bluuebunny/crossref_metadata_2025 huggingface dataset:
Pandemic caregiving: Results from a survey of Alzheimer’s disease research center study partners
Authors: Sewell Margaret , Neugroschl Judith A. , McSpedon Sinead , Weinrib Gila , Woodhead Jessica , Loizos Maria , Zhu Carolyn W , Sano Mary
Published: June 2023

Background

Caregivers are at increased risk for psychological distress and social isolation. The COVID‐19 pandemic presents extra challenges for caregivers of research participants.

Method

Using NACC’s caregiver COVID survey as a model, we developed a 25‐item questionnaire with Likert‐type questions concerning the pandemic’s impact on caregiving, the emotional/cognitive health of the research participant, and willingness to participate in research. Data was collected in summer 2021, with responses focused on 3/2020‐3/2021. ADRC participants with CDR ≥ 1 and their caregivers were identified. Data was previously collected on 267 participants with CDR 0‐0.5.

Result

32 caregivers of research participants (50% adult children, 41% spouses, 9% other) completed the survey (15‐75 minutes). Participants were 59% female (mean age 80 and education 15y). 66% non‐Hispanic White, 13% non‐Hispanic Black, 19% Hispanic. Mean CDR SOB was 12±5. Demographics on the 267 normal/MCI participants not shown.

Caregivers (55%) felt “some‐extremely” isolated compared to 39% of CDR 0‐0.5 participants; mean caregiver isolation scores were 3.4/5 and 2.5/5 for those who cared for participants with CDR = 3 and 1‐2, respectively. Caregivers (91%) and participants (56%) found the pandemic “some‐extremely” disruptive; mean caregiver disruption scores were 4/5, 3.6/5 and 3.8/5 for those who cared for participants with CDR = 3, 2 and 1, respectively. Caregivers (63%) said that vaccination “very‐extremely” reduced caregiving stress. 41% endorsed “a lot” as to how challenging it was to ensure participants complied with COVID safety precautions. 47% felt that COVID “moderately‐severely” impacted the participant’s cognition. Caregivers’ biggest barriers were lack of access to day programs (31%), decreased support from family/friends (31%), and lack of in‐person medical care (25%). 42% of caregivers were “somewhat‐extremely” uncomfortable with in‐person research. Caregivers (63%) said that going forward, flexibility of in‐person vs. remote evaluations was “very‐extremely” important.

Conclusion

This diverse group of caregivers reported more isolation and disruption than CN/MCI participants, particularly with participants with CDR’s of 2‐3. Caregivers also expressed continued desire to participate in research. Research centers should be mindful of the impact of isolation, loss and stress (e.g. helping loved ones with cognitive impairment manage safety protocols). Increased social work services and prioritizing flexibility (e.g. telehealth) is key.
Increasing Asian Americans’ and Pacific Islanders’ representation in research: Updates from the CARE research recruitment registry
Authors: Park Van Ta , Meyer Oanh L. , Tsoh Janice Y. , Nam Bora , Tzuang Marian , Vuong Quyen , Chun Heather , Hinton Ladson , Gallagher‐Thompson Dolores , Kanaya Alka , Grill Joshua D.
Published: June 2023

Background

The underrepresentation of Asian Americans and Pacific Islanders (AAPIs) in Alzheimer’s disease and related dementias (ADRD) research is a significant concern given that they are the fastest growing racial group in the US. The Collaborative Approach for AAPIs Research and Education (CARE) research recruitment registry is a collaboration among multiple academic and community partners aimed at creating a sustainable research recruitment source.

Methods

Between October 15, 2020 and January 17, 2022, 7,455 AAPIs enrolled in the CARE registry. The enrollment survey and outreach materials are available in 7 languages: English, Chinese (Simplified/Traditional), Hindi, Korean, Samoan, and Vietnamese. With input from CARE’s community advisory board, CARE was strategically promoted with a focus on health research across the lifespan, including ADRD. Participants can enroll online, by phone, or in‐person. A protocol for CARE‐supported recruitment requests was developed and was presented at four Brain Trust Meetings to promote CARE to the research community.

Results

The mean age of participants is 53.4 years, including 2,130 middle‐aged (50‐64 years old) and 2,373 older (≥65 years old) participants who may be targeted groups for ADRD research. Overall, 11% (n = 819) reported having ADRD (mean age = 62.8; SD = 15.2). Among the 810 caregivers (mean age = 51.2; SD = 14.6), 37% were ADRD caregivers. Most participants who had self‐reported ADRD (96.2%) and caregivers (78%) were foreign‐born. Most participants with ADRD were Vietnamese (83.6%), followed by Chinese (12.5%). The major cultural groups among ADRD caregivers were Chinese (47.7%), Vietnamese (29%), Korean (10%), Asian Indian (7.7%), and Japanese (7%). Participants from several AAPI cultural groups were smaller in numbers (e.g., Filipino, Native Hawaiians and Pacific Islanders), however, we anticipate they will grow following targeted outreach efforts. Of the 32 recruitment referral requests, 21 were aging‐related, including 18 ADRD or ADRD‐caregiving studies. 798 CARE participants had been referred to participate in 20 requesting studies.

Conclusions

CARE has successfully recruited over 7,400 participants despite limitations to conduct in‐person outreach during the COVID‐19 pandemic. The registry is poised to be a valuable recruitment source and a resource for fostering meaningful engagement of AAPIs in ADRD‐related research.
The impact of version update of an automated brain volumetry software: Possibility of mixed use and repeatability of clinical findings
Authors: Zhao Lei , Luo Yishan , Mok Vincent C.T. , Shi Lin ,   the Alzheimer Disease Neuroimaging Initiative
Published: June 2023

Background

As a tool of automated brain volumetry, AccuBrain has been widely used to identify brain structural changes in different neurological diseases with the older version (IV1.2). As AccuBrain underwent a substantial revision update (IV2.0) for segmentation algorithms recently, a comparison of the two versions would be necessary to identify and characterize any differences that could affect the interpretation and clinical translation of the older research findings.

Method

We included 200 Alzheimer’s disease (AD) patients (75.3±7.6 years old, 44.0% women) and 200 normal control (NC) subjects (75.2±5.6 years old, 41.5% women) with 3D T1‐weighted scans processed with AccuBrain IV1.2 and IV2.0. To measure the volumetric difference or agreement of the two versions, we calculated the mean relative absolute error (MRAE, i.e., the mean of |(V2‐V1)/V1| for each volumetric measure) and intraclass correlation coefficient (ICC) between two versions regarding the volumes of typical brain structures, lobar atrophy indices and the quantitative medial temporal lobe atrophy (QMTA) score. In addition, we investigated the difference of the two versions regarding volumetric associations with age using ANCOVA, with the volumetric measures as the dependent variable, the version as fixed variable and age as the covariate. An interaction term between version and age was additionally included in the model to determine whether these two versions were statistically different in this respect.

Result

The ICC between the volumetric measures of the two versions were >0.85 for absolute volumes of typical brain structures (e.g., hippocampus) and >0.60 for lobar atrophy indices and QMTA (Table 1), indicating moderate to good agreement between versions. Furthermore, the MRAE indicated substantial difference between versions with >5% for half of the measures, and >10% for QMTA and most lobar atrophy indices, where the MRAE was slightly larger in AD than NC. There were no significant differences between versions regarding their volumetric associations with age (Table 2) for either NC or AD group (regression lines shown for NC in Figure 1∼2).

Conclusion

The two versions of AccuBrain are not suggested for a mixed use. Previous research findings with older version may be repeatable with the new version of AccuBrain.
Resting‐State Connectivity Changes in Older Adults with Sleep Disturbance
Authors: Kim Hyun , Zhu Xi , Zhao Yiming , Bell Sophie A. , Cohen Daniel E. , Lee Seonjoo , Goldberg Terry E.
Published: June 2023

Background

Sleep and related disorders could lead to changes in various brain network connectivities, but little is known about the role of Aβ burden—a key Alzheimer’s disease (AD) biomarker—in the relationship between sleep disturbance and altered functional connectivity in older adults. This study examined the association between sleep disturbance, Aβ positivity, and with‐in and between resting‐state functional connectivity networks using a large‐scale dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Method

Sample was consisted of 413 individuals (mean age 76.56±7.20; 57.5% cognitively normal, 30.3% mild cognitive impairment, and 12.1% AD) who had completed sleep measures (Neuropsychiatric Inventory), CSF‐Aβ42 data, and resting‐state fMRI scans at baseline. Functional connectivity within Salience (SN), Default Mode (DMN) and Frontal Parietal networks (FPN) were compared between participants with sleep disturbance versus without sleep disturbance. The interaction between Aβ positivity and sleep disturbance were evaluated controlling for age, diagnosis status, gender, sedatives and hypnotics use, and hypertension.

Result

Sleep disturbance was associated with reduced connectivity in the SN (β = 0.04, P = 0.006) but not with DMN or FPN. Additionally, sleep disturbance interacted significantly with Aβ positivity in altered with‐in connectivity of SN (β = 0.10, P = 0.003), DMN (β = 0.07, P = 0.0048), and FPN (β = 0.09, P = 0.03) networks.

Conclusion

Sleep disturbance may lead to altered connectivity in the SN and further change various within and between functional networks in the presence of amyloid burden.
‘Some dance to remember’: Exploring the introduction of an adaptive Irish Céilí dance programme for people living with dementia and their carers in Ireland
Authors: Stritch Jennifer Moran , McKenna Carmel ,   Loss and Grief Research Group at TUS
Published: June 2023

Background

This presentation reflects on a two‐year interdisciplinary arts‐based Masters by Research project which explored the psychosocial effects of a pilot adaptive Irish Céilí dance programme for people living with dementia and their carers. The Céilí dance activity was adapted to reflect participants’ levels of mobility, agility, ability, and cognitive skills.

Method

Between October 2019 and February 2020 field work involving people living with dementia and professional carers was conducted in a day care/respite centre based in the mid‐west region of Ireland. A phenomenological approach was adopted to investigate the lived experience of participants. Semi‐structured interviews with people living with dementia and professional care staff were conducted before, during and after the dance programme. All interviews were transcribed, and a thematic analysis lens applied to the data to facilitate analysis of emerging themes, commonalities and differences.

Result

Key research themes include: enhanced reminiscence for the participant living with dementia, a greater sense of inclusion, and authentic mutual connectivity for both people with dementia and their carers who took part in the dance activity.

Conclusion

An adaptive Irish Céilí dance programme can enhance the quality of life for people living with dementia and care staff. The research suggests that this dance programme warrants expansion to other dementia care facilities throughout Ireland and potentially internationally in areas with significant Irish cultural connections.
Discordance in treatment effects on clinical and imaging outcomes in recently published amyloid removing trials
Authors: Kate Mara ten , Barkhof Frederik , Schwarz Adam J.
Published: June 2023

Background

Longitudinal changes in volumetric MRI (vMRI) are correlated with longitudinal changes in cognition and function in subjects with Alzheimer’s disease (AD). In clinical trials, vMRI has been used as an exploratory outcome measure with the assumption that an effective treatment would slow down brain atrophy, in addition to slowing down cognitive decline. We have recently shown that in clinical AD trials published up to November 2020, treatment effects on clinical outcomes were associated with treatment effects on vMRI measures1. Here, we assess these relationships in three more recently published trials (Donanemab2, Lecanemab3, Lanabecestat4,5), and compared it to our previous findings.

Method

Treatment effects were computed as the percent slowing in change from baseline in the active group relative to the control group for clinical (ADAS‐Cog, MMSE, CDR‐SB) and imaging (whole brain volume [WBV], ventricular volume [VV], hippocampal volume [HV]) outcomes. We assessed the concordance in directionality and magnitude of treatment effects between variables.

Result

In trials published up to November 2020, treatment effects on ADAS‐Cog and CDR‐SB were directionally concordant and significantly associated with treatment effects on WBV and VV. The trials with Donanemab and Lecanemab, amyloid‐removing antibodies, showed a clear discordance between treatment effects on all three cognitive scales and global brain atrophy (WBV and VV), with decreased cognitive decline being accompanied by an increase in atrophy (illustrated for ADAS‐Cog and WBV in Figure 1). In contrast, results from the trials with Lanabecestat, a BACE inhibitor, were more consistent with the historical relationship.

Conclusion

Both Donanemab and Lecanemab, two monoclonal antibodies with amyloid‐removal properties, showed a discrepancy in treatment effects on cognition and brain atrophy. Possibly, the atrophy reflects acute reductions in brain volume related to the removal of amyloid from the brain (“pseudo‐atrophy”). Further regional analyses and follow‐up imaging studies may help elucidate the mechanism and temporal evolution.

References:

1. Ten Kate M et al., submitted

2. Mintun MA et al. N Engl J Med 2021;384:1691:

3. Swanson CJ et al. Alzheimers Res Ther 2021;13:80.

4. Zimmer JA et al. Alzheimers Dement 2021;7:e12123:

5. Wessels AM et al. JAMA Neurol 2020; 77(2):199
Understanding the impact of social stigma on the patient journey in Alzheimer’s disease through social media narratives
Authors: Monfared Amir Abbas Tahami , Stern Yaakov , Doogan Stephen , Farid Nardin , Karahan Esra , Zhang Quanwu
Published: June 2023

Background

Patients living with Alzheimer’s disease (AD) and their caregivers/health care providers (HCP) recognize the importance of social stigma; however, traditional surveys do not capture nuances of experienced stigma. We sought to systematically study stigma in AD using social media narratives.

Method

Online narratives posted by patients with AD, caregivers, and HCPs (ie, stakeholders) were collected from 84 public social media sites from 1998‐2021. Using RLS Reveal’s Natural Language Processing (NLP) platform, we identified stakeholder narratives containing ‘stigma’‐related terms. NLP algorithms and manual curation, alongside subject matter expert review, were used to analyze the narratives. Data were examined by stages of the patient journey: pre‐diagnosis, diagnosis, and post‐diagnosis.

Result

A total of 112,464 online narratives from AD stakeholders were screened; 4,392 (4%) that specifically mentioned stigma‐related terms were identified and are the focus of this analysis. Most narratives were by caregivers (n = 1917), followed by patients (n = 342) and HCP (n = 306). The majority of narratives (n = 3968; 90.3%) were in the post‐diagnosis phase of the patient journey, followed by diagnosis (n = 304; 6.9%), and pre‐diagnosis (n = 120; 2.7%). In the pre‐diagnosis phase, 78% of the narratives were posted by caregivers, 11% by HCPs, and 11% by patients. Lack of support was the most common theme identified in 73/120 (60.8%) of pre‐diagnosis narratives – mostly by caregivers (38/73; 52.1%). During the diagnosis phase, 47% of the narratives were posted by caregivers, 28% by HCPs, and 25% by patients. A feeling that support/advocacy is lacking was a common theme, and identified in 128/304 (42.1%) of the diagnosis phase narratives. In the post‐diagnosis phase, 78% of the narratives were posted by caregivers, 10% by HCPs, and 12% by patients; the fear/worry caused by stigma was the most common theme and identified in 2467/3968 (62.2%) of these narratives. In addition, stakeholders discussed the feeling of shame related to the AD diagnosis – a theme identified in 1,017/3,968 (25.6%) of post‐diagnosis narratives.

Conclusion

We found that social media narratives by various AD stakeholders identified a negative impact of stigma throughout the patient journey.
Assessment of myelin in Alzheimer’s by a R1 and the relationship to amyloid burden
Authors: Bolaños Alfredo D , Kohli Akshay , Kecskemeti Steven R , Alexander Andrew L , Betthauser Tobey J , Pasquesi Mary‐Elizabeth , Nair Veena A. , Prabhakaran Vivek , Li Shi‐Jiang , Bendlin Barbara B
Published: June 2023

Background

Alzheimer’s disease (AD) is well known as a grey matter disorder, characterized by substantial and progressive neurodegeneration. However, less is known about myelin loss in AD, particularly as the disease progresses in severity. To gain a better insight on the role of myelin over the clinical and biologic progression of AD, we tested for differences in quantitative relaxometry R1, a metric sensitive to brain myelin, among individuals who were cognitively unimpaired (CU), diagnosed with mild cognitive impairment (MCI), and diagnosed with AD, in addition to testing for associations between R1 and amyloid PET. Understanding the course of myelin injury in disease progression is expected to address the gap in knowledge about the trajectory of myelin alterations in AD.

Methods

Participants from the Alzheimer’s Disease Connectome Project underwent T1‐weighted (T1w) MPnRAGE with motion‐correction and amyloid imaging with [11C]PiB PET. Composite T1w images and R1 maps were reconstructed at 1mm isotropic resolution. T1w scans were bias‐field corrected and denoised before undergoing tissue segmentation. R1 was sampled and bilaterally averaged across cortical‐adjacent white matter (WM). An average WM‐R1 was generated for each participant by calculating the mean of cortical regions R1. MANOVA and regression analyses were used to analyze the difference and relationship between each group’s WM‐R1 and PiB‐Index.

Result

The three groups showed an association with PiB‐Index and WM‐R1, Pillai’s Trace = 0.28, F(4, 110) = 4.56, p<0.01. Participants with AD showed higher amyloid and lower WM‐R1. In contrast, UC and MCI participants showed lower amyloid and WM‐R1. A significant correlation was found in individuals with AD wherein amyloid burden was positively correlated with WM‐R1 across the whole brain, R2 = 0.64, F(1, 6) = 10.99, p = 0.016.

Conclusion

Our findings indicate myelin differences by clinical status, in addition to relationships between amyloid and R1 indices of myelin. While AD was associated with lower myelin as indexed by R1, we unexpectedly found that higher cortical amyloid in AD was associated with higher myelin indexed by R1, suggesting an increase in myelination as AD progresses. Overall, lower myelin in clinical AD, accompanied by the higher myelin with greater amyloid burden suggests possible reparative mechanisms in response to neurodegeneration in AD.
A machine learning‐based multiple imputation method for the health and aging brain among latino elders study
Authors: Zhang Fan , Petersen Melissa , Johnson Leigh , Hall James , O'Bryant Sid E.
Published: June 2023

Background

The Health and Aging Brain among Latino Elders Study (HABLE) project seeks to understand the biological, social and environmental factors that impact brain aging among diverse communities. HABLE, like many other NIH funded data‐sharing projects, has important data assets for various uses, including social, environmental and behavioral data, and multiple data flow pathways. A common methodological issue for data collection in such a large survey‐based, behavior, behavioral, or environmental epidemiology study is missing data. It is impossible to achieve machine learning (ML) if data contains missing values. Therefore, developing new imputation methodology has become a very urgent task for HABLE.

Method

In this study, we developed a ML‐Based Multiple Imputation method. First, we built four ML‐Based Imputation models (Support Vector Machine (SVM), Random Forest (RF), eXtreme Gradient Boosting (XGB) and lasso and elastic‐net regularized Generalized Linear Model (GLMNET)). Then we adapted the above four ML‐Based methods to multiple imputation. Lastly, we evaluated our ML‐Based Multiple Imputation method in comparison with lowest of detection (LOD), random drawing from a lef‐censored normal distribution (ND), k‐nearest neighbors (kNN), local least squares (LLS), and random forest (RF), Singular value decomposition (SVD), Bayesian principal component analysis (BPCA).

Result

Our results show that ML‐Based Multiple Imputation method can have lower Normalized Root Mean Square Error (NRMSE) in missing value imputation and higer prediciton performance in machine learning.

Conclusion

The choice of missing handling methodology has a significant impact on the accompanying statistical analyses of alzheimer’s disease. The Machine Learning‐Based Multiple Imputation Method performs well for our alzheimer’s disease models. It can also be applied to other disease data analysis.
Estimating bidirectional transition and post‐reversion of mild cognitive impairment
Authors: Qin Yao , Yu Hongmei
Published: June 2023

Background

The natural trajectory of reversion from MCI to normal cognition (NC) and the cognitive pattern post‐reversion have been poorly explored in the existing literature. The main goals of this study were as follows: (1) to quantitatively predict bidirectional transitions of MCI (reversion to NC and progression to dementia); (2) to explore patterns of future cognitive changes post‐reversion; and (3) to estimate the effects of selected covariates on transition probabilities in the course of cognitive loss.

Method

The National Alzheimer’s Coordinating Center database was funded by a National Institute on Aging/National Institutes of Health grant (U24 AG072122). Data for this study comprised 24,220 observations from 6,651 participants with an MCI diagnosis at study entry during at least two visits between June 2005 and February 2021. Defining NC and MCI as transient states and dementia as an absorbing state, we explored the fate of MCI and future cognitive changes post‐reversion using the continuous‐time, multi‐state Markov model, which provides information on the transition probability between multiple states, hazard ratio, mean sojourn time, and total length of stay over 15 years.

Result

Transition intensity of re‐progression to MCI for post‐reversion was 0.3168, 2.48 times greater than the progression from MCI to dementia or reversion from MCI to NC. For the post‐reversion participants, the chance of progressing to dementia increased by 2% per year. participants who re‐progressed to MCI had an approximately 40% probability of reversing to NC again over the 15‐year period. participants stayed in the post‐reversion NC state for 3.2667 years (range 2.9349–3.6360) and in the MCI state for 1.7605 years (range 1.5134–2.0480) before progressing to dementia. Age, cognitive function, daily activity ability, and depressive symptoms were significant predictors of progression to dementia.

Conclusion

There were distinct transition dynamics between amnesic MCI (aMCI) and nonamnesic (naMCI). The post‐reversion participants remained at increased risk of re‐progression to MCI or progression to dementia in the long term. Findings in this study can serve as valuable references for relevant research and healthcare professionals to help understand the natural history of cognitive loss and create proactive plans and targeted interventions.
Positive effect of moderate alcohol intake for AD
Authors: Wu Xinxing , Nelson Peter T , Cheng Qiang
Published: June 2023

Background

Alzheimer’s disease (AD) is one most common forms of dementia, and it slowly gets worse over time and progresses at different rates. At present, the factors affecting AD are largely unclear. Finding effective ways to prevent and lower the potential risk of dementia is important and necessary.

Method

First, we adopted the statistical method, chi‐square test, to analyze alcohol factors differentiating subjects with AD from Control with healthy cognition, as well as the relationship between alcohol intake and APOE, on a large‐scale data, National Alzheimer’s Coordinating Center (NACC); then, we used logistic regression analysis to analyze the factorsincluding APOE e4 carrier and alcohol intake‐related variables for the group of Control and AD; further, we used another dementia, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which was a recently defined common neurodegenerative disease mimicking the clinical symptoms of AD to do an adjusted analysis. The rules used to label subjects on NACC were given in Table 1.

Result

We focused on the association analysis of five alcohol intake‐related variables, including ALCOHOL, ALCOCCAS, ALCFREQ, ALCDEM, and ALCDEMIF, with APOE and AD on NACC (a detailed description of these variables and their corresponding demographics were given in Table 2). We found that there existed significant associations of alcohol‐related variables, such as ALCDEM and ALCDEMIF, with AD and APOE, respectively (see Tables 3 and 4); further, considering APOE as a potential covariable with alcohol‐related variables, we analyzed their association with AD subpopulation and control subpopulation, and discovered that APOE aggravated AD, while moderate alcohol intake had a potentially positive effect on AD (see Table 5). Also, we performed adjustment analysis by LATE and noted that the relationship between AD and alcohol intake was closer than that between LATE and alcohol intake (see Table 6).

Conclusion

We discovered that moderate alcohol intake positively affected AD, and was much more obvious than LATE. Our study will potentially contribute to understanding the different alcohol factors of AD (or LATE) and support the development of effective intervention strategies for AD.
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

Background

Allelic 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.

Method

Ferroptosis 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.

Result

We 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.

Conclusion

We 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

Background

Some 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).

Method

The 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.

Result

Mean 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).

Conclusion

Our 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

Background

Dysfunction 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.

Method

Volumetric 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).

Result

In 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.

Conclusion

These 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

Background

Alzheimer’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.

Method

This 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).

Result

Higher 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).

Conclusion

The 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

Background

In 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.

Method

Assessment 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.

Result

To 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).

Conclusion

Low 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

Background

Alzheimer’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.

Methods

Participants 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).

Results

We 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.

Conclusion

The 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

Background

The 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).

Method

We 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.

Result

The 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.

Conclusion

The 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

Background

It 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.

Method

Stem 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.

Result

Proportions 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.

Conclusion

This 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.