bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy
Authors: Belaidi Abdel Ali , Masaldan Shashank , Southon Adam , Kalinowski Pawel , Acevedo Karla , Appukuttan Ambili , Portbury Stuart , Lei Peng , Agarwal Puja , Leurgans Sue E. , Schneider Julie A , Conrad Marcus , Bush Ashley I , Ayton Scott 
Published: June 2023

AbstractBackgroundAllelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer’s disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron‐dependent regulated cell death pathway.MethodFerroptosis was induced in the N27 neuronal cell model of ferroptosis using multiple agents (erastin, RSL3, iron, cysteine depletion). The severity of ferroptosis was measured by several toxicity assays (MTT, LDH) and lipid peroxide probe (C11BODIPY). Iron levels in the temporal inferior cortex was gathered from 608 deceased subjects in the memory and aging project (MAP, Chicago, USA). Iron levels were quantified and analyzed using multiple regression models stratified by APOE genotype.ResultWe report that apoE is a potent inhibitor of ferroptosis (EC50≈10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron‐dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer’s disease was stronger among those with the adverse APOE‐ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele’s heighted risk of AD.ConclusionWe show that apoE protects against ferroptic neurodegeneration through regulating autophagy and identified an increased risk of AD diagnosis associated with the apoE risk allele in a clinical study. These findings support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.
Electrocardiogram differences in cognitively unimpaired PSEN1‐E280A carriers and non‐carriers from the Alzheimer’s Prevention Initiative Autosomal‐Dominant Alzheimer’s Disease Colombia Trial
Authors: Vasquez Daniel , Giraldo‐Chica Margarita , Malek‐Ahmadi Michael H. , Jaramillo Carlos J , Acosta‐Baena Natalia , Espinosa Alejandro , Ramos Claudia , Aguillon David , Aponte Claudia , Londoño Jennifer , Hu Nan , Su Yi , Ehrhard Patricia , Sink Kaycee M. , Tariot Pierre N. , Reiman Eric M. , Ríos‐Romenets Silvia , Lopera Francisco ,   API ADAD Colombia Trial Group
Published: June 2023

AbstractBackgroundSome but not all studies have found compromised myocardial function and amyloid deposition, related or unrelated to amyloid‐β pathology itself, in persons with late‐onset Alzheimer’s Disease (AD). Other changes in QT interval, heart rate variability, and QRS voltages have been described in the electrocardiogram (ECG), but those are not consistent between studies. We explored differences in several ECG measures in cognitively unimpaired (CU) Presenilin 1 (PSEN1)‐E280A carriers and non‐carriers from the Alzheimer’s Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841).MethodThe trial enrolled 252 CU 30–60‐year‐old participants. We included participants (144 PSEN1‐E280A mutation carriers and 71 non‐carriers) in these analyses who were enrolled in the trial during their first screening attempt. Baseline cardiovascular data and medical history were obtained by medical assessment and blood sample. Interval durations, QRS voltages of all leads, and the diagnosis were taken from baseline ECG. T‐test, chi‐square, correlation, and effect size were used in the data analysis. The p values in this are exploratory.ResultMean age (years) for carriers was 36 and 43 for non‐carriers. Years of education, sex, and clinical variables like body mass index, cholesterol, hemoglobin A1c, TSH, and previous cardiovascular disorders were similar between groups. There were no differences in the heart rate, PR, QRS, or corrected QT interval duration. Voltages in AVL and DI leads were lower in carriers than non‐carriers with a low size of effect (0.42 vs. 0.50, p = 0.03; 0.64 vs. 0.71, p = 0.04, respectively), while the other ten leads and low voltage in any of the 12 derivates did not show any difference. There was also a negative and small correlation between voltage and age for DII, V6, and AVR (‐0.146, ‐0.144, ‐0.137; p = 0.03,0.03,0.04; respectively).ConclusionOur findings suggest no clinically significant difference in ECG parameters between PSEN1‐E280A mutation carriers compared to non‐carriers. Since intramyocardial deposits of amyloid‐β are age‐dependent, it is likely that there are low levels of these deposits in young CU individuals. Longitudinal studies with larger samples that include CU patients might identify ECG‐related changes associated with amyloid‐β cardiac deposits.
Longitudinal basal forebrain atrophy in association with amyloid‐β positivity and dementia severity
Authors: Xia Ying , Maruff Paul , Bourgeat Pierrick , Dore Vincent , Villemagne Victor L , Rowe Christopher C. , Coulson Elizabeth J , Fripp Jurgen 
Published: June 2023

AbstractBackgroundDysfunction of the cholinergic basal forebrain (BF) system and deposition of amyloid‐β (Aβ) are early pathological features in Alzheimer’s disease (AD). Degeneration of the BF in association with Aβ burden and cognitive decline has not been well studied, particularly in AD prior to dementia. We assessed the longitudinal trajectory patterns of the global BF volume, and the relationship to Aβ levels and clinical disease severity in older adults. The hippocampal volume (HV) trajectories were also assessed for reference.MethodVolumetric measures of the BF and HV were quantified from the MRIs of 521 participants (age = 72.6±5.9, 52.8% female, CDR range 0‐1) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study, who had Aβ‐PET imaging and longitudinal structural MRI (follow‐up over 4.3±2.6 years). Aβ load was quantified using CapAIBL and Aβ+ was defined for centiloid values >20. Participants were classified at baseline based on their being cognitively unimpaired (CU, CDR = 0) or symptomatic (CDR = 0.5‐1) and Aβ status, which were CU Aβ‐, CU Aβ+ (preclinical AD), symptomatic Aβ‐ and symptomatic Aβ+ (prodromal AD and AD) (Table 1). BF and HV volumes were standardized using the mean and standard deviation of the relevant measures in the CU Aβ‐ group at baseline. Linear mixed effect models were used to compare the changes over time (slope) of BF and HV in different clinical groups. The magnitude of the difference in slopes between groups was assessed using Cohen’s d (summarised in Table 2).
ResultIn CU Aβ‐, age‐related atrophy was greater in the BF compared to the HV (Cohen’s d = 0.811). Compared to the CU Aβ‐ group, the rate of atrophy was significantly faster for BF and HV in the preclinical AD group, and this decline was even greater in the prodromal AD and AD group (Figure 1 and Table 2). The symptomatic Aβ‐ group showed greater rate of BF atrophy than the CU Aβ‐ group, while there was no difference in the rate of HV atrophy.ConclusionThese findings provided prospective evidence confirming early vulnerability of the BF in aging as well as differentiated BF degeneration that was associated with baseline Aβ positivity and dementia severity.
Insulin‐growth factor 1 (IGF‐1) in older adults with the concomitant presence of Alzheimer’s disease and type 2 diabetes mellitus
Authors: Zanarelli Paloma , Grigoli Marina Mantellatto , Cominetti Marcia Regina 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) may be related to changes in insulin pathways, suggesting that individuals with type 2 diabetes mellitus (T2DM) are more likely to develop AD compared to healthy individuals. Insulin plays an important role in the mechanisms related to brain activity, especially in the formation of memories. Given the similarity between insulin‐like growth factor (IGF‐1) and insulin itself, this molecule has the ability to bind to the insulin receptor, but with low affinity. In addition to the brain, IGF‐1 is present in several tissues, acting as a mediator of physiological responses related to neuronal protection against toxicity caused by glucose deprivation and oxidative stress, in addition to playing an important role in apoptosis, cell proliferation and differentiation. In vitro studies have demonstrated the potential that this protein has to decrease tau protein hyperphosphorylation, one of the pathological hallmarks of AD. Moreover, in response to neuronal damage, IGF‐1 promotes neurogenesis and synaptogenesis.MethodThis is a cross‐sectional study, based on the assumptions of quantitative research, approved by the Ethics Committee of Federal University of São Carlos, SP, Brazil (CAAE: 12968413.1.0000.5504). It has been developed with a sample of 36 participants aged over 60 years, users of health services in the municipality. Specific inclusion and exclusion criteria and the MMSE and CDR cognitive assessment instruments were applied to participants from all groups. Quantification of IGF‐1 plasma levels was performed using the ELISA technique (Enzyme‐Linked Immunosorbent Assay).ResultHigher plasma levels of IGF‐1 were found in older adults with AD and concomitant T2DM when compared with older adults with diabetes (T2DM) (p = 0.0167) and healthy participants (p = 0.0003).ConclusionThe increase in IGF‐1 levels in plasma of older adults with AD+T2DM and T2DM groups may indicate an initial compensatory response against neuronal damage in the elderly with both diseases or T2DM. The findings and conclusions of the present study are exploratory, and further studies with larger sample sizes are needed to draw a firm conclusion.
Participant characteristics, modifiable dementia risk, and associated goal setting within a large online, multi‐domain, risk factor management program (BetterBrains) to delay cognitive decline
Authors: Rosenich Emily , Pirotta Stephanie , Mills Andrea , Norfolk Maya , Yassi Nawaf , Brodtmann Amy , Rajaratnam Shanthakumar W , Pase Matthew P. , Bush Ashley I , Ayton Darshini , Maruff Paul , Lim Yen Ying ,   BetterBrains Research Group
Published: June 2023

AbstractBackgroundIn 40% of cases, dementia can be attributed to potentially modifiable risk factors (RFs) such as poor vascular health, poor sleep, low mood, and low social/cognitive engagement.1 BetterBrains (betterbrains.org.au) is a prospective, blinded endpoint, 24‐month randomised controlled trial to test the effectiveness of an online, person‐centred, RF management program in delaying cognitive decline2 in middle‐aged adults (40‐70 years) with a family history of dementia.MethodAssessment of RFs in vascular health, social/cognitive engagement, mood, and sleep are conducted and participants with risk in at‐least 1 domain are enrolled. The primary outcome is favourable cognitive performance at 24‐months, defined as the absence of decline on at least one out of four cognitive tests. All participants (control/intervention) receive educational blogposts. Intervention participants also receive at least six person‐centred telehealth consults with a “BetterBrains coach” trained in motivational interviewing to set and achieve goals to reduce identified RFs.ResultTo date, 599 participants have been enrolled in BetterBrains. Blinded baseline descriptive analyses revealed high trial acceptability, with <3% of participants who completed baseline withdrawing from the trial. Participants who completed RF assessment (n = 459) were mostly female (80%), aged 59.4 years, and have 15.2 years of education on average. Risk in all domains is most common (29.6%), followed by risk in social/cognitive engagement, sleep, and vascular health (16.9%) (Fig 1). Of those randomised, behaviour change goals (n = 429 goals) most commonly target vascular RFs (e.g., increasing physical activity, lowering blood pressure/cholesterol) (41%) and low levels of social/cognitive engagement (e.g., attending community/social groups, learning a language) (26.1%), mapping closely to the most common modifiable RFs (Fig 1).ConclusionLow attrition rates indicates high acceptability of the BetterBrains methodology. However, the current sample consists mostly of younger adult females with high educational attainment. There is high co‐occurrence of modifiable RFs in the sample, consistent with observations of clustering of RFs in adult populations.3,4 When categorised, personalised behaviour change goals occurred most commonly within the vascular health and social/cognitive engagement domains, aligning with prescriptive components used in previous lifestyle prevention trials.4 Variation in modifiable RF profiles confirms the validity of a personalised, multidisciplinary approach.
Longitudinal association between multimorbidity, cognitive decline and neuropsychiatric symptoms
Authors: Moon Chooza , Zhang Meina , Wang Boxiang , Hoth Karin F 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia afflicting more than 5.8 million older adults in the United States. In AD, cognitive decline and neuropsychiatric symptoms are more pronounced in those who have chronic conditions. These chronic conditions often co‐occur with other chronic conditions, known as multiple chronic conditions (MCCs). This study aimed to examine the longitudinal association between the number of chronic conditions with cognition and neuropsychiatric symptoms by cognitive status.MethodsParticipants were 21,219 community dwelling individuals from the longitudinal National Alzheimer’s Coordinating Center (NACC, U24 AG072122) database (mean age = 71.8 ± 9.8; 42.8% male). Participants completed a medical history interview, cognitive assessment, and the Neuropsychiatric Inventory (NPI), approximately every two years over a 15‐year period. Number of MCCs was characterized as the sum of clinician‐diagnosed chronic conditions (i.e., cardiovascular, metabolic, sleep, respiratory, and psychological conditions;range 0‐18). The analysis focused on memory (Craft Story 21 recall immediate and delayed), processing speed (Trails A), and executive function (Trails B, Coding, animal naming). We used mixed effect models to test whether the number of MCCs was associated with a change on each cognitive test and number neuropsychiatric symptoms by clinician diagnosed cognitive status (i.e., normal cognition, mild cognitive impairment (MCI) presumed AD etiology, MCI presumed without AD etiology, MCI with AD etiology, dementia with AD etiology, dementia with non‐AD etiology).ResultsWe found that the mean number of chronic conditions were, 2.2 ± 1.8 in cognitively normal individuals, 2.8 ± 2.0 in MCI with AD etiology, 2.8 ± 2.0 in MCI with non AD etiology, 2.7±1.9 in dementia with AD etiology, 3.0±2.1 in dementia with non‐AD etiology. Compared to cognitively normal adults, individuals with more severe cognitive impairment (i.e., groups with dementia) and a higher number of MCCs demonstrated greater decline in immediate and delayed memory recall, Trails A, animal naming, and coding (p <0.05), as well as the number of neuropsychiatric symptoms (p <0.05) over time accounting for age, sex, and education.ConclusionThe findings suggest that having a higher number of chronic conditions is associated with longitudinal decline in cognition and neuropsychiatric symptoms.
Comparing Mini‐Mental Status Exam baseline data of cognitively normal individuals who declined to Alzheimer’s disease versus cognitively normal non‐decliners in the SIU Longitudinal cognitive aging study
Authors: Porter Nicholas , Zec Ronald F , Kohlrus Stephanie R. , Ala Tom , Hollinshead Madison G. , Bakir Danah , Agamah Alikem Miriam , Unnam Pavani , Chaulagain Suchana , Hascup Erin R. , Trivedi Mehul Alkesh 
Published: June 2023

AbstractBackgroundThe Mini‐Mental Status Exam (MMSE) is one of the most commonly used cognitive screening measures for diagnosing cognitive impairment in older adults. In the present study, we examined whether or not there were baseline differences in MMSE scores between cognitively normal individuals who developed Alzheimer’s disease over time (decliners) versus individuals who did not decline over time (non‐decliners).MethodWe included 67 participants who were administered the MMSE during a baseline assessment. All participants were enrolled in the SIU Longitudinal Cognitive Aging Study (SIU LCAS) as controls who were free of cognitive impairment at their baseline visits. Participants were divided into two groups (decliners versus non‐decliners). There were 25 participants in the decliner group and 39 participants in the non‐decliner group. Average age of decliners was 70.84, while average age of non‐decliners was 71.67. Average education of decliners was 15.76 years, while average education of non‐decliners was 16.49 years. The ratio of females to males was 4:1 among decliners and 1.6:1 among non‐decliners. A two‐sample t‐test was used to examine differences between the two groups with respect to their baseline MMSE scores.ResultThe decliner group (mean age = 70.8) was significantly younger than the non‐decliner group (mean age = 71.7). There were no significant differences between the two groups for education or gender distribution. 11 decliners had autopsy confirmed AD, while 14 decliners had AD diagnosis without autopsy. There were 5 individuals in the non‐decliner group with no evidence of AD pathology on autopsy. The decliner group had significantly lower baseline MMSE scores compared to the non‐decliner group (p < 0.05). MMSE scores for decliners compared to non‐decliners using WORLD backwards was 28.96 versus 29.44, respectively, and was 28.32 versus 28.85, respectively, when using serial 7’s.ConclusionThe results of the present study indicate that there are subtle differences in baseline MMSE scores (approximately 0.5 points) in older adults who decline to AD compared to older adults who remained cognitively normal. More studies with larger sample sizes, including more participants with brain autopsy, are needed to confirm these findings.
Familial Alzheimer’s Disease‐linked Swedish mutation impairs APP axonal transport
Authors: Feole Monica , Dragisic Neda , Bhat Pratiksha , Devoto Victorio Martin Pozo , Stokin Gorazd B. 
Published: June 2023

AbstractBackgroundIt is well‐established that most familial Alzheimer’s disease (AD) mutations alter processing of the amyloid precursor protein (APP) and perturb the balance between its proteolytic fragments. Considering different APP fragments play a role in its axonal transport, we here ask whether familial APP mutations impair axonal transport and homeostasis.MethodStem cells‐derived human neurons were transduced with either APPwt_GFP or APPswe_tRFP. Time‐lapse movies were analyzed using tracking algorithms to describe axonal transport parameters. Immunocytochemistry was performed to assess APP localization. To evaluate the impact of APPswe on other cargoes we also studied axonal transport of Rab5 endosomes.ResultProportions of movement, velocity, and distances of APPswe particles were decreased in anterograde direction compared to wt, while increased pauses and reversions were found. Accumulation of APP at the soma compared to neurite was found for APP mutant vs wt. Moreover, effect of APPswe resulted in the enlargement of Rab5 endosomes vs ctrl. Furthermore, to validate other effects of the APP mutant on Rab5, we studied its transport and found changes in some parameters compared with the ctrl.ConclusionThis work shows that APPswe impairs axonal transport. The change found on anterograde transport of APPswe, goes in hand with its accumulation at the soma vs neurite. Moreover, our results suggest that the Swedish mutation affects other proteins linked with APP, as described for the early‐endosome protein, Rab5. In line with many studies conducted on APP, our data suggest once more the importance of understanding as many mechanisms as possible involved in the biology of this protein.
Evaluation of fall risk and associated factors in patients with dementia
Authors: Kilicaslan Kimya , Tulek Zeliha , Gurvit Hakan , Bilgiç Başar , Hanagasi Hasmet 
Published: June 2023

AbstractBackgroundFalling, which is common in the elderly and leads to negative consequences, can also be seen in dementia patients. The aim of this study is to determine the risk of falls in patients with dementia and to evaluate the factors associated with falls.MethodThe sample of this cross‐sectional study consisted of 95 patients with a diagnosis of definite dementia who attended a dementia outpatient clinic in a university hospital in Istanbul between January and March 2020. Patients using assistive devices while walking were not included in the study. A sociodemographic form, DENN Fall Risk Assessment Scale, Mini Mental State Test (MMSE), Neuropsychiatric Inventory (NPI), Apathy Assessment Scale (AES), Clinical Dementia Rating Scale (CDR), Cornell Depression in Dementia Scale (CSDD), Lawton and Brody Instrumental Activities of Daily Living (Lawton IADL), and Katz Activities of Daily Living (Katz ADL) Scale were used for data collection.ResultsIt was determined that 53.7% of the patients were female and the mean age was 73.1±11.4. Most of the patients (64.2%) had Alzheimer’s type dementia, 49.5% had mild or moderate dementia, 75.8% had an additional chronic disease, 22.1% were semi‐dependent in movement activity. 47.4% of the individuals had a history of fall in the last month, 48.9% had fallen at least 2 times, the average number of falls was 1.5±0.5, 70.5% of the patients had injuries after falling, and the mean DENN Fall Risk score was found to be 10.4±3.4. In the group with a history of falling non‐Alzheimer dementias were more common (p = 0.018), NPI symptom (p<0.001) and bother (p<0.001) scores were higher, Lawton IADL scores were lower (p = 0.009), AES clinician (p = 0.054) and caregiver (p = 0.052) scores and Cornell depression score (CSDD) (p = 0.005) were higher.ConclusionFalling, which is the most common geriatric syndrome in dementia patients, can lead to negative patient outcomes. Most dementia patients have a history of falling and post‐fall injury. Factors associated with falls in dementia patients should be known, and appropriate nursing interventions should be made to prevent falls by recognizing the risk of falling. More work is needed on this subject.