’s disease (AD) is a significant comorbidity in iNPH patients, and the presence of AD pathology is associated with worse shunting outcomes. Cerebrospinal fluid (CSF) concentrations of AD-associated biomarkers in iNPH patients are universally reduced and the exact mechanism related to this is unknown. Objective: Our aim was to study the effects of ventricular volume on CSF AD-associated biomarker levels in iNPH patients, to determine whether a dilution effect occurs and to assess if brain AD pathology contributes to this effect. Methods: A total of 153 iNPH patients had lumbar CSF samples available for analysis, along with brain MRIs of sufficient quality. Automated image analysis software was used to determine the volume of different brain segments. Volumes normalized for age, sex and head size were used for analysis. Brain biopsy data on AD pathology was also available. Results: None of the intracerebral ventricular volumes correlated with CSF levels of AD-associated biomarkers, indicating no dilution effect was present in this context. However, in iNPH patients positive for amyloid-β pathology in the biopsy, the volume of the fourth ventricle correlated inversely with all investigated biomarkers. Conclusions: Intracerebral ventricular volumes do not correlate with AD biomarker levels in CSF, arguing against a dilution effect. However, in patients with AD pathology, the volume of the fourth ventricle is inversely correlated with CSF T-Tau and P-Tau181 levels, suggesting a complex relationship between brain AD pathology, CSF flow and CSF volume in iNPH patients.
Kanika Mehta, Jedidiah I Morton, Agus Salim, Kaarin J Anstey, Jonathan E Shaw, Dianna J Magliano
Rising rates of hospitalization for dementia in people with type 2 diabetes and the general population in Australia
Abstract: Background: Few recent studies have examined the trends in dementia hospitalization in high-income countries. Objective: To estimate the trends in hospitalization for dementia in people with type 2 diabetes (T2DM) and the general population in Australia using linked, national databases. Methods: Australians with T2DM and registered on the National Diabetes Services Scheme (n = 438,264), and the general population (n = 8,090,993) from 2010–2011 to 2016–2017 served as the study cohort. Annual rates of hospitalization for dementia were calculated for individuals aged ≥50 years. Following this, the trends in the rate of hospitalization were estimated using joinpoint regression and summarized as annual percent changes (APCs). Results: Increases in hospitalization for dementia over time were observed for the T2DM and the general population; APC 5.2 (95% CI 3.5, 7.3) and 9.4 (95% CI 3.8, 14.3), respectively. The absolute rate of dementia hospitalization was found to be higher in the T2DM than the general population. For vascular dementia, a higher age- and sex-standardized rate of hospitalization was observed for the T2DM population compared to the general population. Conversely, the rate of hospitalization for Alzheimer’s disease was higher in the general population than in the T2DM cohort. Further, a higher dementia hospitalization rate was observed among males compared to females in both T2DM, and the general population. Conclusions: Despite the previous studies reporting a decline in dementia incidence in high-income countries, the rate of dementia hospitalization in Australia has risen steadily from 2010–2016 in both T2DM individuals and the general population.
Yanyu Zhai#, Kaili Lu#, Yuan Yuan, Ziyao Zhang, Lixia Xue, Fei Zhao, Xiaofeng Xu, Hongmei Wang #These authors contributed equally to this work.
Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway
Abstract: Background: Alzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse. Objective: This study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes. Methods: Male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot. Results: Semaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade. Conclusions: The results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.
Patricia A Deverka, Jalayne J Arias, Grace A Lin, Jessica Zwerling, Kathryn A Phillips
Alzheimer’s disease blood-based biomarker testing: A stakeholder-informed assessment of coverage considerations
Abstract: Background: Recently published clinical studies suggest that blood-based biomarker tests (BBMTs) for Alzheimer’s disease (AD) provide value, but in the U.S., neither public nor private payers currently cover these tests. Objective: To describe considerations for payer coverage of AD BBMTs that would need to be addressed to facilitate timely diagnosis and equitable patient access if clinical utility is demonstrated. Methods: We performed a targeted literature review to characterize predictable coverage barriers for BBMTs and inform the development of an interview guide. We conducted semi-structured interviews with clinicians, researchers, test developers, and a patient advocate and former payer (N=12) to assess the barriers and refine the proposed key considerations for obtaining payer coverage. Results: Stakeholders noted that payers will require evidence of clinical validity and utility of BBMTs as part of their coverage determinations contingent on the specific indication for testing, with insufficient evidence for screening applications currently. Stakeholders also agreed that there are evidence gaps for use of BBMTs in patients from ethnic and racial minority communities that must be addressed. Given the shortage of memory specialists, stakeholders noted that limiting testing coverage authorization to specialists could be harmful to patients, particularly the underserved. Interviewees also agreed that patients with mild cognitive impairment or early-stage AD could benefit from earlier diagnosis to avoid progressing to moderate disease and limiting eligibility for new disease-modifying therapies. Conclusions: If BBMTs meet criteria for clinical utility, anticipating and planning for coverage and reimbursement before widespread implementation will be critical to ensuring broad, equitable access to BBMTs.
Jacob Labonte, Michael A Sugarman, Erika Pettway, Henrik Zetterberg, Kaj Blennow, Nicholas J Ashton, Thomas K Karikari, Hugo J Aparicio, Brandon Frank, Yorghos Tripodis, Brett Martin, Joseph N Palmisano, Eric G Steinberg, Irene Simkin, Lindsay A Farrer, Gyungah R Jun, Katherine W Turk, Andrew E Budson, Maureen K O'Connor, Rhoda Au, Lee E Goldstein, Robert A Stern, Thor D Stein, Ann C McKee, Wei Qiao Qiu, Jesse Mez, Sarah J Banks, Michael L Alosco
Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers
Abstract: Background: Sex differences have consistently been identified on autopsy, neuroimaging, and cerebrospinal fluid outcomes related to Alzheimer’s disease (AD), but the exact mechanisms for these associations are unclear. Blood-based biomarkers are practical alternatives for the investigation of mechanisms of AD, in addition to accurate disease detection and monitoring. Objective: The objective of this study was to examine sex differences across a panel of blood-based plasma biomarkers in participants with and without cognitive impairment due to AD. Methods: Plasma samples were collected from 567 participants from across the AD diagnostic continuum (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia) and analyzed for glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau at threonine 181 (p-tau181), and total tau (t-tau). Baseline and longitudinal analyses evaluated for any significant associations between sex and AD-related plasma biomarkers. Results: Females were found to have higher plasma GFAP compared to males at baseline regardless of cognitive diagnosis. Among those with AD dementia, females were also found to have higher NfL levels compared to males. Longitudinal analyses found that higher plasma NfL at baseline was associated with an increased risk of worsening AD dementia status only in women. No significant findings were observed for p-tau181 or t-tau. Conclusions: This study found significant sex differences in plasma biomarkers of GFAP and NfL. Further research is needed to better understand the underlying mechanisms mediating these differences.
Bowen Yang, Aygun Teymur, Chenling Tang, Tianfu Wu (Handling Associate Editor: Rabab Al-Lahham)
V-set and immunoglobulin domain containing 4 as a potential predictor of Alzheimer’s disease and advanced aging
Abstract: Background: V-set and immunoglobulin domain containing 4 (VSIG4) emerges as a significant player in the immune system pathways. It has been previously identified as a potential hub gene for Alzheimer’s disease (AD) and aging, underscoring its importance in understanding these conditions. Objective: This study aimed to evaluate the diagnostic potential of serum VSIG4 and identify trends in serum VSIG4 in relationship with other biomarkers and neurological tests. Methods: ELISA was used to measure the serum concentration of VSIG4 in AD, compared to healthy subjects. The relationship between VSIG4 levels and the age of the subjects, as well as other AD-related serum proteins and various measures of cognition was examined. Results: VSIG4 was significantly elevated in the serum of AD patients compared to healthy controls (p=0.0074). Significant correlations were identified between serum VSIG4 and other notable proteins related to AD and inflammation, such as total tau, neurofilament light (NfL), YKL-40, CD14, FABP3, and TNF-α. Significant correlations were also identified between VSIG4 concentration and the results of neurological tests. Conclusions: Serum VSIG4 may reflect neuroinflammation and altered lipid processing, affecting the cognitive performance of AD and aging.
Mehdi Alami, Echarki Zerif, Abdelouahed Khalil, Nabil Hajji, Charles Ramassamy, Guy Lacombe, Benoit Laurent, Alan A Cohen, Jacek M Wikowski, Denis Gris, Ton Bunt, Olaf van Tellingen, Katsuiku Hirokawa, Tamas Fulop, Hicham Berrougui
Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ1-42-induced neurotoxicity and neuroinflammation in cellular models of Alzheimer’s disease
Abstract: Background: Alzheimer's disease (AD) is a chronic brain degenerative disease that leads to dementia. Objective: The aim of the present study is to investigate the neuroprotective impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (empagliflozin and dapagliflozin) on tau phosphorylation, oxidative stress, and neuroinflammation. Methods: We used MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, annexin-V-FITC kit, and DCFH-DA (dichloro-dihydro-fluorescein diacetate) to respectively evaluate the effect of the SGLT2i (empagliflozin and dapagliflozin) on amyloid-β (Aβ)1-42-induced neuronal death, apoptosis, and oxidative stress. The expression of NLRP3-inflammasome, phospho-Tau181, glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CdK5), and histone deacetylase 6 (HDAC6), was quantified by flow cytometry. Drug distribution in the mice’s brains was assessed by liquid chromatography-mass spectrometry (LC-MS). Results: Aβ1-42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ1-42-induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology. Mechanistically, the last effect involved the modulation of GSK-3β and CdK5 protein expression. However, the tested treatments did not modify the Aβ1-42-stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution. Conclusions: SGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ1-42-induced neurotoxicity.
Pelin Sordu, Merve Alaylıoğlu, Bedia Samancı, Ersel Bulu, Zeynep Ece Kaya Güleç, Başar Bilgiç, Haşmet Ayhan Hanağası, İbrahim Hakan Gürvit, Turgut Ulutin, Erdinç Dursun, Duygu Gezen-Ak
Cerebrospinal fluid HSP90AA1, HSPA4, and STUB1/CHIP levels in Alzheimer’s disease, mild cognitive impairment, and frontotemporal dementia
Abstract: Background: The data that we gathered from a protein-protein interaction (PPI) prediction tool, FpClass, and a limited number of studies indicated that the chaperones HSP90AA1, HSPA4, STUB1/CHIP might interact with amyloid-β (Aβ) and/or tau and could subsequently be co-released into the cerebrospinal fluid (CSF). Therefore, we investigated CSF levels of HSP90AA1, HSPA4, and STUB1/CHIP in Alzheimer's disease (AD), Non-AD mild cognitive impairment (Non-AD MCI), and frontotemporal dementia (FTD) cases. Methods: The CSF levels of HSP90AA1, HSPA4, STUB/CHIP, and core AD biomarkers were determined by ELISA in AD (n=90), Non-AD MCI (n=27), FTD (n=15), and subjective cognitive impairment (SCI) (n=20) subjects. Results: HSP90AA1 levels were significantly higher in AD cases compared to the SCI subjects. The CSF levels of STUB1/CHIP were significantly lower in AD, Non-AD MCI and FTD cases compared to the SCI subjects. STUB1/CHIP levels of FTD cases were significantly lower than all other groups. HSPA4 levels was correlated with core AD biomarkers (Aβ1-42, p-Tau, t-Tau) regardless of disease. Non-APOE ε4 carrier FTD cases also had significantly lower STUB1/CHIP levels than other groups. Conclusions: The STUB1/CHIP holds promise as a potential biomarker for distinguishing between SCI subjects, AD, and FTD. Furthermore, APOE might serve as an additional discriminatory factor that might be integrated with this chaperone for enhanced discrimination.
Anna L Parks, Ayush Thacker, Daniel Dohan, Liliana A Ramirez Gomez, Christine S Ritchie, Joanna Paladino, Sachin J Shah
A qualitative study of people with Alzheimer’s disease in a memory clinic considering lecanemab treatment
Abstract: Background: People with Alzheimer’s disease (AD) now have access to disease-modifying treatment with anti-amyloid monoclonal antibodies (mAbs). Their perception of risks and benefits and approach to treatment decisions remain unknown. Objective: We aimed to understand how people with AD weigh the benefits and costs of anti amyloid mAbs and incorporate these into decisions about treatment. Methods: We conducted semi-structured interviews with people with biomarker- or imaging-confirmed AD and mild or moderate cognitive impairment who were seen at memory care clinics and discussed lecanemab with a clinician. Interviews were recorded, transcribed, and deidentified. Thematic analysis identified themes and subthemes. Results: Among 22 participants (mean age 70, 8 [36%] women, 22 [100%] White), analysis revealed 3 major themes and associated subthemes: 1) People with AD sought and obtained information from different sources—advocacy organizations, the Internet, and clinicians; 2) Hopes, expected benefits, and the existential threat of dementia drove willingness and readiness to start lecanemab; 3) Individual traits, family factors, and degree of trust in expertise influenced how people balanced risks and benefits. Some would accept treatment at any cost; others carefully weighed risks and burdens, but were motivated by supportive families, insurance coverage, and trust in expertise; for a few, costs decidedly outweighed their personal benefits. People with AD desired more individualized information and to hear more from patients who took the medication. Conclusions: Results from this first qualitative study of people with AD considering treatment with anti-amyloid mAbs can inform clinician, health system and policy efforts to individualize decisions.
Yixi Wang, Zhuokai Wu, Yiheng Zheng, Haimeng Wang, Bin Cheng, Juan Xia
Unraveling the genetic underpinnings of mitochondrial traits and associated circulating inflammatory proteins in Alzheimer’s disease: Mitochondrial HtrA2-T cell CD5 negative axis
Abstract: Background: Previous studies with limited sample sizes have indicated a link between mitochondrial traits, inflammatory proteins, and Alzheimer’s disease. The exact causality and their mediation relationships remain unclear. Objective: Our study aimed to delve into the genetic underpinnings of mitochondrial function and circulating inflammatory proteins in the pathogenesis of Alzheimer’s disease. Methods: We leveraged aggregated data from the largest genome-wide association study, including 69 mitochondrial traits, 91 circulating inflammatory proteins, and Alzheimer’s disease. Bidirectional mendelian randomization (MR) analyses were performed to investigate their primary causal relationships. Thereafter a two-step MR mediation analysis was utilized to clarify the modulating effects of inflammatory proteins on mitochondria and Alzheimer’s disease. Results: Our study identified mitochondrial phenylalanine-tRNA ligase and 4-hydroxy-2-oxoglutarate aldolase as risk factors for Alzheimer’s disease, and serine protease HtrA2 and carbonic anhydrase 5A as protective factors against Alzheimer’s disease. Four inflammatory proteins (T-cell surface glycoprotein CD5, C-X-C motif chemokine 11, TGF-α, and TNF-related apoptosis-inducing ligand) played protective roles against Alzheimer’s disease. Axin-1 and IL-6 increased the risk of Alzheimer’s disease. Furthermore, T-cell surface glycoprotein CD5 was found to be a significant mediator between mitochondrial serine protease HTRA2 and Alzheimer’s disease with the two-step MR method, accounting for 10.83% of the total effect. Conclusions: Our study emphasized mitochondrial HtrA2-T cell CD5 as a negative axis in Alzheimer’s disease, offering novel perspectives on its etiology, pathogenesis, and treatment.
Naomi LP Starmans, Anna E Leeuwis, Edwin Bennink, Sebastiaan L Meyer Viol, Sandeep SV Golla, Jan Willem Dankbaar, Esther E Bron, Geert Jan Biessels, L Jaap Kappelle, Wiesje M van der Flier, Nelleke Tolboom, on behalf of the Heart-Brain Connection Consortium (Handling Associate Editor: Ahmed Bahrani)
Dynamic PET imaging in patients with unilateral carotid occlusion shows lateralized cerebral hypoperfusion, but no amyloid binding
Abstract: Background: Carotid occlusive disease is a risk factor for cognitive decline. A possible underlying etiology is that hemodynamic impairment results in decreased cerebral perfusion, exacerbated amyloid-β accumulation (Aβ) and poorer cognitive performance. Objective: We aimed to determine whether patients with unilateral internal carotid artery (ICA) occlusion have less cerebral perfusion and more Aβ in the ipsilateral than in the contralateral hemisphere, and whether perfusion and Aβ are associated with cognitive functioning. Methods: We included 20 patients (age 67.2±7.0 years, 8 females, MMSE 29 [27-29]) with unilateral ICA occlusion, which underwent neuropsychological assessment and dynamic 18F-Florbetaben positron emission tomography (PET). Global and regional relative perfusion (R1) and binding potential (BPND) were obtained from the PET-images using a simplified reference tissue model. We performed Wilcoxon signed-rank tests to examine differences between hemispheres within subjects and linear regression to investigate associations with cognitive functioning. Results: Median global R1 was 0.911 (0.883-0.950) and global BPND was 0.172 (0.129-0.187). R1 was lower in the hemisphere ipsilateral to the ICA occlusion than in the contralateral hemisphere (0.899 [0.876-0.921] versus 0.935 [0.889-0.970]). BPND did not differ significantly between hemispheres (ipsilateral 0.172 [0.124-0.181] versus contralateral 0.168 [0.137-0.191]). Neither cerebral perfusion nor Aβ burden were associated with cognitive functioning. Conclusions: Patients with unilateral ICA occlusion did not have more Aβ in the ipsilateral hemisphere than in the contralateral hemisphere despite ipsilateral hypoperfusion. Perfusion and Aβ were unrelated to cognitive functioning. This indicates that cognitive impairment in patients with ICA occlusion is not due to exacerbated Aβ accumulation.
Hao Wu#, Zhen Sun#, Jinghuan Gan, Chen Wen, Zhihong Shi, Shuai Liu, Yong Ji #These authors contributed equally to this work.
Efficacy of cholinesterase inhibitors treatment in dementia with Lewy bodies: A 3-year follow-up ‘real world’ study
Abstract: Background: Dementia with Lewy bodies (DLB) is the second most common dementia after Alzheimer's disease. Currently, no specific therapeutic agents are available for DLB. However, evidence of cholinergic deficits suggests that enhancing central cholinergic function may be a viable therapeutic approach. Objective: To assess cognitive changes in DLB patients treated with cholinesterase inhibitors (ChEIs) in a real-world setting. Methods: This retrospective study in a prospective database analyzed data from three dementia clinics between May 2012 and December 2022. Patients with DLB were divided into two groups: those treated with ChEIs and those untreated. Differences in changes in multiple cognitive-related scales between the two groups were analyzed. Results: The study included 204 DLB patients, with 133 (65.2%) in the ChEIs group and 71 (34.8%) in the non-ChEIs group. Initial demographic and clinical characteristics were similar between groups. Over time, patients in the ChEIs group showed significantly higher scores on the Mini-Mental State Examination and the Montreal Cognitive Assessment compared to the non-ChEIs group, indicating improved cognitive function. No significant differences were observed in activities of daily living scores. Conclusions: ChEIs improved cognitive symptoms in DLB patients in the “real world” study. These findings are consistent with those from a previous small-sample randomized controlled trial. Longitudinal data indicate sustained benefits with continuous ChEIs use in three years. Overall, ChEIs show substantial potential for improving cognitive symptoms in DLB patients.
Mervyn JR Lim#, Jaclyn Tan#, Caroline Robert, Wei Ying Tan, Narayanaswamy Venketasubramanian, Christopher Chen, Saima Hilal (Handling Associate Editor: Ralph Buchert) #These authors contributed equally to this work.
The effect of hippocampal subfield volumes on cognitive decline and incident dementia in a memory clinic cohort
Abstract: Background: The hippocampus plays a central role in cognition and hippocampal atrophy is a key hallmark of Alzheimer’s disease. Evidence has suggested associations between hippocampal subfield volumes and specific cognitive domains and dementia risk. However, to our knowledge, no study has examined the role of hippocampal subfield volumes in cognitive decline across different domains over time. Objective: We investigated associations between hippocampal subfield volumes and changes in cognitive domains together with incident dementia in a memory clinic cohort. Methods: Associations between hippocampal subfield volumes and cognitive decline over three years (n=443) were analyzed using generalized estimating equations, and associations with incident dementia (n=283) using multiple logistic regression. Results: At baseline, all hippocampal subfield volumes were associated with diagnosis of dementia, while the CA4-dentate gyrus, molecular layer, subicular complex, and fimbria volumes were associated with diagnosis of CIND. Over three years, all subfields except the hippocampal fissure were associated with memory. Decreased molecular layer (OR:2.26, 95%CI:1.50;3.50) size was associated with increased risk of dementia. Conclusions: Our findings suggest that hippocampal atrophy of the cornu ammonis, CA4-dentate gyrus, and molecular layer may first manifest with cognitive impairment in memory before other subfields of the hippocampus, and that molecular layer volume may be an early biomarker of dementia. Further research demonstrating the biological role of hippocampal subfields in specific cognitive domains is required.
Fatma Saaoud, Lu Liu, Keman Xu, Yifan Lu, Ying Shao, Mohammed Ben Issa, Xiaohua Jiang, Xianwei Wang, Xiaolei Liu, Michael Autieri, Sheng Wu, Juncheng Wei, Jun Yu, Rihab Bouchareb, Avrum Gillespie, Jin Jun Luo, Laisel Martinez, Roberto Vazquez-Padron, Jianxin Sun, Huaqing Zhao, Hong Wang, Domenico Pratico, Xiaofeng Yang
Alzheimer’s disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized memory impairment. Neuroinflammatory processes, mediated by glial and immune cells, contribute to neuronal damage. Emerging evidence implicates innate immune mechanisms, including trained immunity and cell trans-differentiation, in AD pathogenesis, though their roles remain unclear. Objective: To investigate transcriptomic changes in the 3xTg-AD mouse model, focusing on trained immunity and cell trans-differentiation in disease mechanisms. Methods: RNA-sequencing was performed on brain tissue (cortex plus hippocampus) from 11-month-old female 3xTg-AD and wild-type mice (n=3/group). Differentially expressed genes (fold change>1.5, p<0.05) were identified and followed by bioinformatics and knowledge-based transcriptomic profiling. Public AD datasets were also analyzed. Results: 3xTg-AD mice exhibited 316 upregulated and 412 downregulated genes. Downregulated genes included those for blood-brain barrier protein, while upregulated genes related to cerebrospinal fluid. Increased expression of proinflammatory markers, as well as genes related to cell differentiation, proliferation, activation, and adhesion. Upregulation of genes associated with cell migration and trans-differentiation suggests a potential role for inflammation and cellular plasticity. Additionally, genes involved in inflammasome pathways, immunometabolism, and trained immunity were upregulated. Mechanistically, these genes were modulated by knockdown of trained immunity promoter SET-7, overexpression of trained immunity inhibitor IL-37, and knockout of inflammasome genes IL-1 receptor, caspase-1, and pattern recognition receptor CD36. Conclusions: The finding underscore the potential role of trained immunity and cell trans-differentiation in AD, revealing a mechanistic framework in which danger-associated molecular patterns drive innate immune responses, inflammasome activation, and cell plasticity contribute to AD, offering therapeutic targets for neuroinflammation and cellular reprogramming.
Shanshan Wang#, Li Han#, Hong Ni, Shaofa Ke, Tengwei Pan, for the Alzheimer’s Disease Neuroimaging Initiative #These authors contributed equally to this work.
Association of cerebrospinal fluid ciliary neurotrophic factor levels with cognitive decline
Abstract: Background: Ciliary neurotrophic factor (CNTF) has been identified as a neuroprotective cytokine that can alleviate cognitive impairment in preclinical studies, although the association of cerebrospinal fluid (CSF) CNTF levels with cognitive decline and disease progression in living humans remains unclear. Objective: This study aimed to explore the association between baseline CSF CNTF levels and the rate of cognitive decline in cognitively unimpaired (CU) and cognitively impaired (CI) older people respectively. Methods: A total of 667 participants were included in the study, comprising 161 CU and 506 CI individuals, with an average follow-up time of 3.97 years (SD = 2.99). Linear mixed-effects models were fitted with the Mini-Mental State Examination (MMSE) scores as the primary outcome. As sensitivity analyses, we used another three commonly used cognitive measures as secondary outcomes to test the robustness of our findings. In addition, a Cox proportional hazards model was used to the mild cognitive impairment (MCI) subgroup to investigate the association between baseline CSF CNTF levels and the progression from MCI to dementia. Results: We observed that higher baseline CSF CNTF levels were linked with a slower rate of cognitive decline in the CI group, while this association was absent in the CU group. These findings were consistent across different cognitive measures. Among MCI participants, higher levels of CSF CNTF were associated with a slower rate of disease progression to dementia. Conclusions: The association between CSF CNTF levels and both cognitive decline and disease progression highlights the potential of CNTF as a therapeutic target in the context of Alzheimer's disease and related cognitive disorders.
Sophie Pellerin, Bérengère Houzé, Christophe Bedetti, Natalie Phillips, Simona Maria Brambati (Handling Associate Editor: Marco Calabria)
Connected speech profiles in mild cognitive impairment reflect global cognition
Abstract: Background: Mild cognitive impairment (MCI), a prodromal stage of Alzheimer’s disease (AD) for many individuals, is accompanied by widespread connected speech (CS) changes (e.g., shorter CS samples, mention of fewer semantic content units, lower syntactic complexity). Nevertheless, findings on CS in MCI are heterogeneous. This heterogeneity, combined with the heterogeneity in cognition in MCI suggests that there could exist more than one CS profile in this population. Objective: We aimed to determine if there are multiple CS profiles in MCI and whether these potential CS profiles are characterized by distinct cognitive presentations. Methods: CS characteristics were extracted from the samples of 109 controls and 210 individuals with MCI from the COMPASS-ND study database. A Two-Step Cluster Analysis was then carried out to identify potential CS profiles in MCI. These profiles were compared to one another and to controls in terms of their linguistic and cognitive characteristics. Results: We identified two CS profiles in MCI, characterized by reduced syntactic complexity and semantic content and by dysfluencies, longer CS samples, and reduced semantic idea density and efficiency, respectively. The reduced semantic content/syntactic complexity profile was also characterized by various cognitive difficulties (e.g., visuospatial, episodic memory, executive functioning domains) in comparison with controls, whereas the increased production and reduced idea transmission effectiveness profile had relatively isolated episodic memory difficulties. Conclusions: CS analysis could be a helpful screening tool to identify individuals with MCI who show greater cognitive difficulties and who would most benefit from more extensive cognitive and/or medical testing as well as from cognitive and/or psychological interventions.
Bo-Ra Kang, Young-Hyeon Bae, Seong Hun Park, Hye-Yun Kang
Feasibility of a developed cognitive training system based on virtual reality with smart mirror for expert in community older cognitive disabled persons setting
Abstract: Background: Numerous stroke survivors reintegrating into the community experience cognitive challenges that restrict their engagement, subsequently contributing to additional cognitive decline and adversely affecting their quality of life. Objective: This study seeks to feasibility a cognitive training system based on virtual reality with a smart mirror designed for cognitive disabled persons with chronic stroke in the community setting. Methods: Ten cognitive disabled persons with chronic stroke aged 60 years older, each with independent mobility in the community, were involved in this study. The validation process included a 30-minute cognitive training session administered twice a week for eight weeks. The feasibility of cognitive function assessments employed the MoCA-K and CoSAS. Additionally, a usability test was performed at the end of the experiment using SUS and the Adapted IMI. The Wilcoxon signed rank test was then employed to compare pre- and post-cognitive function results. Results: The feasibility of the implemented cognitive training system based on virtual reality with smart mirror revealed significant differences in the total score, delayed recall, and orientation items of the MoCA-K (p<0.05). Additionally, a notable improvement was observed in the accuracy and response time of task performance in the CoSAS (p<0.05). Usability test results indicated an SUS mean score of 73.5 (SD 17.25) and an Adapted IMI score of 5.63 (SD 1.55), surpassing suggested thresholds for usability tests. Conclusions: Providing a cognitive training system tailored for the community, this approach aims to the prevention and recovery of cognitive issues in the older cognitive disabled persons with chronic stroke.
Franziska Kiene, Helmut Hildebrandt, Mandy Roheger (Handling Associate Editor: Vincent Koppelmans)
Towards characterizing subjective cognitive decline in older adults
Abstract: Background: Subjective cognitive decline (SCD), where older adults perceive a persistent decline of cognitive abilities without showing an objective cognitive impairment, may represent a preclinical stage of Alzheimer’s disease (AD) in some individuals. Objective: The complex characteristics of SCD cannot only be revealed by existing self-report questionnaires. Rather, it is necessary to involve individuals affected in the research process with methods like focus group discussions (FGDs). Methods: Study conduction took place in three steps: telephone interview, neuropsychological assessment and questionnaires, four FGDs with 16 older adults (11 female, 5 male) affected by SCD. FGDs were analyzed with qualitative content analysis using an inductive - deductive code system. Results: Although the neuropsychological assessments did not indicate a cognitive impairment, participants reported a decline for all cognitive domains within the FGDs, especially for the memory- and speech domain, with declining word-finding abilities as the most salient symptom. Participants reported strong concerns related to SCD and difficulties in social participation. Conclusions: SCD seems to go beyond age-related cognitive changes, but as individuals do not show an objective cognitive impairment (yet), their symptoms are often not taken seriously enough. The FGDs revealed information that questionnaires or neuropsychological tests do not capture. The gained insight into SCD symptoms, related coping strategies and concerns is important to be able to develop measures for identifying individuals at risk for a transition to AD and to develop intervention measures that aim at delaying a further decline and increasing the quality of life of individuals affected.
Jiahui Sun#, Fei Teng#, Yu Cao, Hui Pei, Lina Ma, Wei Wei, Hao Li #These authors contributed equally to this work.
Peripheral blood immune cell phenotypes and Alzheimer’s disease: A mediation Mendelian randomization study
Abstract: Background: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Although peripheral immune cells have been implicated in the pathology of AD, the causal relationship between peripheral blood immune cells and AD remains to be fully elucidated. Objective: To examine the association between peripheral blood immune cell phenotypes and AD, mediated by peripheral blood metabolite, a two-step Mendelian randomization (MR) analysis was performed. Methods: Summary statistics were obtained from the two largest independent cohorts. We explored bidirectional univariable MR analysis to explore causal associations and assessed the mediated proportion of peripheral blood metabolite phenotypes. Results: The proportion of IgD+ CD38- B cells (Bm1) were found to increase the risk of AD in both the FinnGen database (p = 0.033) and the UK Biobank (p = 0.034). Conversely, hematopoietic stem cells were associated with a decreased risk of AD in the FinnGen database (p = 0.045) and the UK Biobank (p = 0.017). Mediation analysis revealed indirect effects of the proportion of Bm1 on AD through cysteine levels (β = 5e-3), Acetylcarnitine (C2) to propionylcarnitine (C3) ratio (β = 4.5e-3), and Gamma-glutamyl-alpha-lysine levels (β = 2.6e-3), with mediated proportion of 19.4%, 16.9% and 9.6% of the total effect, respectively. Additionally, hematopoietic stem cells influenced AD through Glycolithocholate sulfate levels (β = 1.5e-3), with a mediated proportion of 3.5%. Conclusions: Our findings demonstrate that two peripheral blood immune cell phenotypes impact the risk of AD. These immune cells may influence AD through various peripheral blood metabolite, identifying potential intervention targets for individuals at risk.
Iris Blotenberg#, Andrea E Zülke#, Melanie Luppa, Felix Wittmann, Thomas Fankhänel, Solveig Weise, Juliane Döhring, Catharina Escales, Robert P Kosilek, Irina Michel, Christian Brettschneider, Anke Oey, Birgitt Wiese, Jochen Gensichen, Hans-Helmut König, Thomas Frese, Hanna Kaduszkiewicz, Wolfgang Hoffmann, Steffi G Riedel-Heller*, René Thyrian* #These authors contributed equally to this work. *These authors share last authorship.
Factors associated with a healthy diet and willingness to change dietary behavior in older adults at increased risk of dementia
Abstract: Background: Healthy dietary patterns have been linked to reduced risks for cardiovascular diseases and dementia, making nutrition an essential part of a comprehensive approach for dementia prevention. Knowledge about factors associated with a healthy diet in people with increased dementia risk is scarce. Objective: To analyze dietary habits and associated factors in older adults with increased dementia risk in Germany. Methods: We used baseline-data of the AgeWell.de-trial (n = 1001, %female = 52.2, Mage = 69.0, SD = 4.9). Nutrition was assessed using a composite score, comprising 11 components covered by national recommendations for a healthy diet (range = 0-11 points). Linear regressions assessed associations of sociodemographic, social, health-related and psychological factors with consumption of a healthy diet. Further, we assessed stages of change based on the transtheoretical model of behavior change. Results: Consumption of a healthy diet was moderate (Median = 4, IQR = 2). Female sex (b = 0.64, 95% CI: 0.41, 0.88), higher levels of motivation for healthy eating (b = 0.22, 95% CI: 0.10, 0.34) and higher self-efficacy (b = 0.33, 95% CI: 0.20, 0.46) were linked to a healthy diet. Regarding the stages of behavior change, the majority were in the maintenance stage (45.2%), followed by the contemplation (21.5%) and precontemplation (21.2%) stages. Conclusions: Results suggest room for improvement regarding a healthy diet in our sample. Lifestyle-based interventions in older adults should be tailored towards current levels of motivation and self-efficacy of participants. Including modules targeting motivation and self-efficacy might help maximize intervention effectiveness.
Songren Wei#, Chenyang Li#, Wenxuan Li, Fumiao Yuan, Jingjing Kong, Xi Su, Peng Huang, Hongbo Guo, Jiangping Xu, Haitao Sun (Handling Associate Editor: Yi Tang) #These authors contributed equally to this work.
Glial changes and gene expression in Alzheimer's disease from snRNA-seq and spatial transcriptomics
Abstract: Background: Alzheimer's disease (AD) is characterized by cortical atrophy, glutamatergic neuron loss, and cognitive decline. However, large-scale quantitative assessments of cellular changes during AD pathology remain scarce. Objective: This study aims to integrate single-nuclei sequencing data from the Seattle Alzheimer's Disease Cortical Atlas (SEA-AD) with spatial transcriptomics to quantify cellular changes in the prefrontal cortex and temporal gyrus, regions vulnerable to AD neuropathological changes (ADNC). Methods: We mapped differentially expressed genes (DEGs) and analyzed their interactions with pathological factors such as APOE expression and Lewy bodies. Cellular proportions were assessed, focusing on neurons, glial cells, and immune cells. Results: RORB-expressing L4-like neurons, though vulnerable to ADNC, exhibited stable cell numbers throughout disease progression. In contrast, astrocytes displayed increased reactivity, with upregulated cytokine signaling and oxidative stress responses, suggesting a role in neuroinflammation. A reduction in synaptic maintenance pathways indicated a decline in astrocytic support functions. Microglia showed heightened immune surveillance and phagocytic activity, indicating their role in maintaining cortical homeostasis. Conclusions: The study underscores the critical roles of glial cells, particularly astrocytes and microglia, in AD progression. These findings contribute to a better understanding of cellular dynamics and may inform therapeutic strategies targeting glial cell function in AD.
Elisa R Torres, Eloise M Lopez-Lambert, Barbara B Bendlin (Handling Associate Editor: Kimberly Campbell)
Psychometrics of the Lifetime Total Physical Activity Questionnaire in adults with a history of depression
Abstract: Background: Depression earlier in life is a risk factor for dementia later in life. Physical activity is associated with less risk of depression and dementia. However, prevention of Alzheimer's disease may be most effective before the onset of brain pathology, which precedes dementia symptoms by 20+ years, requiring the measure of physical activity across the life course. Objective: Assess the reliability and validity of the Lifetime Total Physical Activity Questionnaire (LTPAQ) in community-dwelling cognitively intact adults with and without a history of depression. Methods: Test-retest reliability was assessed with intraclass correlations (ICC). Evidence of construct validity was assessed with descriptive statistics using the contrasted group approach and a priori hypotheses testing with each intensity (sedentary, light, moderate, vigorous) within each domain (school/occupation, transportation, household, leisure-time) across the life course (school-age, adolescence, young adult, middle adult). Results: Evidence of test-retest reliability and construct validity was found during school-age and adolescence for moderate school/occupation (ICC=0.562, p=0.006; ICC=0.605, p=0.003, respectively) and household (ICC=0.945, p<0.001; ICC=0.829, p<0.001, respectively); during young adulthood for moderate school/occupation (ICC=0.844, p<0.001), transportation (ICC=0.747, p<0.001), and household (ICC=0.608, p=0.002); and during middle adulthood for moderate transportation (ICC=0.977, p<0.001). At both time points, there were zero reported school-age vigorous school/occupation and household; adolescent vigorous transportation; young adult vigorous household; and middle adult vigorous transportation and household physical activity. Conclusions: The LTPAQ may be used to examine physical activity across the life course and risk for Alzheimer's disease in community-dwelling cognitively intact adults with and without a history of depression.
