bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remote and unsupervised digital memory assessments can reliably detect cognitive impairment in Alzheimer’s disease
Authors: Berron David , Olsson Emil , Andersson Felix , Janelidze Shorena , Tideman Pontus , Düzel Emrah , Palmqvist Sebastian , Stomrud Erik , Hansson Oskar 
Published: January 2025

AbstractBackgroundRemote unsupervised cognitive assessments have the potential to complement and facilitate cognitive assessment in clinical and research settings.MethodHere we evaluate the usability, validity and reliability of unsupervised remote memory assessments via mobile devices (see Figure 1) in individuals without dementia from the Swedish BioFINDER‐2 study and explore their prognostic utility regarding future cognitive decline in combination with a plasma marker for p‐tau217.ResultUsability was rated positively. The app was easy to use with clear instructions, a majority of participants enjoyed completing the tests and preferred digital assessments over pen‐and‐paper tests, and more than 80% of participants found the frequency and length of remote assessments were appropriate. Remote memory assessments showed good construct validity with traditional neuropsychological assessments (see Figure 2) and were significantly associated with medial temporal lobe subregional tau‐PET and downstream MRI measures (see Figure 3). Memory performance at baseline was associated with future cognitive decline and prediction of future cognitive decline was further improved by combining remote digital memory assessments with plasma p‐tau217. Finally, retest reliability was moderate for a single assessment and good for an aggregate of two sessions.ConclusionOur results demonstrate that unsupervised digital memory assessments might be used for diagnosis and prognosis in Alzheimer’s disease, potentially in combination with plasma biomarkers.
Early presentations of dementia across cultures: Analysis of primary care data from a diverse population
Authors: Zabihi Sedigheh , Bestwick Jonathan P , Bothongo Phazha LK , Zhang Qiqi , Carter Christine , Roche Moïse , Morgan‐Trimmer Sarah , Birks Yvonne , Wilberforce Mark , Dobson Ruth , Noyce Alastair J , Robson John , Walter Fiona M , Cooper Claudia , Marshall Charles R 
Published: January 2025

AbstractBackgroundDementia is associated with a range of non‐cognitive features that can occur during the prodromal phase. Improved recognition of non‐cognitive presentations of dementia could reduce inequalities in dementia diagnosis, particularly if sociocultural factors influence rates of help‐seeking for cognitive symptoms. We aimed to investigate presentations to primary care in the years before dementia diagnosis in a deprived and ethnically diverse population with universal access to health care.MethodWe conducted a nested case‐control study using electronic health care records on 1,016,277 individuals from primary care practices in East London, UK between 1990 and 2018. Individuals with a diagnosis of dementia were compared to controls without dementia. We ran a matched analysis (four controls matched to each person with dementia according to age and sex) using multivariable logistic regression to assess the associations between pre‐diagnostic presentations to primary care with subsequent diagnosis of dementia. We analysed three time periods (<2, 2‐5, 5‐10) before diagnosis.ResultWe included 4,137 individuals and 15,754 controls in the matched analysis (51.8% White; 42.7% Black, South Asian and other ethnicities). Neuropsychiatric presentations including depression (odds ratio [OR] = 2.71; 95% CI: 2.33 to 3.16), anxiety (OR = 1.67; 95% CI: 1.46 to 1.92), initiation of antipsychotic medication (as a proxy for psychotic symptoms) (OR = 5.84; 95% CI: 4.80 to 7.11) and insomnia (OR = 1.69; 95% CI: 1.31 to 2.17) were more frequent in the years before dementia diagnosis. Associations were found for autonomic features including constipation (OR = 1.54; 95% CI: 1.39 to 1.71) and incontinence (OR = 2.63; 95% CI: 2.32 to 2.97) up to a decade, and hypotension (OR = 1.89; 95% CI: 1.35 to 2.63) up to five years before dementia diagnosis. Sensory features including hearing loss (OR = 1.36; 95% CI: 1.14 to 1.63), imbalance and dizziness were also associated with subsequent dementia diagnosis. Memory difficulty was more strongly associated with subsequent dementia diagnosis than any non‐cognitive presentation (OR = 51.00; 95% CI: 43.87 to 59.29).ConclusionA range of non‐cognitive presentations are seen during the prodromal period of dementia in a diverse population. Improved recognition of these associations could increase access to dementia diagnosis, through improved recognition of potential presenting symptoms in people from different backgrounds.
Exploring the Immediate Impact of APOE ε4ε4 Genotype Disclosure among Latinos
Authors: Caro Daniela Diaz , Rodriguez Sophia , Wetmore John Brandon , Godinez Jonathan D , Camarillo Itzel A , Goldman Jill , Uhlmann Wendy R. , McCain Sarah , Caban Maria , Leu Cheng‐Shiun , Abraido‐Lanza Ana F , Lantigua Rafael A. , Chung Wendy K , Roberts J. Scott , Siegel Karolynn , Ottman Ruth 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) risk is markedly increased among APOE ε4/ε4 homozygotes. Previous studies of APOE genotype disclosure impact have included few ethnic minorities. This study addresses this gap by investigating the immediate impact of disclosing an APOE ε4/ε4 genotype in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a Latino community‐based study.MethodsIDEAL participants attended semi‐structured genetic counseling sessions conducted via Zoom in Spanish or English by certified genetic counselors. Sessions included a PowerPoint presentation covering genetics, genotype results, risk estimates, and AD prevention methods. Risk estimates were based on data from the Washington Heights‐Inwood Columbia Aging Project, a longitudinal study conducted in the same communities. The estimate of risk to age 85 among ε4 homozygotes was 55%. We transcribed session recordings and conducted content analysis.ResultsEleven ε4/ε4 participants aged 41‐64 attended risk evaluation sessions (English 8, Spanish 3). Six had a family history of AD (first‐degree 1, distant 5). Nine were women and two men. Overall, participants did not show strong emotional reactions. Many expressed surprise, accompanied by thoughtful reflections on the connection between their AD risk and perceived memory problems or emotional well‐being. Participants generally appreciated the information provided during the genetic counseling sessions because it offered insights into the importance of AD risk awareness and prevention strategies.ConclusionLatinos at high AD genetic risk showed limited immediate emotional response to risk disclosure and appreciated the information that was shared. Longitudinal analyses may provide further insight into the impacts of this disclosure.This study is supported by the National Institute on Aging (R01 AG062528) and registered in ClinicalTrials.gov (NCT04471779).Keywords: Alzheimer's disease, APOE ε4ε4, genetic counseling, Latinos, qualitative research, risk disclosure
Harmonised neuropsychological assessment for Vascular Cognitive Disorders: a Delphi consensus study
Authors: Bentvelzen Adam C. , Kochan Nicole A. , Sachdev Perminder S. ,   VasCog‐2 Neuropsychological Consortium
Published: January 2025

AbstractBackgroundHarmonization of neuropsychological assessment for vascular cognitive disorders (VCD) is important for ensuring the highest standards for diagnostic and post‐diagnostic care. A battery jointly proposed by the NINDS‐CSN has received much support. Considering significant developments in the field, and an urgent need for consensus on remote and computerised assessment methods, an international expert group was commissioned to develop an updated harmonized battery and associated assessment guidelines for VCD using the Delphi process.MethodsA modified Delphi consensus method was used, involving an iterative, multi‐staged series of structured surveys with feedback of anonymized responses from experts in the neuropsychological assessment of vascular cognitive disorders. Three rounds were planned, with the possibility of a fourth round, if required to reach consensus. Literature reviews on harmonized neuropsychological assessment were conducted by a team of researchers, which informed the first structured questionnaire. Consensus was sought on the cognitive domains and subdomains that should be assessed, on specific tests per domain, and for additional guidelines including on non‐traditional assessment methods and cultural‐linguistic considerations. Consensus was defined as agreement or disagreement on any statement of ≥ 75%, near consensus as 66 – 75%, and <66% as non‐consensus. Statements that reached consensus were removed from subsequent rounds, as were most that had non‐consensus, with some being reworded. A virtual meeting was held for experts to discuss contentious issues and advise on the process.ResultForty‐four experts in neuropsychological assessment from a range of international regions consented to participate, and 31 completed the Round 1 survey. The final survey is being completed, then the assessment battery and additional guidelines will be finalized to be approved formally by all participants.ConclusionThe harmonized neuropsychological assessment standards could be adopted internationally and complement the NINDS‐CSN battery, thereby further facilitating consistent neuropsychological assessment of VCD between clinicians and researchers.
Spermidine Treatment Attenuates Systemic and Gut Oxidative Stress, Neuropathology and Cognitive Deficits in D‐galactose Induced Aging Rats
Authors: Saiyasit Napatsorn , Pratchayasakul Wasana , Kangwan Napapan , Kaorop Wichida , Maneechote Chayadom , Kunasol Chanon , Ngowthammatas Nattapat , Arunsak Busarin , Donchada Suriphan , Kongkaew Aphisek , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundOur previous studies reported that D‐galactose (D‐gal) administration for four to eight weeks caused metabolic disturbance, brain mitochondrial dysfunction, and brain aging, leading to cognitive dysfunction in similar with natural aging condition. Spermidine is a polyamine that can be found naturally. Spermidine has been showed the beneficial effects on various models, such as attenuating metabolic/gut impairments in obesity, and ameliorating memory loss in aged model. However, those beneficial effects of spermidine in D‐galactose‐induced aging condition is still unclear.MethodEighteen female Wistar rats were divided into two groups which received either NSS as a control group (n = 6) or D‐gal (150 mg/kg/day, n = 12), subcutaneously for total twenty weeks. At week 12, D‐gal‐treated rats were divided into two subgroups; NSS as a vehicle and spermidine (20 mg/kg/day), orally for 8 weeks (n = 6 per subgroup). At the end of protocol, the cognitive tests; novel object location (NOL) and novel object recognition (NOR) were performed. After animals were euthanized, brain/gut tissues and blood samplings were collected to determine the biochemical parameters.ResultSystemic/gut oxidative stress by increasing the serum malondialdehyde (MDA) level and attenuating colon SOD2 protein expression respectively were shown in D‐gal‐treated rats (Figure 1A‐B). Levels of colon ZO‐1 mRNA was decreased in D‐gal‐treated rats, in comparison to control group (Figure 1C). Upregulation of hippocampal senescence‐associated b‐galactosidase (SA‐b‐gal), elevation of brain mitochondrial ROS level, and cognitive impairment by reducing the percentage of preference index of NOL and NOR were also observed in D‐gal‐treated rats (Figure 1D‐E, G‐H). Interestingly, spermidine treatment in D‐gal‐treated rats alleviated serum MDA and upregulated colon SOD2 protein levels, compared to D‐gal‐treated rats with vehicle (Figure 1A‐B). Spermidine also reduced hippocampal SA‐b‐gal protein expression, decreased brain mitochondrial ROS level and swelling (Figure 1D‐F), and attenuated the learning and memory impairment by restoring the percentage of preference index of NOL and NOR in D‐gal‐treated rats (Figure 1G‐H).ConclusionOur findings suggest that spermidine exerts the beneficial effects on cognition through reducing systemic/brain oxidative stress in D‐galactose‐induced aging rats. Therefore, it is possible that spermidine should be considered as a novel therapeutic option for ameliorating neuropathology in aging condition.
Mitochondria Localized MicroRNAs and Alzheimer’s disease
Authors: kumar Subodh 
Published: January 2025

AbstractBackgroundMitochondria plays a crucial role at synapses in providing synaptic energy, healthy synaptic function, and cognitive functions. Amyloid‐beta and phosphorylated tau protein oligomers cause severe mitochondrial defects in Alzheimer’s disease (AD), which leads to the lack of synaptic energy and impaired synapse functions in AD. MicroRNAs (miRNAs) present within the mitochondria are involved in multiple mitochondrial activities and mitochondrial function. Mitochondrial dysfunction is well established in AD; but status of mitochondria localized miRNAs are unknown in AD. This current study is focused on the identification of mitochondria localized miRNAs in AD and to unveil their possible roles in disease pathogenesis.MethodMitochondria and cytosolic fraction were extracted from postmortem AD brains (n = 5) and cognitively normal postmortem brains (n = 5). Mitochondria purity was characterized by transmission electron microscopy (TEM) and immunoblot analysis of mitochondrial marker proteins. Mitochondria activity was determined by mitochondrial function assay. Further, total RNA was extracted from mitochondria and cytosolic fraction and subjected to miRNAs HiSeq analysis. The significantly deregulated mitochondrial miRNAs were further validated on large number of AD postmortem brain and subjected to in‐silico bioinformatic analysis.ResultTEM analysis, immunoblotting and mitochondrial function assay confirmed the extraction of intact and active mitochondria from AD and control postmortem brains. MiRNAs HiSeq analysis showed the mitochondria localized distribution of some novel miRNAs in AD and control samples. We found some miRNAs localization and differential expression in mitochondrial fraction relative to cytosolic fraction. Our validation analysis unveiled previously unknown, most potential mitochondria localized miRNAs in AD. Further, in silico bioinformatic analysis revealed the critical roles of mitochondrial localized miRNAs in several mitochondrial function and synaptic pathways in AD.ConclusionOur study discovered some novel mitochondria localized miRNAs, which could be a potential therapeutic target to retrieve mitochondrial and synaptic dysfunction in AD.
Evaluating the Impact of Combined Clinical and Genetic Risk Factors on Dementia Onset
Authors: Andrews Shea J , Solsberg Caroline Warly , Renton Alan E. , Fulton‐Howard Brian , Yokoyama Jennifer S. , Yaffe Kristine 
Published: January 2025

AbstractBackgroundIntegrating clinical and genetic risk factors for dementia in a precision medicine framework can play a crucial role in primary prevention. Here, we ascertained the proportion of individuals who are at heightened risk of developing dementia based on their family history, genetic, and clinical risk factors and evaluated how the additive burden of these risk indicators is associated with incident dementia.MethodWe analyzed longitudinal data from 3,395 diverse older adults, dementia‐free at baseline with follow‐up and whole genome sequencing, enrolled in the National Alzheimer’s Co‐coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative (Table 1). Our risk indicators comprised: 1) self‐reported first‐degree relative with cognitive impairment; 2) carriage of the APOE*e4 allele; 3) an AD polygenic risk score, incorporating 24 variants and normalized for genetic ancestry, ranking in the top 2% (AD‐PRS); 4) presence of dominantly inherited AD mutations in PSEN1, PSEN2, or APP; and 5) a score of ≥6 on a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (mCAIDE), comprised of age, sex, education, obesity, hypertension, and hypercholesterolemia. We calculated the total risk burden as the sum of these indicators. Cox proportional hazard models were employed to estimate the risk of dementia progression associated with increasing risk burden.ResultsAmong participants, 55% had a family history of dementia, 36% were APOE*e4 carriers, 33% had high mCAIDE scores, 2.2% had extreme AD‐PRS, and none had ADAD mutations. Distribution of risk indicators was as follows: 20% had none, 41% one, 32% two, 7.5% three, and 0.2% four (Figure 1). Our analysis revealed a graded increase in dementia risk with more indicators: compared to those with none, individuals with one, two, three, or four indicators had 1.67, 3.14, 4.41, and 15.22 times increased dementia risk, respectively (Figure 2).ConclusionThe majority of our cohort exhibited at least one dementia risk indicator, with a higher risk burden markedly increasing dementia risk. These findings underscore the value of integrating genetic and clinical risk factors in predicting dementia, highlighting the potential of precision medicine in guiding preventive strategies for at‐risk individuals.
Elucidating the role of mitochondrial Alzheimer’s Disease risk gene LACTB in myeloid cells
Authors: Molina Carmen Romero , See Wen Yi , Patel Tulsi , Liu Yiyuan , Marcora Edoardo , Goate Alison M. 
Published: January 2025

AbstractBackgroundWhile compelling evidence highlights the importance of myeloid cells in the etiology of Alzheimer’s Disease (AD), the relevance of immunometabolism still requires further exploration. Our analysis integrating AD genetics and myeloid cell genomics shows that lower levels of LACTB expression in myeloid cells is protective against AD, a finding supported by proteomics studies. As a mitochondrial active‐site serine protein, LACTB has implications for mitochondrial morphology and bioenergetics. LACTB levels are also linked to succinyl‐carnitine levels, a metabolite predicted to be protective for AD risk. Furthermore, LACTB has been associated with tumorigenesis and obesity, suggesting a potential role in cell dynamics and lipid metabolism, although its function remains elusive.MethodHuman immortalized THP‐1 cells monocytes were differentiated into macrophages and treated with small‐interfering RNA to knock‐down LACTB (KD) expression. CRISPR‐edited human induced pluripotent stem cells (hiPSC) were generated to knock‐out (KO) LACTB and differentiated into microglia cells (iMGL). Metabolomic and lipidomic analyses were outsourced with collected samples, and functional assays evaluating how LACTB alters myeloid cell functions were performed.ResultOur studies revealed an upregulation of LACTB expression upon differentiation (in iMGLs compared to iPSCs, and in THP‐1 macrophages compared to monocytes) and LPS stimulation. Downregulation of LACTB in THP‐1s and iMGLs resulted in elevated succinyl‐carnitine levels, and THP‐1 LACTB KD cells showed an increase in histone succinylation levels, which might indicate epigenetic modulation. We also detected a reduction in nascent protein synthesis levels in our LACTB KD and KO models. Additionally, lipidomics showed a decrease in acylglycerides, and an increase in cholesterol efflux was observed in THP‐1 LACTB KD cells.ConclusionLACTB potentially modulates myeloid cell function by modifying protein synthesis and lipid metabolism. Future directions include a novel xenotransplantation model involving the direct introduction of human microglia precursor cells into the mouse brain to study the effects of LACTB on microglia in‐vivo and in the context of disease using 5xFAD mice. The distinct identity of LACTB as an enzyme, coupled with its protective phenotype upon reduced expression and the potential of succinyl carnitine as a biomarker, makes it a promising therapeutic target in AD.
Midlife Sensory and Motor Measures Among Best Predictors in Parsimonious Models of Long‐Term Cognitive Decline and Onset of Cognitive Impairment in Middle‐Aged Adults
Authors: Merten Natascha , Pinto A Alex , Paulsen Adam J , Chappell Richard J , Chen Yanjun , Engelman Corinne D. , Hancock Laura M , Johnson Sterling C. , Schubert Carla R 
Published: January 2025

AbstractBackgroundOver the past decades, many risk factors for dementia have been identified including sensory and motor functions. Established risk scores to predict onset of cognitive impairment and/or dementia (e.g., the CAIDE and Framingham Risk Score) often focused on cardiovascular risk factors and have not been updated in more recent generations. Risk scores for asymptomatic middle‐aged people, which are based on practical test batteries will be useful for targeted population screenings. The aim of this study was to construct a parsimonious risk prediction model of 10‐year cognitive decline and impairment using factors measured in midlife in a current cohort.MethodThis longitudinal study is based on N = 1529 (54% women, mean age 49 years) Beaver Dam Offspring Study participants with data from baseline, 5‐year and 10‐year follow‐up. We assessed objectively measured and self‐reported hearing, vision, olfactory, and motor function, lifestyle, cardiovascular and general health factors, and blood‐based markers of inflammation, neurodegeneration, and amyloid. We determined 10‐year cognitive decline (trail‐making test B time;10% most decline) and cognitive impairment (neurocognitive case review). We constructed least absolute shrinkage and selection operator (LASSO) logistic regression models with 10‐fold cross‐validation and evaluated predictive ability via receiver operating characteristic curves (AUCs). The effect selection percentage indicated the percentage of times specific predictors were selected in the n = 100 bootstrapped samples of models and was used to establish final models.ResultsThere were N = 121 cognitive decline and N = 217 cognitive impairment cases. The six top predictors for cognitive decline (age, income, fine‐motor skill performance, olfactory function, peripheral artery disease, serum neurofilament light chain protein (NfL)) and for cognitive impairment (sex, fine‐motor skill performance, olfactory function, self‐rated vision, alcohol consumption, NfL) yielded models with an AUC of 0.80(95% confidence interval:[0.76‐0.83]) and 0.73[0.69‐0.77], respectively.ConclusionIn middle‐aged adults, measures of sensory and motor function and NfL were among the best predictors of 10‐year onset of cognitive decline and impairment and only 6 factors were needed to achieve acceptable to excellent AUCs. Cross‐validation in another cohort is needed to verify these factors as reliable and valid predictors to identify those at high risk for neurodegeneration and cognitive decline who could benefit from early prevention and intervention strategies.