Scoping Review
Jonathan P Williams, Yiqi Zhu, Ramkrishna K Singh, Kebede Beyene, Rohan Rani, Xian Kapetanakos, Amanda Dias, Katherine McGuire, Ramana Kolady, Kim Lipsey, Sridharan Gopalsamy Ramaswamy, Vishnuvardhan Thotakura, Jean-Francois Trani, Ganesh M Babulal
The effect of anti-seizure medications on Alzheimer’s disease (AD) risk and AD-related symptoms: A scoping review
Abstract: Background: As the fastest-growing segment of the population, adults over 65 are at the greatest risk for Alzheimer’s disease (AD). Older adults often use anti-seizure medications (ASMs), which can negatively impact cognitive function, mood, and behavior, mimicking AD or its symptoms. Understanding the effects of ASMs across diverse older adults is crucial, given that some ethnoracial groups are at higher risk for AD or more severe symptoms compared to non-Hispanic Whites. Objective: To summarize the current evidence on the association of ASMs with AD risk and AD-related symptoms and explore the inclusion of ethnoracial minority groups in these studies. Methods: Data sources included PubMed/MEDLINE, EMBASE, and SCOPUS for English-language studies published between 1990-2024. Selected studies were peer-reviewed, cross-sectional, longitudinal, case-control, and clinical trials on AD dementia or its symptoms and ASMs. Study quality was rated by the Oxford Centre for Evidence-Based Research Medicine. Results: A total of 27 studies with 1,241,796 participants were included. Data on AD risk from level IB-IIIB evidence studies showed mixed results, with some indicating an increased association with ASM use [OR = 1.05-1.16, 95% CI: 1.01–1.24]. Studies on AD-related symptoms from level IB-IV evidence also showed mixed results. Only three North American studies explicitly included race/ethnicity, and most were conducted in European countries. Conclusions: ASM use may be modestly associated with an increased risk of AD among the older adult population, but current data are inconclusive. The association of ASMs on AD-related symptoms varied. Future studies should emphasize reporting sociodemographic data and include diverse cohorts to enhance the applicability of findings.
Systematic Review
Shu-Dong Qiu#, Dan-Dan Zhang#, Li-Yun Ma, Qiong-Yao Li, Lan-Yang Wang, Yu-Dong Wang, Yong-Chang Wang, Shi-Yin Xiong, Lan Tan #These authors contributed equally to this work.
Associations of metabolic syndrome with risks of dementia and cognitive impairment: A systematic review and meta-analysis
Abstract: Background: Previous studies have linked metabolic syndrome (MetS) to dementia risk. Objective: We conducted a systematic review and meta-analysis to assess the association between MetS and dementia as well as cognitive impairment, with additional focus on individual MetS components. Methods: We systematically searched the PubMed, Embase, and Cochrane Library databases from inception through July 2024. We used random-effects models to calculate relative risks (RRs) and odds ratios (ORs) with 95% confidence intervals (CIs). Publication bias was evaluated using the Egger's test, while potential sources of heterogeneity were investigated through meta-regression, subgroup, and sensitivity analyses. Results: Our analysis included 21 studies with 411,810 participants. MetS was associated with increased risks of all-cause dementia (RR = 1.33, 95% CI = 1.03-1.71, I² = 85.8%) and vascular dementia (RR = 2.07, 95% CI = 1.32-3.24, I² = 10.1%), but not Alzheimer’s disease (RR = 1.10, 95% CI = 0.64-1.91, I² = 81.8%). Regarding cognitive impairment, longitudinal studies showed an increased risk (OR = 1.38, 95% CI = 1.24-1.53, I² = 3.3%), with similar findings in cross-sectional studies (OR = 1.65, 95% CI = 1.19-2.28, I² = 85.3%). Conclusions: This study found that MetS is significantly associated with increased risks of dementia and cognitive impairment, with each component potentially being a modifiable factor. These findings may guide clinicians in recommending lifestyle interventions to prevent cognitive decline and promote brain health.
Systematic Review
Kenji Fuseya, Yu Mimura, Shinichiro Nakajima, Masaru Mimura, Koji Kasanuki, Yoshihiro Noda
A systematic review and meta-analysis on the characteristics of transcranial magnetic stimulation treatment protocols for patients with Alzheimer’s disease
Abstract: Background: Alzheimer's disease (AD) is the most common neurodegenerative condition causing dementia. Currently, there has been no established non-pharmacological treatment for cognitive decline in patients with AD. Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be effective as a non-invasive treatment for improving cognitive function in AD. Objective: This study aimed to examine the characteristics of rTMS treatment protocols for patients with AD Methods: We conducted a systematic literature search on clinical trials on rTMS for improving cognitive decline in patients with AD, using the PubMed, PsycINFO, and Scopus databases and performed a meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. To clarify which cognitive domains in AD are improved by rTMS, meta-analyses were conducted on both global cognitive function and on each cognitive domain including verbal memory, processing speed, and executive function. In addition, sub-analyses of the treatment details of rTMS parameters including stimulation sites, stimulation frequency, stimulation intensity, and with/without the neuro-navigation technique and meta-regression analyses adjusting for gender, education, and the number of rTMS pulses were performed. Results: The results showed significant improvements in global cognitive function, while no significant findings in verbal memory, processing speed and executive function. No significant results were found in subgroup analysis or meta-regression. Conclusions: To enrich the evidence for cognitive enhancement in AD with rTMS, the randomized controlled trials using a unified rTMS protocol with a larger sample size are warranted.
Short Communication
Emmanuel Morain, Alexandra Fayel, Philippe De Linares, Julien Dumurgier, Emmanuel Cognat, Claire Paquet
Domestic violence in Lewy body dementia: A national study
Abstract: A descriptive study using a transversal national online survey to evaluate the prevalence and characteristics of behavioral and psychological symptoms (BPSD) of dementia with Lewy bodies (DLB), and specifically, the perpetration of violent acts against primary caregivers. 196 responses, obtained in one month, were analyzed. Delirium, hallucinations, anxiety, and apathy were the most frequently reported BPSD symptoms (over 80% of responders). Primary caregivers expressed the highest degree of distress from agitation and aggressive behavior. Moreover, 45.9% of primary caregivers reported being the target of violent behaviors from DLB patients. No statistical association was found between the presence of BPSD and violent acts.
Short Communication
Christian LoBue, Barbara E Stopschinski, Nil Saez Calveras, Amber Salter, Doug Galasko, Chris Giza, C Munro Cullum, Peter M Douglas, John Hart
A preliminary study on plasma markers across cognitive stages and links to a history of mild traumatic brain injury
Abstract: Potential implications of a history of mild traumatic brain injury (mTBI) during aging are understudied. Seven plasma markers were measured in matched participants having normal cognition, mild cognitive impairment (MCI) and dementia of the Alzheimer’s type (DAT) with and without a history of mTBI. Phosphorylated tau181 showed a moderate effect size for being greater in mTBI+ individuals having MCI and DAT, and effect sizes for lower amyloid-β 42/40 and higher neurofilament light were seen for mTBI+ DAT individuals. This preliminary report shows a potential role of plasma-derived markers in detecting associations between mTBI history and the development of Alzheimer’s disease and related disorders.
Short Communication
Hannah Roberts, Yimin Fang, Kathleen Quinn, Tiarra Hill, Mackenzie R Peck, Andrzej Bartke, Kevin N Hascup, Erin R Hascup
Lifespan of male and female APP/PS1 and APPNL-F/NL-F mouse models of Alzheimer’s disease
Abstract: Alzheimer’s disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APPNL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in male APPNL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.
Commentary
Poul F Høilund-Carlsen, Thomas J Werner, Abass Alavi
The unsafe profile of lecanemab
Abstract: Lack of data from the US Food and Drug Administration (FDA) Adverse Event System makes analyses of the risks of newly approved anti-Alzheimer's antibodies inadequate to determine whether such risks justify the minimal clinical benefits reported. A recent disproportionate analysis in the Journal of Alzheimer's Disease by Ge et al. is a case in point. Among serious adverse effects, it only addresses amyloid associated imaging abnormalities, whereas the even more threatening ones, brain tissue loss and therapy-related death, are not mentioned. We urge the FDA to prioritize monitoring of all adverse effects and encourage transparency from the drug manufacturers.
José Enrique Arriola-Infante, Ernesto García-Roldán, David García-Solís, Alba Marta Marín-Cabañas, Andrea Luque-Tirado, Ángela Almodóvar-Sierra, María Bernal Sánchez-Arjona, Didier Maillet, Emilio Franco-Macías
TMA-93 (binding by images): Cutoffs optimization based on Alzheimer’s disease biomarkers
Abstract: Background: With the arrival of new disease-modifying treatments for Alzheimer’s disease (AD), feasible cognitive tests, also for illiterate patients, are needed to screen those requiring deeper evaluation among individuals presenting with memory complaints. The TMA-93, a brief binding memory test, has proven useful for diagnosing early AD, and is supported by normative data that accounts for age and cognitive reserve. Objective: To compare the sensitivity of different TMA-93 cutoffs in detecting AD pathology. Methods: A retrospective analysis was performed on a biobank sample of patients with confirmed AD pathology via amyloid PET or cerebrospinal fluid (CSF) biomarkers. The sensitivity of six TMA-93 cutoffs was evaluated: the 10th, 15th, and 20th percentiles based on traditional norming (TN) and regression-based norming (RBN). False negatives (FN) characteristics were also analyzed. Results: A total of 270 AD-positive patients (96 by amyloid-PET, 174 by CSF biomarkers) were included, comprising 224 with mild cognitive impairment and 46 with mild dementia. The 15th percentile using RBN demonstrated substantial sensitivity (80.4%), higher than that of the 10th percentile, and also provided a more uniform distribution across normative groups compared to the TN approach. Higher global cognition (Mini-Mental State Examination score) and, in patients over 70, lower cognitive reserve (Cognitive Reserve Questionnaire), were linked to a greater likelihood of FN results. Conclusions: The 15th percentile cutoff based on RBN, accounting for age and cognitive reserve, improves sensitivity for detecting AD pathology, making it a valuable screening tool for memory complaints. Future normative data from biomarker-negative subjects may enhance the sensitivity of cognitive tests.
Sophia Kraake, Melanie Luppa, Dorothee Saur, Jens Dietzel, Jan-Philipp Bach, Steffi G Riedel-Heller, Janine Stein
Social functioning in individuals with Alzheimer's disease and the situation of caregivers
Abstract: Background: Changes in social functioning may be a significant parameter for the early detection of Alzheimer's disease (AD). Currently, research on social functioning in AD across the entire spectrum of the disease is lacking. Objective: The aim of this study was to describe the social functioning of persons with AD at each stage of the disease and to investigate how impaired social functioning affects caregiver burden. Methods: Cross-sectional data was derived from memory clinics across Germany as part of the pilot study “Social functioning in individuals with AD and the situation of caregivers”. A total of N = 87 relatives providing care for individuals with mild (n = 20), moderate (n = 40), and severe (n = 23) AD were included. Social functioning of individuals with AD was measured via the caregiver-rated German version of the Social Functioning in Dementia Scale (SF-DEM); caregiver burden was assessed using the Zarit Caregiver Burden Interview (ZBI-12). Differences between mild, moderate, and severe AD in terms of sociodemographic characteristics and the level of social functioning were examined. A robust linear regression analysis was conducted to examine the association between social functioning and caregiver burden. Results: Social functioning was lower in moderate and severe AD than in mild AD. Higher levels of social functioning were associated with less caregiver burden. Conclusions: This study highlights the importance of integrating social functioning assessments into clinical practice for improving the early detection, diagnosis and interventions for AD. Early interventions to enhance social functioning may diminish caregiver burden.
Evan L Thacker, Reena Karki, Rachel Gabor, Natalie J Blades, Russell P Sawyer, Cyrille N Kouambo Beckodro, Quinn Preece, Samuel Prince, McKay M Smith, Sarah R Gillett, Suzanne E Judd, Richard E Kennedy, Jorge R Kizer, Deborah A Levine, William M McClellan, Manjula Kurella Tamura, Frederick W Unverzagt, Virginia G Wadley, Mary Cushman
Leptin, adiponectin, body mass index, and incident cognitive impairment
Abstract: Background: Disordered metabolism affects risk for cognitive decline, Alzheimer’s disease, and other dementias, likely through pathways involving adipokines. Objective: Analyze incident cognitive impairment in relation to leptin, adiponectin, body mass index, and other risk factors. Methods: Nested case-control study within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort of 30,239 adults in the US. Cases with incident cognitive impairment (n = 489) scored >1.57 SD below demographically adjusted means on ≥2 of 3 cognitive tests: word list learning, word list delayed recall, and category fluency. Cognitively intact controls (n = 583) were randomly selected within demographic strata. Leptin and adiponectin were assayed in thawed blood that had been stored at baseline. Results: In participants with normal weight, lower leptin was associated with higher odds of cognitive impairment. Relative to leptin = 25 ng/mL, adjusted ORs were 1.5 (95% CI: 1.2, 1.9) at leptin = 15 ng/mL, 0.8 (0.8, 0.9) at leptin = 30 ng/mL, and 0.5 (0.4, 0.8) at leptin = 45 ng/mL. In participants with obesity, higher adiponectin was associated with higher odds of cognitive impairment. Relative to adiponectin = 25 ng/mL, adjusted ORs were 0.8 (95% CI: 0.7, 1.0) at adiponectin = 15 ng/mL, 1.1 (1.0, 1.2) at adiponectin = 30 ng/mL, and 1.3 (1.0, 1.7) at adiponectin = 45 ng/mL. Associations of adipokines with cognitive impairment varied across levels of other risk factors. Conclusions: Adipokines, in concert with body mass index, play complex roles in cognitive health, with many avenues open for further investigation.
Sohyun Jeong, Lisha Lin, Alvaro-Pascual Leone, Yi-Hsiang Hsu
Type 2 diabetes and late-onset Alzheimer’s disease and related dementia: A longitudinal cohort study integrating polygenic risk score
Abstract: Background: The inherent genetic effects were not established between type 2 diabetes (T2DM) and Alzheimer’s disease and related dementia (ADRD). Objective: We aimed to investigate the association between T2DM and ADRD by integrating T2DM polygenic risk score (PRS) and applying matching in every subgroup. Methods: We utilized UK Biobank First-occurrences datasets. T2DM were 1:1 matched to non-T2DM using propensity scores generated by 8 covariates; age at diagnosis, sex, cerebrovascular disease, ischemic heart disease, hypertensive disorders, lipid disorders, obesity, and mood disorders. T2DM PRS was additionally matched in T2DM PRS matched analysis. Subgroup analyses by age at diagnosis, sex, and APOE4 genotype were performed with the same matching criteria within each subgroup. Cox proportional hazard and Fine & Gray competing risk model were utilized. Results: In T2DM PRS unmatched cohort, 24,583 T2DM were 1:1 matched to non-T2DM. The mean age at diagnosis was around 62 years old, with females constituting 60%. Up to 25-year follow-up, ADRD rate/1000 person-years was 0.88 versus 1.52 (Non-T2DM versus T2DM); PRS unmatched (cHR: 1.72, 95% CI: 1.46-2.03) and matched (cHR:1.75, 95% CI: 1.47-2.09). Except for older age onset (≥75 years), the other subgroups demonstrated significantly increased ADRD risks in T2DM. T2DM PRS was higher in non-ADRD group across all subgroups. Contrarily, T2DM PRS was higher in ADRD in younger onset group (<55 years). Conclusions: T2DM is one of the strong risk factors of ADRD but genetic T2DM effect does not contribute to ADRD risk. However, a genetic link might be present in younger age onset group.
Tanja J de Rijke, Dianne Vasseur, Wiesje M van der Flier, Mirella MN Minkman, Hanneke FM Rhodius-Meester, Nicolaas A Verwey, Ellen MA Smets, Leonie NC Visser
Exploring interdisciplinary perspectives on the implementation of personalized medicine and patient-orchestrated care in Alzheimer’s disease: A qualitative study within the ABOARD research project
Abstract: Background: The concepts of ‘personalized medicine’ and ‘patient-orchestrated care’ in Alzheimer's disease (AD) lack standard conceptualization, which presents challenges for collaborative and interdisciplinary care. Objective: We explored the interpretations and perspectives of professionals involved in interdisciplinary work on a large-scale project, “ABOARD”, with the aim to implement personalized medicine and patient-orchestrated care in AD. Methods: Semi-structured interviews were conducted with 30 professionals and audio-recorded. Two researchers independently coded the data inductively, followed by a thematic analysis. Results: According to professionals across different disciplinary backgrounds (mean age 45.7 years; 53.3% female), personalized medicine pertains to the relevant options that an individual has, informed by biomedical and psychosocial factors, whereas patient-orchestrated care captures factors relevant to the decision-making process. Professionals differed in their views on patient-orchestrated care regarding its desirability and feasibility. The concepts were viewed as similar by professionals, as both involve personal preferences while ultimately assigning responsibility to the clinician. However, implementation challenges persist, and no thematic differences were found between clinicians and other AD-related professionals. Conclusions: AD professionals have shared interpretations and perspectives on implementation of personalized medicine but differed in their views on patient-orchestrated care. Personal preferences are seen as part of personalized medicine, but not yet reflected in definitions in the AD field and beyond. Critical discussions on the challenges and existing doubts are necessary for both personalized medicine and patient-orchestrated care. Multi-level implementation changes are needed for both concepts, which warrants stakeholder involvement as well as support and resources from the entire AD field.
Shizhen Lei, Yani Liu
Identifying microglia-derived NFKBIA as a potential contributor to the pathogenesis of Alzheimer’s disease and age-related macular degeneration
Abstract: Background: Alzheimer’s disease (AD) and age-related macular degeneration (AMD) place considerable health burden on affected individuals and significant economic burden on society. Objective: This study aims to explore the shared cellular and molecular mechanisms underlying the pathogenesis of AD and AMD. Methods: The investigation in this study is conducted via single-cell and bulk tissue transcriptomic analysis. Transcriptomic datasets of AD and AMD were obtained from the GEO database. The shared differentially expressed genes (DEGs) in control and AD- and AMD-affected samples were identified. Functional enrichment analysis for DEGs was subsequently performed. Then, the protein-protein interaction (PPI) network of these DEGs was established via the STRING database and hub genes of this network were identified by Cytoscape software. Single-cell transcriptomic analysis was performed using Seurat R package to explore their expression in different cell types. Results: Differential analysis identified 127 shared DEGs of the two diseases, including 71 upregulated and 56 downregulated genes. Upregulated DEGs were enriched in inflammation, gliogenesis, cell apoptosis, and response to bacterial and viral infection and downregulated DEGs were enriched in mitochondrial function and energy production. PPI network and Cytoscape determined 10 hub genes, of which the NFKBIA gene was associated with the severity of both AD and AMD. Moreover, single-cell transcriptomic analysis showed that NFKBIA was highly expressed in microglia from disease-affected tissues. Conclusions: The findings indicated that microglia with high NFKBIA expression were important contributors to the progression of both AD and AMD. Microglia-derived NFKBIA might serve as a potential therapeutic target for AD and AMD.
Kerry A Howard, Lauren M Massimo, Brian Witrick, Lu Zhang, Sarah F Griffin, Lesley A Ross, Lior Rennert
Investigation of risk of Alzheimer’s disease diagnosis and survival based on variation to life experiences used to operationalize cognitive reserve
Abstract: Background: Alzheimer’s disease dementia (AD) is a debilitating progressive neurodegenerative disease. Life experiences are hypothesized to build cognitive reserve (CR), a theoretical construct associated with delayed onset of AD symptoms. While CR is a key moderator of cognitive decline, operationalization of CR is varied resulting in inconsistencies within the literature. Objective: This study explored the relationship between life experiences used as proxies of CR and risk of AD diagnosis and death following diagnosis. Methods: We explored results based on 30 different published CR operationalizations, including two standardized questionnaires and an investigator-developed lifecourse indicator. Using data from the Memory and Aging Project, we applied Cox proportional hazard models to evaluate the impact of operationalization on time to outcomes. Results: Hazard ratios, indicating instantaneous risk of AD or death for a standard deviation increase in the CR proxy utilized as a predictor, ranged from 0.80-1.40 for AD diagnosis and 0.80-1.29 for death following diagnosis. Among nine predictors that showed a significant reduction in risk of AD, there was a decrease of between 12% and 19%. Three predictors were associated with reduced risk of death, with 13%-20% reduction, while two predictors were associated with 18%-22% heightened risk of death following diagnosis. Conclusions: Model results were highly sensitive to CR operationalization. Based on the variation in results, composite measures that incorporate multiple lifecourse variables may still be the most comprehensive and faithful representation the CR. Attention to methodology and refining of measurement are needed to make use of CR and promote healthy aging.
Alzbeta Katonova, Ross Andel, Vanesa Jurasova, Katerina Veverova, Francesco Angelucci, Vaclav Matoska, Jakub Hort
Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer’s disease biomarkers
Abstract: Background: KLOTHO-VS heterozygosity (KL-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction. Objective: We investigated whether 1) KL-VSHET is associated with lower AD biomarker burden (Aβ42, Aβ42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by APOE ε4 status and clinical subgroup. Methods: Participants (n=223) were categorized as cognitively healthy (n=38), aMCI-AD (n=94), and AD dementia (n=91). KLOTHO genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between KL-VSHET, sαKl levels, and biomarkers, stratified by APOE ε4 status and clinical subgroup. Results: Overall, the associations between KL-VSHET and higher CSF Aβ42 and Aβ42/40 ratio were non-significant (ps≥0.059) except when restricted to APOE ε4 carriers only (β=0.11, p=0.008 and β=0.16, p=0.033, respectively). Within clinical subgroups, KL-VSHET was positively associated with Aβ42/40 ratio only in aMCI-AD (β=0.23, p=0.034). No significant associations were observed between KL-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β=-0.25, p=0.036) and a positive association with Aβ42/40 ratio in APOE ε4 non-carriers (β=0.24 p=0.047). Conclusions: KL-VSHET may help protect against amyloid pathology, particularly in the presence of APOE ε4, and regardless of APOE status in aMCI-AD.
Gülsel Ayaz, Pelin Sordu, Umut Can Küçüksezer, Haşmet Hanağası, Merve Alaylıoğlu, Hakan Gürvit, Duygu Gezen-Ak, Başar Bilgiç, Erdinç Dursun, Turgut Ulutin
Association of glycoprotein 1b and miR-26a-5p levels with platelet function in Alzheimer’s disease
Abstract: Background: Alterations in biochemical and molecular pathways in Alzheimer’s disease (AD) may be evident in the brain, blood cells, and vessels. Platelets regulate blood hemostasis and play key roles in neurodegenerative diseases like AD. miR-26a-5p and GP1b may affect platelet functions (PF), with miR-26a-5p as a diagnostic/therapeutic target and GP1b linking vascular and neurological disorders in AD progression. Objective: This study explores the roles of GP1b and hsa-miR-26a-5p in regulating PF in AD. Methods: 85 participants, including 43 AD, and 45 controls, were included. PF induced by ADP were assessed by optical density and white matter changes by MRI Axial FLAIR. Serum levels of von Willebrand Factor and GP1b were measured by ELISA. Platelet receptor expressions of CD62P and CD42b (GPIb) were measured by flow cytometry, and levels of hsa-miR-26a-5p and hsa-miR-24-3p by qRT-PCR. Results: ADP-induced PF was significantly reduced in AD (p=0.016). Flow cytometry showed significantly low CD42b and high CD62P expression in AD, respectively (p< 0.0001, p=0.014). Serum GP1b levels were significantly higher in AD (p=0.018). Additionally, hsa-miR-26a-5p expression was significantly low in AD (p=0.001), and a positive correlation was found between the expression levels of hsa-miR-24-3p and hsa-miR-26a-5p in both controls; and AD (r=0.4149, p=0.0051, 95% CI=0.1256-0.6392; r=0.6820, p=0.0023, 95% CI 0.4728–0.8184) Conclusions: This study highlights increased serum GP1b levels with decreased both platelet surface GP1b levels and hsa-miR-26a-5p expressions in AD. GP1b and hsa-miR-26a-5p might have essential roles on PF in AD.
Amy Lastuka, Michael R Breshock, Kayla V Taylor, Joseph L Dieleman (Handling Associate Editor: Jianping Jia)
The costs of dementia care by US state: Medical spending and the cost of unpaid caregiving
Abstract: Background: There are 5.5 million people living with dementia in the United States (US), with the cost of unpaid care making up a significant portion of the care costs. Objective: Summarize variation in the cost of dementia care across the US and examine the association between medical spending and costs of unpaid care at the state level. Methods: We estimated total cost for dementia by combining recent medical spending estimates from the Disease Expenditure project and unpaid care cost estimates from Lastuka and colleagues. Hours of unpaid care were valued as the hourly wage of a home health aide. We used linear regression to measure the association between the cost of unpaid care and medical spending. The spending that would have occurred if unpaid care had been provided by professional home health care workers was used to measure the cost of unpaid care. Results: The annual cost of care attributable to dementia in 2019 was $53,502 (95% uncertainty interval [UI] 46,135–60,594) per case. The contribution of unpaid care to total costs varied by state, ranging from 70.2% (95% UI 64.3-75.4) in the District of Columbia to 89.9% (95% UI 87.8-91.5) in Arizona. We found that higher costs of unpaid care were associated with lower medical spending on nursing facility care. Conclusions: The large variation in total costs of dementia shows that the economic burden of dementia care is distributed unevenly throughout the US.
Shitao Wang, Guoshuai Luo, Guangxin Sun, Mengen Zhang, Yaqin Qin, Jinghong Lu, Hui Xu, Zongyou Li
A polymorphism in the BIN1 gene influences its expression and is associated with the risk of Alzheimer’s disease: An integrated analysis
Abstract: Background: The correlation between rs7561528 and the risk of Alzheimer’s disease (AD) has been reported with varying results, and the potential mechanism of rs7561528 in influencing AD risk remains unexplored. Objective: This study aims to examine the impact of rs7561528 on AD risk and to investigate its potential mechanism. Methods: This study initially synthesized previously published data to investigate the correlation between rs7561528 and AD risk. Subsequently, an expression quantitative trait loci analysis was conducted to determine whether rs7561528 modulates the expression of BIN1 in human brain tissue. Results: Our findings revealed that the rs7561528A allele notably escalates the risk of AD in the Caucasian population (OR = 1.17, 95% CI = 1.07–1.28, I² = 33.5%). Similarly, the rs7561528AG genotype also significantly heightens the risk of AD in the same population (OR = 1.18, 95% CI = 1.05–1.31, I² = 21.7%). Further analysis demonstrated that the combined rs7561528AA+AG genotype substantially amplifies the risk of AD in the Caucasian population (OR = 1.21, 95% CI = 1.08–1.36, I² = 30.0%). Ultimately, we discovered that rs7561528 modulates the expression of BIN1 in human brain tissue. Conclusions: rs7561528 could potentially affect the risk of AD by regulating the expression levels of BIN1 in human brain tissue. This discovery enhances our understanding of novel mechanisms through which rs7561528 may contribute to AD risk.
Fangyu Li, Menghan Zheng, Jianping Jia
Validate association of gene loci and establish genetic risk prediction models for late-onset Alzheimer’s disease in Chinese populations
Abstract: Background: More than 60 independent single-nucleotide polymorphisms (SNPs) have been associated with Alzheimer’s disease risk by genome-wide association studies in European. Objective: We aimed to confirm these SNPs in Chinese Han populations and investigate the utility of these genetic markers. Methods: Altogether 1595 late-onset Alzheimer’s disease (LOAD) patients and 2474 controls from Chinese population were recruited. We replicated the association of 68 SNPs with LOAD and established polygenetic risk score (PRS) prediction model using significant SNPs. Meta-analysis for MS4A6A rs610932 and PICALM rs3851179 were performed. Results: According to our findings, 14 out of 68 SNPs are validated significantly associated with LOAD (adjusted p<0.05) after adjusting age and sex in the Chinese population. Besides, after stratification by APOE ε4 status, almost all SNPs retain markedly relationship with LOAD in APOE ε4 noncarriers. However, few loci retain correlation in APOE ε4 carriers. Furthermore, the area under the receiver operating characteristic curve prediction model for distinguishing LOAD patients from normal subjects were 0.614 for PRS and 0.689 for PRS and APOE. In addition, meta-analysis including this study of East Asian populations confirmed that rs610932 and rs3851179 were dramatically related to the LOAD (OR=0.85, 95% CI=0.74-0.97; OR=0.87, 95% CI=0.83-0.91). Conclusions: Despite genetic heterogeneity, there are still common loci among different races. PRS based on AD risk-associated SNPs may supplement APOE for better assessing individual risk for AD in Chinese. Besides, interactions between genes and gene environment affect the impact of risk allele on diverse populations.
Yu-Han Chen, Zhi-Bo Wang, Xi-Peng Liu, Zhi-Qi Mao for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yi Tang)
Cerebrospinal fluid LMO4 as a synaptic biomarker linked to Alzheimer’s disease pathology and cognitive decline
Abstract: Background: LIM-domain-only 4 (LMO4) is involved in neurodevelopment and synaptic plasticity, but its role in the pathogenesis of Alzheimer's disease (AD) remains unclear. Objective: To investigate the association between cerebrospinal fluid (CSF) LMO4 levels and core AD biomarkers, neurodegeneration, and cognitive decline. Methods: We included 703 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Associations between CSF LMO4 and AD biomarkers (Aβ42, Ptau181, amyloid PET) and postmortem neuropathology were evaluated. We also explored cross-sectional and longitudinal associations between CSF LMO4 and neurodegeneration and cognitive function. Receiver operating characteristic (ROC) analysis assessed the diagnostic accuracy of CSF LMO4 in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD cases. Mediation analysis explored the potential mediating role of CSF LMO4 between Aβ pathology and tau pathology. Results: LMO4 levels were decreased in participants with abnormal Aβ levels and cognitive impairment. Lower CSF LMO4 levels were associated with increased Aβ and tau pathology, brain atrophy, cognitive decline, and postmortem neuropathology. CSF LMO4 partially mediated the relationship between Aβ and tau pathology and demonstrated acceptable discriminative ability in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD from non-AD cases. Conclusions: CSF LMO4 plays a crucial role in the pathogenesis and progression of AD and may represent a potential therapeutic target for AD treatment.
Makaela A Mews, Adam C Naj, Anthony J Griswold, Alzheimer’s Disease Genetics Consortium, Jennifer E Below, William S Bush (Handling Associate Editor: Andrew Saykin)
Brain and blood transcriptome-wide association studies identify five novel genes associated with Alzheimer’s disease
Abstract: Background: Genome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, enabling assessment of how genetically-regulated gene expression influences AD risk. However, previous AD-TWAS have been limited by small expression quantitative trait loci (eQTL) reference datasets or reliance on AD-by-proxy phenotypes. Objective: To perform the most powerful AD-TWAS to date using summary statistics from the largest available brain and blood cis-eQTL meta-analyses applied to the largest clinically-adjudicated AD GWAS. Methods: We implemented the OTTERS TWAS pipeline to predict gene expression using the largest available cis-eQTL data from cortical brain tissue (MetaBrain; N=2,683) and blood (eQTLGen; N=31,684), and then applied these models to AD-GWAS data (Cases=21,982; Controls=44,944). Results: We identified and validated five novel gene associations in cortical brain tissue (PRKAG1, C3orf62, LYSMD4, ZNF439, SLC11A2) and six genes proximal to known AD-related GWAS loci (Blood: MYBPC3; Brain: MTCH2, CYB561, MADD, PSMA5, ANXA11). Further, using causal eQTL fine-mapping, we generated sparse models that retained the strength of the AD-TWAS association for MTCH2, MADD, ZNF439, CYB561, and MYBPC3. Conclusions: Our comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants, which enables us to further understand the genetic architecture underlying AD risk.
Suhaas Penukonda#, Srivats Srinivasan#, Takashi Tarumi, Tsubasa Tomoto, Min Sheng, C Munro Cullum, Rong Zhang, Hanzhang Lu, Binu P. Thomas #These authors contributed equally to this work.
One-year exercise improves cognition and fitness and decreases vascular stiffness and reactivity to CO2 in amnestic mild cognitive impairment
Abstract: Background: Amnestic mild cognitive impairment (aMCI) is often a precursor stage to Alzheimer’s disease (AD). Aerobic exercise (AE) has received increasing attention in the prevention of AD. While there is some evidence that it improves neurocognitive function in older individuals, the effect of exercise in the long-term is not well understood. Objective: To assess the effect of long-term exercise on cognition, fitness, vascular stiffness, and cerebrovascular reactivity (CVR). Methods: In this prospective clinical trial, 27 aMCI participants were enrolled into two groups and underwent 12 months of intervention. One group (n=11) underwent AE training (6M/5F, age = 66.2 years), and the control group (n=16) performed stretch training (ST group, 9M/7F, age = 66.4 years). Both groups performed training three times per week with duration and intensity gradually increased over time. CVR was measured at pre- and post-training using blood-oxygenation-level-dependent MRI. Results: In the AE group, aerobic fitness improved (p=0.034) and carotid artery stiffness decreased (p=0.005), which was not observed in the ST group. In all participants, decreases in carotid artery stiffness were associated with increases in aerobic fitness (p=0.043). The AE group displayed decreases in CVR in the anterior cingulate cortex and middle frontal gyrus (p<0.05, FWE corrected); the ST group did not show significant changes in CVR. Several measures of cognition (i.e., inhibition and delayed recall), neuropsychiatric symptoms, and functional status ratings improved only in the AE group. Conclusions: These results suggest that AE may alter cerebral hemodynamics in patients with aMCI which may improve cognitive, psychological, and functional status.
Augusto Magno Tranquezi Cordeiro#, Monique Patricio Singulani#, Leda Leme Talib, Orestes Vicente Forlenza #These authors contributed equally to this work.
Down syndrome and Alzheimer’s disease: Oxidative stress in the neurodegenerative process
Abstract: Background: Individuals with Down syndrome (DS) generally show neuropathological features of Alzheimer disease (AD). The trisomy of chromosome 21 causes an imbalance of antioxidant systems, which can be linked to AD pathophysiology. Objective: Verify the difference between the activity of antioxidant enzymes and products of the oxidation process in peripheral blood in non-trisomic (NT) and trisomic (DS) adults and elders and respective associations with cognitive impairment. Methods: A total of 120 subjects were included in this study. Sociodemographic and clinical information were collected as per protocol for participants in DS and NT groups. The cognitive state of the DS participants was established according to the Brazilian version of the Cambridge Examination for Mental Disorders of Older People with Down’s syndrome and Others with Intellectual Disabilities (CAMDEX-DS). The CAMDEX interview was used for this purpose for participants in the NT group. Plasma samples were collected to evaluate protein carbonyl content, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE). Results: We found increased levels of SOD and CAT activity in the DS group. When the groups were stratified by cognitive decline, elevated levels of SOD and CAT activity were found both in DS groups with and without decline. The activity of GPx was similar between the groups, as well as MDA and HNE. Conclusion: The results suggest that alterations of the antioxidative processes can be implicated in the onset of neurodegeneration observed in individuals with DS.
Yanfen Zhen, Lijuan Gao, Jiu Chen, Lihua Gu, Zhijun Zhang
Altered face perception in amnestic mild cognitive impairment: Evidence from representational similarity analysis of event-related potential
Abstract: Background: Structural changes in medial temporal lobes including the fusiform gyrus, a critical area in face recognition, precede the progression of amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD). However, how the neural correlates of face processing altered in aMCI, as well as their association with cognitive impairments, remain unclear. Objective: Using electroencephalogram (EEG), we explored the electrophysiological markers of face-specific visual processing alterations in aMCI and examined their relationship with cognitive deficits. Methods: We recruited participants with aMCI (n=32) and healthy controls (HC, n=41) and used a passive viewing task to measure the event-related potential (ERP) in response to faces and non-face objects. To compare face processing in aMCI patients and HCs, we adopted mass univariate analysis and representational similarity analysis (RSA) to explore aMCI-related alterations in ERPs. Results: We found that face inversion effect (FIE) in P1 amplitudes was absent in aMCI patients. Also, compared to HCs, aMCI patients exhibited a lack of right hemisphere advantage in N170 in response to faces. Furthermore, representation similarity analysis of ERP in posterior-temporal regions revealed that aMCI patients represent face and non-face objects distinctively from HCs in the early processing stage. Additionally, the FIE in P1 amplitude positively correlated to aMCI patients’ visuospatial functions. Conclusions: These findings showed aMCI-related changes in the early perceptual processing of faces and highlights the potential of the FIE in P1 amplitude and ERP patterns over occipital-temporal regions as electrophysiological markers for aMCI and AD.
Xiao Chen#, Peilu Wang#, Yilin Tang, Susan Veldheer, Tingting Geng, Liang Sun, Yaqi Li, Xiang Gao #These authors contributed equally to this work.
Marijuana use and subjective cognitive decline in middle-aged and older adults: Analysis of the Behavioral Risk Factor Surveillance System survey
Abstract: Background: Marijuana impairs the brain development and function among adolescents, but little is known about whether marijuana use is associated with subjective cognitive decline (SCD) among adults. Objective: We investigated the cross-sectional association between marijuana use and past-year SCD in a representative sample of US adults aged 45 years and older. Methods: The study population included 100,685 participants from five cycles of the Behavioral Risk Factor Surveillance System (BRFSS). Participants self-reported their marijuana use in the past month and whether they experienced SCD or SCD-related functional limitations in the past year. Participants were categorized into past-month marijuana non-users and past-month marijuana users. Among users, they were further classified as occasional (<10 days) and frequent users (≥10 days). The weighted, multivariable logistic regression models were fitted to examine the association between marijuana use and past-year SCD, adjusting for age, sex, educational level, chronic disease status, and other potential confounders. Results: The sample included 94.2% (94,818/100,685) of past-month marijuana non-users and 5.83% (5,867/100,685) of users. Among the users, 59.3% (3,477/5,867) were frequent users. Compared with past-month marijuana non-use, past-month marijuana use was significantly associated with higher odds of past-year SCD (OR=1.70, 95% CI: 1.41, 2.05). The higher frequency was associated with higher odds of having past-year SCD in a dose-response manner (p Trend<0.001). Similar associations remained for the SCD-related functional limitations. Conclusions: We found that past-month marijuana users reported higher rates of past-year SCD, a finding consistent with prior literature linking marijuana use with cognitive decline. Future prospective studies are warranted to confirm these findings.
Virve Kärkkäinen, Toni Saari, Sanna Hannonen, Minna Rusanen, Juha-Matti Lehtola, Hannu Uusitalo, Ville Leinonen, Bernd Thiede, Kai Kaarniranta, Anne M Koivisto, Tor P Utheim
Altered tear fluid protein expression in persons with mild Alzheimer’s disease in proteins involved in oxidative stress, protein synthesis, and energy metabolism
Abstract: Background: Tear fluid (TF) is a protein-rich solution that reflects pathophysiological changes in Alzheimer’s disease (AD). Objective: In this study, we examined whether TF proteins were differently expressed in persons with mild AD dementia compared to cognitively healthy controls (CO). Methods: We analyzed data from 53 study participants including 34 CO (mean age, 71 years; Mini-Mental State Examination [MMSE] score, 28.9 ± 1.4), and 19 patients with AD (Clinical Dementia Rating, 0.5–1; mean age, 72 years; MMSE score, 23.8 ± 2.8). All participants underwent cognitive testing, as well as neurological and ophthalmological examinations. TF was collected using Schirmer strips, and TF protein content was evaluated using mass spectrometry-based proteomics and label-free quantification. Results: We found that 16 proteins exhibited significantly upregulated expression in the AD group compared to the CO group (p ≤ 0.05). These proteins were NP1L4, BODG, CYTC, RNAS4, PCD, RNT2, AL1A3, SYSC, TPIS, CLH1, PGAM1, EIF3L, 5NTC, HNRNPA2B1, PYGL, and ERO1α. No proteins were significantly downregulated in the AD group compared to the CO group. Conclusions: Our results support the hypothesis that TF is a potential source of biomarkers for AD. Part of those proteins with altered expression have previously linked to increased oxidative stress, changed protein synthesis, and disturbed regulation of energy metabolism related to AD or neurodegenerative disease. The present results indicate the value of continued investigation of TF proteins in AD.
Shuge Gui, Fan Zeng, Zhou Wu, Saori Nonaka, Tomomi Sano, Junjun Ni, Hiroshi Nakanishi, Masafumi Moriyama, Takashi Kanematsu
Lipopolysaccharides from Porphyromonas gingivalis indirectly induce neuronal GSK3β-dependent synaptic defects and cause cognitive decline in a low-amyloid-β-concentration environment in Alzheimer’s disease
Abstract: Background: Lipopolysaccharides from Porphyromonas gingivalis (P.gLPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of P.gLPS on synaptic defects remains unclear. Objective: In this study, we tested our hypothesis that P.gLPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment. Methods: MG6 microglia or N2a neurons was treated with P.gLPS (0.1 μg/mL), soluble Aβ42 (0.1 μM) or AL (combined P.gLPS and soluble Aβ42 at 0.1 μM). Results: In cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ42, P.gLPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APPNL-F/NL-F mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia. Conclusions: These observations demonstrate that P.gLPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.
