bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher plasma antioxidant nutrient levels associated with slower cognitive decline among individuals with APOE‐e4: an investigation of the MIND trial
Authors: Liu Xiaoran , Rajan Kumar B , Beck Todd , Tangney Christy C , Dhana Klodian , Willett Walter C. , Aggarwal Neelum T. , Sacks Frank , Barnes Lisa L. 
Published: January 2025

AbstractBackgroundObservational studies have shown a protective association between antioxidant nutrients and lower risk of Alzheimer’s disease. Results from dietary intervention trials remain inconclusive. The effect of APOE‐e4, the strongest risk factor for AD, on responsiveness to dietary interventions remains largely uninvestigated. We examined whether the association of plasma nutrient levels and changes in global cognition over three years differed by the APOE‐e4 allele among MIND trial participants.MethodThe study included 601 participants from the MIND trial with APOE‐e4 genotype. Plasma nutrients were analyzed using HPLC at Harvard School of Public Health. Cognitive function was evaluated with a 12‐test battery from which a composite of global cognition was derived. Mixed‐effect regression model was used to examine the association of plasma nutrient levels, the APOE‐e4 allele and cognitive decline.ResultThe mean age was 70.4 years for the 428 APOE‐e4 non‐carriers and 69.8 years for the 174 carriers (p = 0.08) (Table 1). Among APOE‐e4 carriers, individuals in the highest tertile of lutein and zeaxanthin, alpha‐carotene, and beta‐carotene had a significantly slower cognitive decline by 0.16 standardized unit (SU) [SE = 0.07, p = 0.03], 0.16 SU [SE = 0.07, p = 0.02], and 0.18 SU [SE = 0.07, p = 0.01], respectively, when compared with the lowest tertile (Figure 1). Among APOE‐e4 carriers, individuals in both the moderate and the highest tertiles of lycopene (0.24 ± 0.07, p = 0.001, 0.19 ± 0.07, p = 0.01) and beta‐cryptoxanthin (0.26 ± 0.07, p = 0.000, 0.20 ± 0.07, p = 0.01) had slower cognitive decline than those in the lowest tertileAmong APOE‐e4 non‐carriers, there was no association, except individuals in the moderate tertile of lutein and zeaxanthin which showed slower declines (0.08 ± 0.04, p = 0.04) compared to the lowest tertile.When comparing APOE‐e4 carriers and non‐carriers at high plasma levels (75th percentile) of alpha‐tocopherol, lutein and zeaxanthin, beta‐carotene, lycopene, and beta‐cryptoxanthin, APOE‐e4 carriers had slower global cognitive decline ranging from 4.7% to 21% (p<0.05 for all).ConclusionHigher plasma antioxidant nutrients were associated with significantly slower cognitive decline among APOE‐e4 carriers in the MIND trial participants, suggesting the potential effects of antioxidant nutrients in mitigating the genetic risk posed by APOE‐e4.
Mechanisms by which varicella zoster virus contributes to Alzheimer’s disease pathologies
Authors: Nagel Maria A. , Bubak Andrew N. , Mueller Niklaus H. , Niemeyer Christy S. , Mahalingam Ravi 
Published: January 2025

AbstractBackgroundVaricella zoster virus (VZV) reactivation, manifesting as herpes zoster, increases dementia risk. Herein, we review the literature supporting the biological plausibility of VZV contributing to AD pathologies and examine the unique ability of VZV to induce amylin that has been found in blood vessels and parenchyma of AD patients.MethodWe conducted a literature review on VZV and dementia to elucidate a potential model for how VZV reactivation intersects with AD. Further, we cloned the human amylin promoter into a luciferase reporter plasmid that was transfected into primary human brain vascular adventitial fibroblasts. Cells were then infected with multiple strains of VZV (Gilden, vOka) and HSV‐1 (McKrae, Kos) or transfected with plasmids expressing individual VZV or HSV‐1 proteins. Luciferase activity was subsequently measured.ResultAfter reactivation, VZV has been shown to infect cerebral arteries, produce a similar spectrum of cerebrovascular disease (VZV vasculopathy) similar to that seen in AD, and cause long‐lasting cognitive impairment. Importantly, we found VZV‐infected primary human brain vascular adventitial fibroblasts (HBVAFs) contain intracellular amyloidogenic peptides seen in AD plaques (amyloid‐beta (Ab)‐42, amylin) and amyloid; RNA sequencing showed enrichment of pathways of amyloidosis/AD, with upstream regulators amyloid precursor protein (APP), apolipoprotein E, microtubule‐associated protein tau, presenilin 1, and amylin (IAPP). VZV vasculopathy patient cerebrospinal fluid (CSF) is amyloidogenic, has elevated amyloid and amylin (correlating with anti‐VZV antibody titers), and decreased Ab‐40 that is seen in cerebral amyloid angiopathy (CAA). VZV antigen/DNA co‐localized with amyloid‐containing arteries in select CAA cases. Finally, we found that VZV infection, but not HSV‐1 infection, induces luciferase activity from the amylin promoter and identified a specific immediate early VZV protein that was sufficient to activate the amylin promoter.ConclusionOur studies support the notion that VZV may contribute to AD progression, in part through infection of cerebral arteries, that leads to amylin expression and amyloid deposition. This VZV vasculopathy likely accounts for a subset, if not all, CAA seen in AD brains and is consistent with a previous study linking VZV to vascular dementia.
Advancing a Digital Health Ethics Framework for AD/ADRD
Authors: Largent Emily A. , Karlawish Jason , Wexler Anna 
Published: January 2025

AbstractBackground“Digital health” is a broad term that encompasses a heterogeneous set of scientific concepts and technologies. While digital health tools have the potential to contribute to better health and health care for individuals and communities, they also pose ethical challenges – particularly in the context of Alzheimer’s Disease and Alzheimer’s Disease and Related Dementias (AD/ADRD). There is no single established ethical framework, however, to aid individuals in evaluating the ethical dimensions of digital health tools in the context of AD/ADRD. To advance the development of an ethical framework, we draw on our experiences with the Penn Artificial Intelligence and Technology (PennAITech) Collaboratory for Healthy Aging, which assists in the identification, development, and dissemination of innovative technologies and artificial intelligence methods to support older adults, including those with AD/ADRD in their home environment.MethodsWe employed two primary methods to assist with the development of our framework. First, we reflected on consultations with product developers that we conducted in our roles as leads of the PennAITech Ethics and Policy Core. The Core seeks to identify and address real‐world ethical, regulatory, and policy issues that arise at the intersection of aging, AI, and digital health through consultations. Second, we reviewed the relevant clinical, scientific, ethics, law, and policy literature to identify and characterize enduring and emerging issues.ResultsWe will present our framework for digital health ethics in the context of AD/ADRD and use real world examples to identify and characterize a core set of ethical considerations that cut across many types of digital health tools. These include: assessing and addressing bias; considering risk‐benefit tradeoffs; protecting user privacy; considering environmental impact; measuring value along technical, clinical, usability, and cost dimensions; educating users; and promoting equitable access. For each issue, we also identify potential means of addressing these challenges.ConclusionWidespread adoption of digital health tools has the potential to improve health and health care for individuals, caregivers, and communities affected by AD/ADRD, but realizing this potential requires anticipating and addressing ethical challenges.
Assessment of the brain metabolome following innate immunity stimulation in a non‐human primate model of sporadic CAA
Authors: Patel Akash G , Soliman Muhammad T , Ficaro Lia , Nehete Bharti P , Karimi Sohail , Wang Fengzhu , Kim Hakyoung , Williams Lawrence E , Nehete Pramod N , Jones Drew R. , Wisniewski Thomas , Scholtzova Henrieta 
Published: January 2025

AbstractBackgroundNon‐human primates (NHP) serve as an important bridge for testing therapeutic agents that have been previously shown to be effective in transgenic mouse models. Our earlier published data using an NHP model of sporadic AD‐related pathology that develops abundant cerebral amyloid angiopathy (CAA), squirrel monkeys (SQMs), indicates that chronic treatment with TLR9 agonist, class B CpG ODN, safely ameliorates CAA while promoting cognitive benefits. In the present study, we intended to delineate alterations in brain metabolome induced by chronic CpG ODN administration in order to provide further insight into CpG ODN immunomodulatory capabilities.MethodGlobal metabolomics analysis by HILIC‐LC‐MS was performed on frontal cortex tissue dissected from geriatric SQMs one month after the final CpG ODN or Vehicle (saline) injection. Tandem spectral (MS2) data was searched against the NIST/METLIN libraries for compound identification. Metabolite peak intensities were used for differential metabolite expression (p<0.05) and pathway analysis was performed using Metaboanalyst 5.0.ResultDifferential metabolomics analyses revealed 151 putatively identified metabolites that were significantly altered in the brains of CpG ODN‐treated SQMs. Amino acids were the largest group of metabolites altered, with decreased levels in the CpG ODN group compared to the saline controls. ROC analyses identified several metabolites strongly associated with CpG ODN treatment, including amino acids such as proline and branched chain amino acids valine, leucine, and isoleucine. Furthermore, trimethylamine N‐oxide, a gut microbiome‐derived metabolite previously implicated in AD, was the most downregulated metabolite in the brains of CpG ODN monkeys relative to saline controls. Enrichment analysis identified significantly altered pathways including: “Aminoacyl‐tRNA biosynthesis”, “Valine, leucine and isoleucine biosynthesis”, and “Arginine biosynthesis.”ConclusionOverall, the brain metabolome in an NHP model of naturally occurring CAA pathology was assessed for the first time. We observed decreased levels of several AD‐associated metabolites. These findings further develop our novel concept of immunomodulation in order to provide essential preclinical evidence for CpG ODN use as an effective drug for AD.
Key issues in recruitment for minority aging research in humanitarian settings
Authors: Pirela‐Mavarez Rosa P. , Xu Chun , Terwilliger Joseph D. , Garza Noe , Reyes Roberto , Oropeza Omar , Manusov Eron Grant , Maestre Cristian A. , Alliey‐Rodriguez Ney , Mejia‐Arango Silvia , Melgarejo Jesus D , Parker Cynthia De La Garza‐ , de Erausquin Gabriel A. , Gil Mario , Escobar Romeo , Patel Neela K. , Seshadri Sudha , Maestre Gladys E. 
Published: January 2025

AbstractBackgroundThe increasing number of natural disasters and wars will result in complex emergencies affecting how individuals age. Additionally, the continued complex crises in certain areas of the globe exacerbates risks for chronic health conditions and poverty. Implementing ethical and community‐engaged research in these complex humanitarian settings requires tailored approaches. The South Texas Alzheimer’s Disease Research Center and the Rio Grande Valley Alzheimer’s Disease Resource Center for Minority Aging Research have adopted the humanitarian lens perspective deployed in the Maracaibo Aging Study in Venezuela to promote the recruitment and retention of older adults and their care partners in the Texas/Mexico border. Our objective is to identify and share key issues in recruitment for aging research in a complex humanitarian setting.MethodListening sessions, focus groups, and interviews were carried out to understand barriers, facilitators, beliefs, and preferences of older adults, care partners of people living with dementia, promotoras/community health workers, family physicians, and community‐based organizations to understand their expectations better. Elements of the humanitarian framework and capacity building were informed by the qualitative data and guidance from a senior coalition.ResultLocated in the Texas/Mexico border, the Rio Grande Valley constitutes one of the most impoverished areas in the nation. Competing needs, lack of incentives for participation in research, and fear associated with increasing health care costs were the most frequently cited barriers among residents. We decided to implement several aspects of humanitarian work that were related to efficient research and as a response to community expectations. Advocacy for integrating services into primary and community care was supported through staff training, task‐sharing, and establishing referral and follow‐up mechanisms. Diversifying the research workforce with bilingual and multicultural junior investigators and promotoras further addressed the cultural fluidity. As a result, a research registry of over 400 individuals was built, and more than 400 have participated in different aging studies.ConclusionHumanitarian settings in high‐income and low‐and middle‐income countries share many implementation needs, including scaling up efforts and tackling multiple challenges simultaneously. Community‐engaged aging research in humanitarian settings requires consideration and assessment of evidence‐based planning and execution and impact evaluation.
Ola Mau I Ka Hula: An Intervention Approach Strategy
Authors: Antonio Ke'alohilani Worthington 
Published: January 2025

AbstractThe prevalence of Alzheimer’s disease and related dementias (ADRD) is rising in Hawai`i, where it is projected that 10% of people aged 65+ will be diagnosed with ADRD by 2025. Nationwide, Native Hawaiians and Pacific Islanders (NHPIs) are more likely to have early‐onset ADRD than Whites, Asians, and African Americans. Contributing factors to this are that NHPIs have a higher prevalence of hypertension, obesity, diabetes, and dyslipidemia than other US racial and ethnic groups, which increase the likelihood of ADRD.Ola Mau I Ka Hula is an intervention program being implemented by the Natives Engaged in Alzheimerʻs Research (NEAR): IKE Kupuna Project. This program is the successor to Ola Hou I Ka Hula, the intervention program for the KāHOLO Project that focused on cardiovascular risk factors in Native Hawaiian populations. This culturally‐grounded approach centers on the use of hula and lifestyle interventions to mitigate the vascular risk factors that increase the risk for mild cognitive impairment (MCI) and subjective cognitive impariment (SCI), and subsequently also ADRD. Factors such as socialization, physical activity, and learning a language are known to improve risk for ADRD. By design, hula targets multiple risk factors for ADRD and incorporates these risk reducers with a cultural twist.This approach focuses on building on previous clinical trials and interweaving those interventions, which includes the PILI Lifestyle Program (PLP) and the KāHOLO Project. The melding the culturally‐informed components of traditional hula classes, lifestyle intervention classwork, and cultural classes teaching traditional crafts and knowledge. Community members and hula experts were consulted to adapt and strengthen the intervention strategy and the various curriculum components. The intervention was further adjusted depending on each partnering communityʻs available resources in order to ensure the sustainability of the program.
Stories of Trauma and Strength Among Aging Vietnamese Americans: Qualitative Findings from the Vietnamese Insights into Cognitive Aging Program
Authors: Vu Uyen TM , Farias Sarah Tomaszewski , Hinton Ladson , Park Van Ta , Tiet Quyen Q , Whitmer Rachel A. , Meyer Oanh L. 
Published: January 2025

AbstractBackgroundPrevious research demonstrates that stress and trauma are associated with poor health and increased dementia risk, but this is mostly based on studies of non‐Hispanic Whites. This descriptive analysis delineated the war‐related adversity and trauma in participants of the Vietnamese Insights into Cognitive Aging Program (VIP) study, a new cohort of cognitive aging in Vietnamese individuals in Northern California.MethodVIP is a longitudinal study of 548 Vietnamese Americans aged 65+ years living in Northern California who are seen annually at either research site for three years. During visit 1, a short (15‐20 minutes) semi‐structured interview was conducted with all consented participants about their life and experiences in Vietnam and their immigration to the United States. Using the early life trauma data collected at visit 1 at the Sacramento site, we calculated a total trauma exposure count for all 274 participants and selected out individuals with the highest self‐reported traumas (i.e., top one‐third, see Table 1 for listing of traumas and Table 2 for the frequency distribution of total traumas). We then pulled out the interview data for participants who had consented to be audio‐recorded, whose recordings were of good quality, and whose interviews had been transcribed verbatim. A total of 35 interviews were included in this analysis. Six transcripts were coded independently by two authors until agreement was reached. A codebook was developed, and the remaining transcripts coded and analyzed by the lead author.ResultThe 35 participants had a mean age of 73 years (SD = 5.57). Most were male (71.4%). Forty percent finished high school; 34% had at least a primary school education, and 26% had at least some college. We found six major themes: (1) being imprisoned, (2) challenges after being released, (3) escaping Vietnam, (4) witnessing trauma, (5) experiences of loss, and (6) gratitude and grit (see Table 3).ConclusionResults from this study reveal traumatic events 35 individuals in the VIP at the Sacramento site were exposed to as well as their perseverance. Findings provide potential to explain the relationship between trauma/adversity and cognition and dementia risk that will be explored in future VIP research.
Personal risk perceptions for Alzheimer’s disease and dementia among older adults may not be grounded in knowledge
Authors: Jacova Claudia , Robertson Frank , Gehling Jacklyn , Marx Hannah , Dhaliwal Ravneet K. , Harris Steven 
Published: January 2025

AbstractBackgroundPublic interest in brain health has reached unprecedented levels, yet research on AD/dementia literacy has continued to reveal gaps and misconceptions, especially among those with lower education. The public’s knowledge has often been characterized as particularly weak around AD/dementia risk factors. Here we were interested in whether personal risk perceptions among dementia‐free community‐dwelling older adults are evidence‐based. We investigated whether risk endorsement was associated with the expected personal characteristics, for example increased endorsement of age‐related risk with older age or of diabetes‐related risk with poorer health.MethodWe recruited 279 community‐dwelling participants aged ≥60 years, free of neurocognitive diagnoses, and located within the United States (M age = 73.8, range 60‐96; M education (years) = 14.9, range 10‐20; 52% women). Participants completed an online survey through Qualtrics’ research panel teams where they indicated the factor/s (select all that apply) that contributed to their own risk for AD/dementia including demographic and modifiable factors. They also rated their general health on a 5‐point scale (excellent = 1 to bad = 5). We regressed endorsement (Y/N) of each risk factor on age, education, gender, and self‐rated health. We also summed endorsed risk factors and regressed this overall risk count on the four predictors.ResultRisk factors, from most to least endorsed, were age = 75.6%, physical inactivity = 34.4%; high blood pressure = 26.2%, smoking = 14.7%, diabetes = 14.0%, gender = 11.8%, and education = 5.4%. Overall risk count averaged M = 1.8 (range 0‐7) and self‐rated health averaged M = 2.2 (range 1‐4). Age, gender, and education did not predict endorsement of any risk factor, whereas lower self‐rated health predicted a higher likelihood of endorsing diabetes (OR = 1.6, CI 1.1 = 2.6) but not of any other risk factor. None of the predictors were associated with overall risk count. We examined the contribution of education further by including an education by age interaction term but found no significant relationships in these models either.ConclusionWe found that across educational groups, perceptions of personal risk for AD/dementia appear to be insufficiently grounded in knowledge. Our findings align with previous research highlighting the inadequacy of knowledge around AD/dementia risk factors and risk reduction among older adults. Future health education initiatives should specifically promote a nuanced understanding of risk factors.
Joint modelling of longitudinal AD cognitive markers and incident MCI/dementia quantifies the longitudinal cognitive—AD risk relationship
Authors: Aslanyan Vahan , Ortega Nancy E , Mack Wendy J , Pa Judy 
Published: January 2025

AbstractBackgroundRandomized clinical trials for AD increasingly use composite continuous cognitive endpoints to establish efficacy. While these endpoints provide necessary research and clinical evidence, they do not inform the potential impact on incident MCI/AD. Similarly, studies designed with disease progression as an endpoint fail to incorporate within‐person longitudinal cognitive and functional changes in assessment of disease risk, often relying on baseline measures only, or explore cognitive and functional performance change in separate analyses, independent of conversion. This study incorporates longitudinal change in cognition (measured by Preclinical Alzheimer’s Cognitive Composite (PACC)) and dementia severity (measured by Clinical Dementia Rating—sum of boxes (CDR‐SB)) to measure how longitudinal changes in cognition and function may relate to the risk of disease progression.MethodParticipants were selected from the Harvard Aging Brain Study, a longitudinal study collecting demographic, neuropsychological, and APOE genotyping outcomes. Longitudinal changes in CDR‐SB and PACC score were modelled jointly with conversion to MCI/dementia. All models were adjusted for baseline age, sex, education, and APOE‐e4 carrier status.Result287 participants (27 conversions to MCI/dementia, 59.1% women, baseline age = 73.7 years (SD = 6.2), 27.6% APOE‐e4+, education = 15.8 years (SD = 3.09)) collectively had 1511 observations over a median follow‐up of 2.2 years (range 0‐8.7 years).After adjusting for covariates, PACC score changed by ‐0.016/year (95%CI:(‐0.032, 0.000)) and was associated with hazard ratio (HR) = 1.0405 for progression (95%CI:(1.029,1.054). Survival analysis with baseline PACC score underestimated the association of PACC score and conversion (HR = 1.028 per ‐0.016 between‐individual difference in PACC score, 95% CI: (1.02,1.036)).Similarly, within‐individual CDR‐SB changed by 0.025/year (95%CI:(0.015,0.035)). This change corresponded to HR = 1.081 for progression (95%CI:(1.053,1.111)). Survival analysis with baseline CDR‐SB underestimated the association of CDR‐SB and rate of conversion to MCI/AD (HR = 1.057 per 0.025 between individual difference CDR‐SB, 95%CI:(1.042,1.073)).ConclusionThis study shows the joint effect of within‐individual longitudinal modelling of cognitive and functional performance with incident MCI/dementia. We show that modeling the baseline value only in analyses underestimates the association between cognition or function and risk of incident cognitive impairment. We conclude that longitudinal monitoring and assessment of cognition and function may result in more accurate estimates for risk. Future studies will pursue joint models that include fluid and imaging biomarkers.