bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling the complexities of educational and socioeconomic factors in cognitive decline with an AI model
Authors: Puentes Paola Ruiz , González Nestor , Crovo Daniel , Grimaldi Beatriz , Mukunda Ram
Published: January 2025

Background

High formal education level is widely recognized as a protective factor against cognitive decline, influenced by the reserve hypothesis. However, in multiple studies educational experience is confounded with cultural and socioeconomic factors, leading to contradictory findings. Factors such as an individual’s living environment, including socioeconomic conditions, rather than individual variables such as education, are hypothesized to be factors influencing cognitive decline. This study leverages data from the Mexican Health and Aging Study (MHAS) and the Mexican Cognitive Aging Ancillary Study (Mex‐Cog), which provide information on the living conditions of older adults and their cognitive status. Through artificial intelligence models, this research aims to provide a nuanced understanding of cognitive decline risk factors as it relates to educational and socioeconomic factors.

Methods

The Mexican Health and Aging Study (MHAS) provides national‐level data on individuals aged 50 and over across six waves from 2001 to 2021, including detailed cognitive assessments (Mex‐Cog) in 2016 and 2021. We trained a traditional machine learning and a deep learning algorithm, specifically a random forest and a transformer‐based model, to predict participants' Mini‐Mental State Examination (MMSE) scores. For this task we used a comprehensive dataset that includes historical and current data on demographics, health, health care utilization and insurance, cognition, financial and housing wealth, income, pension, family structure, employment, assistance and caregiving, stress and psychosocial scores, and end of life planning. We employed Shapley‐based analyses to identify the most influential factors and their interactions in the MMSE score predictions. We present our initial findings on factors influencing cognitive decline.

Results

Certain algorithms, especially random forests are superior to other algorithms that we tried to use. Our approach, while limited to the Mexican data, shows, for example, education plus income as a superior indicator of risk for cognitive decline than education alone.

Conclusion

Our model, with further analysis, has far‐reaching public policy implications. We continue to expand the algorithm to include multiple factors beyond education to assess risk of cognitive decline.
Free water and white matter hyperintensities volumes among diverse individuals aged 54 to 103
Authors: Posis Alexander Ivan B. , Maillard Pauline , George Kristen M. , Gilsanz Paola , DeCarli Charles S. , Corrada María M. , Whitmer Rachel A.
Published: January 2025

Background

Free water (FW) and white matter hyperintensities (WMH) are key biomarkers of white matter integrity yet are understudied in racially/ethnically diverse populations and those over age 80. We describe FW and WMH across age, sex, and education in a diverse cohort.

Method

Data were harmonized from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE; mean age = 78±6 years) Study, Study of Healthy Aging in African Americans (STAR; mean age = 69±9 years), and LifeAfter90 (LA90; mean age = 93±2 years) Study, which are ongoing cohorts of racially/ethnically diverse participants who are long‐term members of Kaiser Permanente Northern California. Participants received neuroimaging via 3T MRI, with harmonized protocols, to measure FW and WMH. WMH was log‐transformed and we calculated residual values accounting for total cranial volume. FW and WMH were described by decade of age at scan, gender, race/ethnicity, and education using mean, standard deviation, and range. Differences in FW and WMH by participant characteristics were tested using analysis of variance tests. We tested the interaction of race/ethnicity with each characteristic in relation to FW or WMH using separate linear regression models.

Result

In 840 participants, median age at imaging was 78 years (range = 54‐103). Fifty‐nine percent were women, 42.3% African American/Black, 18.1% Asian, 16.2% Hispanic/Latino, 21.4% White, and 2% Other. As age increased, FW and WMH increased (p<0.01; Table 1; Figure 1). Participants with ≤High School/GED education had greater FW and WMH. Asian participants had the highest overall mean WMH, followed by White and Hispanic/Latino (p<0.01). However, African American/Black participants generally had greater mean WMH when examined across decade of age at scan (Figure 2). The interaction of gender and race/ethnicity was significant such that African American/Black and Asian women generally had slightly lower mean FW compared to men (p = 0.04). There were no significant interactions between decade of age at scan or education with race/ethnicity.

Conclusion

In this diverse cohort, FW and WMH were associated with increased age, and WMH differed by race/ethnicity and gender. Our findings suggest the utility of FA and WMH among diverse individuals, across a large age range, which is critical for advancing neuroimaging biomarker research.
Pathways underlying selective vulnerability to Alzheimer’s disease in aminergic brainstem nuclei
Authors: Ehrenberg Alexander J. , Petersen Cathrine , Pereira Felipe Luiz , Buxton Jessica J. , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Ferretti‐Rebustini Renata Eloah de Lucena , Ferrioli Eduardo , Nitrini Ricardo , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Seeley William , Spina Salvatore , Kaufer Daniela , Grinberg Lea T.
Published: January 2025

Background

The Neuromodulatory Subcortical System (NSS) consists of nuclei exhibiting early vulnerability to tauopathies, including Alzheimer’s Disease (AD). Within the NSS, there is a spectrum of vulnerability that becomes apparent in the earliest stages of AD, offering a chance to probe factors underlying vulnerability to AD.

Method

In this study, we applied bulk RNA sequencing in well‐characterized postmortem human tissue from n = 22 cases at early (Braak 0‐III) AD‐tau stages to understand why this susceptibility gradient exists by examining two nuclei with very similar neurons but differing in their vulnerability to AD the locus coeruleus (LC) and substantia nigra (SN).

Result

We identified 3421 differentially expressed genes between the LC and SN among Braak 0 cases. Gene set enrichment analysis directed attention towards cholesterol homeostasis, neuroinflammation, and oxidative stress as factors potentially underlying the differential vulnerability of the LC and SN to AD.

Conclusion

Weighing the limitations of bulk RNA sequencing against the expression patterns of the constituitive genes within each gene set, we conclude that cholesterol homeostasis likely explains the differential vulnerability of the LC and SN to AD (Figure 1).
Association between in vivo structural integrity of the posterior hypothalamus, cognition and Alzheimer’s disease pathophysiology
Authors: Baillet Marion , Betthauser Tobey J. , Salmon Eric , Jacobs Heidi I.L.
Published: January 2025

Background

Abnormal tau accumulation is first observed in several neuromodulatory subcortical nuclei before its emergence in the allocortex, and long before the first deposits of amyloid‐beta (Aβ) plaques. Crucially, the posterior hypothalamus has been put forward as a critical site for Alzheimer’s disease (AD) pathogenesis but its role in AD‐related processes remains poorly investigated in humans. Here, we aimed to investigate whether the structural integrity of the posterior hypothalamus, as assessed in vivo, is associated with PET‐measured AD pathology and cognitive performance in cognitively unimpaired (CU) and impaired older individuals.

Methods

151 CU individuals, 75 mild cognitive impairment (MCI) and 35 AD patients (mean ± SD age = 76.6 ± 6.7y., 137 women; Table 1) from the ADNI3 dataset were included. The volume of the posterior hypothalamus (corrected for intracranial volume) was derived from structural T1‐weighted images using a deep convolutional network algorithm (Figure 1a). [18F]Flortaucipir‐PET was used to measure tau burden in the entorhinal cortex (standardized uptake volume ratio [SUVR], partial volume corrected values). Amyloid‐β (Aβ) positivity was determined with [18F]Florbetaben‐ or [18F]Florbetapir‐PET in a cortical summary region (SUVR values). Cognition was evaluated with the Preclinical Alzheimer’s Cognitive Composite (PACC). Analyses were adjusted for age, sex, and education.

Results

AD patients exhibited lower posterior hypothalamic volume compared to CU Aβ‐ (p = 0.003) and CU Aβ+ participants (p = 0.01) but no significant difference was observed between CU and MCI patients nor between MCI and AD patients (Figure 1b). Linear regression models revealed that lower posterior hypothalamic volume was associated with higher entorhinal tau‐PET values (p = 0.02, Figure 2a). In addition, CU Aβ+ with higher posterior hypothalamic volume exhibited higher entorhinal tau‐PET values compared to a negative slope in CU Aβ‐ participants (p = 0.05, Figure 2b). Finally, lower posterior hypothalamic volume was related to lower PACC scores (p<0.001, Figure 2c), which was mainly driven by AD patients (p<0.05 for comparisons with CU and MCI, Figure 2d).

Conclusions

Our findings indicate that the posterior hypothalamus is linked to disease‐related pathophysiological and cognitive changes. Future analyses will explore whether posterior hypothalamic volume is associated with inflammatory markers and changes in tau accumulation and cognitive performance over time.
SHIP1 phosphatase as a Late‐Onset Alzheimer’s Disease therapeutic target
Authors: Singhal Kratika , Hamdani Adam K , Jesudason Cynthia D , Beck Daniel E , Clayton Brent , Richardson Timothy I. , Mesecar Andrew D.
Published: January 2025

Background

Alzheimer’s disease (AD) is a highly complex neurological disorder, with Late‐Onset AD (LOAD) being its most common form. INPP5D has been identified as a risk gene for AD and is involved in the TREM2 signaling pathway, which is crucial for microglial activity. INPP5D encodes SHIP1, a protein phosphatase that disrupts TREM2 signaling by converting PIP3 into PIP2, thereby inhibiting the PI3K‐mediated activation of Akt‐dependent signaling, which is essential for the clearance of amyloid oligomers, fibrils, and plaques. SHIP1 is a large, multidomain protein, and many aspects of its structure and function are poorly understood.

Method

We have expressed, purified, and characterized the kinetic and biophysical properties of various domain constructs of SHIP1 to better understand the roles of individual domains. Ongoing work involves screening of inhibitors using a range of biochemical and biophysical assays with different constructs of SHIP1.

Result

The response of different SHIP1 domain constructs with different substrates surprisingly revealed no significant differences in kinetic parameters between different domain constructs with the same substrate suggesting that the various domains surrounding the catalytic domain do not influence catalysis in solution. However, use of a designed chemical probe with a covalent warhead that targets SHIP1 allosterically between the catalytic and C2 domains shows significant inhibition of SHIP1 (in the absence of its SH2 domain) identifying a potential druggable site. X‐ray crystallography was used to confirm the binding pose within this site. Binding affinity with additional compounds has been determined for different domain constructs using enzyme kinetics and biophysical methods including Microscale Thermophoresis (MST) and Differential Scanning Fluorescence (DSF).

Conclusion

SHIP1 is highly active in vitro (solution) without much regulation of its catalytic activity by surrounding domains. A potential druggable site has been identified between the SHIP1 catalytic and C2 domains that can be targeted allosterically by small molecule compounds. These discoveries will aid in identifying new molecules that can inhibit SHIP1 as a potential therapeutic target for AD.

This research was supported by grant 1U54 AG065181 (IUSM‐Purdue TREAT‐AD Center) from the National Institute of Aging, National Institutes of Health.
APOE‐ε4 interacts with the BTBD7 testis‐eQTL to reduce longevity in males
Authors: Park Junyoung , Guen Yann Le , Greicius Michael D
Published: January 2025

Background

The ε4 allele of the APOE gene (APOE‐ε4) and male sex are well‐established risk factors for reduced longevity. While many genetic studies of longevity have modeled sex and APOE, independently, few have considered the interaction of these two risk factors. Here, we model the interaction between APOE‐ε4 and sex in a genome‐wide association study (GWAS) of longevity.

Method

This study included a total of 408,780 participants with 36,981 age‐at‐death (male = 21,912, female = 15,069) and 371,799 last‐known‐age (male = 165,849, female = 205,950) from European ancestry participants in UK Biobank (Table 1). We performed a GWAS stratified by sex to find significant variant APOE‐ε4 genotype interactions associated with longevity using imputed genotype data for common variants (allele frequency>1%). Additionally, we conducted colocalization analyses with expression quantitative loci (eQTL) in GTEx v8 to identify potentially causal genes.

Result

In males (p = 4.1×10−8), but not in females (p = 0.33), we found a significant interaction between APOE‐ε4 and rs11626499 near BTBD7, which was associated with decreased longevity (Figure 1). The survival analysis revealed that in the male APOE‐ε4 carrier group, the individuals with the rs11626499_G had a higher risk of mortality (p = 2.8×10−7, HR = 1.12), but this risk was not observed in the male APOE‐ε4 non‐carrier group (p = 0.06) or in the female APOE‐ε4 carrier group (p = 0.14). Furthermore, the GWAS signal colocalizes with associations of BTBD7 and UNC79 expression in testis (Figure 2).

Conclusion

We identified an interaction between APOE‐ε4 and rs11626499 that increases mortality risk only in males. Additionally, rs11626499_G is associated with decreased BTBD7 and increased UNC79 expression in testis but not in female‐specific tissues. These findings demonstrate the importance of modeling the interaction between APOE and sex in studies of longevity.
Pharmacokinetic Effects of THC and Melatonin Co‐administration in Elderly Population
Authors: Naranjo María Paula , Camargo Fabio , Rao Jagadeesh S , Delgado‐Murillo Laura , Venegas Margarita , Tangarife Maria Alejandra , Arbelaez María Juanita , Gutiérrez Evelyn , Sánchez Laura Tatiana , Shahnawaz Saadia , Ghazaryan Varduhi , De Jesus William Julio , Grimaldi Claudia , Hong Elliot , Mukunda Ram
Published: January 2025

Background

Cannabis‐based therapies have gained interest in treating different ailments in the elderly population, including severe or chronic pain, sleep disturbances, and more recently Alzheimer’s Disease. This raises the importance of understanding the influence of age on the pharmacokinetics (“PK”) of delta‐9 tetrahydrocannabinol (“THC”).

IGC‐AD1 comprises THC at a low concentration and melatonin. The PK of THC/Melatonin co‐administration acquires importance since recent therapeutics employ both drugs in treating insomnia or neurodegenerative diseases in the geriatric population, where baseline PK is key to understanding possible changes because of renal or hepatic failures, and accurately adjusting doses to ensure the safety of those drugs.

Method

Data is presented from a Phase 1 Multiple Ascending Dose (“MAD”) study (n = 10 active), on AD patients and compared to PK data for adults. A review was performed including search results from ScienceDirect, CAS, PubMed, SpringerLink, and Google Scholar, using the terms “Pharmacokinetics”, “Absorption”, “transporter*”, “intestinal”, and “elderly”. Inclusion criteria were the indexed nature of the research, and languages (English, Spanish). No temporal inclusion‐exclusion criteria were considered.

Result

A dose of 2.5mg of THC reaches higher maximum plasma concentrations (Cmax = 2ng/mL), when administered together with 1.5mg of melatonin, and melatonin appears to be metabolized faster when administered with THC. When considering the relationship between the administered dose and Cmax (Cmax/dose), Cmax per dose of the co‐administered THC, 0.0008, is significantly higher than other reported PK data for oral cannabis administration 0.0003 (p<0.01).

Conclusion

Melatonin when administered jointly with THC could play a significant role in THC absorption and PK. We hypothesize, pending more studies, that the higher reported dose‐dependent absorption of THC may be related to the effect of melatonin on gastrointestinal transporters and efflux pumps.
Technology Assistance in Dementia (Tech‐AiD): Leveraging Everyday Technologies to Support Dementia Care
Authors: Kiselica Andrew M
Published: January 2025

Background

Care partners to persons with dementia increasingly use everyday technologies, like smartphones, smart speakers, and wearable device, to improve care and minimize burden. However, there remains a significant gap in effective implementation of these devices in care routines. For example, while as many 90% of care partners own smartphones, less than 50% use these devices on a daily basis, and less than 30% take advantage of their assistive features. As a result, functions that may aid in caring, like GPS for navigation, notes for to‐do lists, and alarm reminders for appointments, are not routinely employed. Thus, there is a need for interventions to improve effective digital technology use among care partners to persons with dementia. This presentation will describe progress in developing a novel program to meet this need, called Technology Assistance in Dementia (Tech‐AiD).

Methods

The presenter will discuss results from four Stage I behavioral intervention development studies, including a qualitative interview study of 22 care partners to better understand technology use, a survey study of 100 care partners to develop improved measures of technology‐based strategies, development of an intervention framework, and a mixed methods study among 10 care partners and 10 healthcare professionals to gather feedback on the intervention.

Results

An initial qualitative research study highlighted six domains of technology use in dementia care and also brought to light drawbacks of technology use, including cost, complexity, and privacy concerns. Next, the survey resulted in the development of the Technology in Caring Questionnaire (TCQ) to capture technology‐based strategy use. These studies informed the development of a treatment framework for Tech‐AiD, which was rated as appropriate, feasible, and acceptable by care partners and healthcare professionals.

Conclusions

The findings set the stage for a Stage IB pilot randomized control trial of Tech‐AiD to evaluate its feasibility, acceptability, and preliminary efficacy.
Communication Bridge 2: Primary and secondary outcomes from a global telehealth randomized controlled trial for persons with primary progressive aphasia and their communication partners
Authors: Rogalski Emily J , Rademaker Alfred , Mooney Aimee , Fried‐Oken Melanie , Bona Matthew , Roberts Angela C
Published: January 2025

Background

Primary progressive aphasia (PPA) is a currently incurable and relatively rare language‐based neurodegenerative dementia syndrome, which negatively impacts communication and quality of life. Non‐pharmacologic interventions show promise but have lacked randomized controlled trials (RCT). Here we report outcomes for Communication Bridge‐2 (CB2), the first global telemedicine speech‐language (RCT) for PPA.

Method

CB2 is an international, single enrollment site, Phase 2, Stage 2, parallel‐group, active control, behavioral RCT delivered via video‐chat to individuals with PPA and their communication partners. CB2 is supported by a custom web application. Participants were randomized 3:2 into one of two arms: Communication Bridge™ a dyadic intervention based on communication participation models, or, the Control intervention, a non‐dyadic intervention based on impairment models. Participants completed two intervention blocks over ∼12 months. Primary outcomes included communication confidence and participation measures assessed at baseline, each intervention block, and ∼12 months post‐enrollment. Other outcomes included word and script performance. Post‐study interviews captured participant experiences and informed feasibility.

Result

Ninety‐five PPA participant dyads (mean enrollment age of PPA participants: 67.1 years, 49% female) were randomized (n = 4 countries). Dropout was <10%. Procedural and documentation fidelity were high (>90%, for both). Theoretical fidelity showed strong within‐arm alignment. Experimental arm superiority was demonstrated at Block 1 for the Goal Attainment Scale, measurement, a primary participation outcome evaluated by a blinded clinician. The Communicative Participation Item Bank showed positive within‐group responsiveness at Block 1 exclusively for the experimental arm. Communication confidence measurement was less responsive. Other outcomes including word and script training, showed significant gains at Block 1 for both groups. Post‐study interviews suggested high feasibility.

Conclusion

Results suggest feasibility and initial efficacy for a global telemedicine intervention, providing an exciting path for implementation and dissemination of clinically meaningful interventions for Alzheimer’s and related dementias using telehealth models that can improve care access.
Digital Assessment Approaches to Overcome Barriers to Cognitive Screening and Monitoring for Older Adults in Primary Care Settings
Authors: Thompson Louisa I.
Published: January 2025

Background

Routine cognitive screening for older adults in primary care could improve AD early detection and streamline referrals for treatment or clinical trials. Digital assessments, especially when self‐administered online, can overcome time barriers to cognitive screening in primary care settings and are conducive to repeat testing for disease monitoring and the evaluation of treatment outcomes. We report preliminary data on the feasibility and acceptability of three digital screening approaches for older adults completing annual follow‐up visits with a primary care provider (PCP)

Methods

Cognitive screening approaches included: 1) remote online screening with the Boston Online Cognitive Assessment (BOCA) 1‐4 weeks prior to the PCP appointment, 2) self‐administered BOCA in the waiting room before or after the appointment, and 3) provider‐administered screening during the appointment using the Digital Clock and Recall (Linus Health DCRTM). Participants also completed a brief in‐clinic cognitive health consultation that included the Montreal Cognitive Assessment (MoCA), test feedback, and recommendations. Five PCPs aided in protocol development and participated in data collection. Potential participants were identified using EMR. Exclusion criteria: dementia or other neurological disease, score of <13 on the t‐MoCA.

Results

48 older adults ages 55‐85 were screened, 34 enrolled, and 4 withdrew. The sample is 54% female, 84% White, education M = 14.8 years. Self‐administration of BOCA in waiting room was discontinued early due to space, time, and coordination challenges. Participants instead completed a second at‐home administration of the BOCA on the day of their appointment. Completion rates were 81% for advance BOCA, 62% for same‐day BOCA, and 86% for in‐clinic DCR. Higher priority health issues and not returning for the consultation visit were primary reasons for withdrawal. Most participants reported a preference for screening at home compared to in‐clinic.

Conclusions

At‐home, self‐administered assessment online and in‐clinic, provider‐administered assessment on a tablet both show preliminary evidence of feasibility and acceptability for cognitive screening and monitoring use in primary care.
Clonal hematopoiesis is associated with a seven‐year delay in the onset of Alzheimer’s disease in APOE ε4/ε4 cases
Authors: Guen Yann Le , Park Junyoung , Talozzi Lia , Belloy Michael E. , Greicius Michael D
Published: January 2025

Background

Recently, clonal hematopoiesis of indeterminate potential (CHIP) was found to be associated with a reduced risk of Alzheimer’s disease (AD) and somatic mutations found in the blood of CHIP carriers were also in microglia‐enriched brain samples (Bouzid et al., 2023, Nature Medicine). We aimed to validate this finding in a larger dataset, explore the effect across APOE genotypes, and examine the association of CHIP with age‐at‐onset.

Method

Bouzid et al. (2023) analyzed the Alzheimer’s Disease Sequencing Project (ADSP) whole‐exome sequencing (WES) 10k subjects release and limited their analysis of this cohort to ε3/ε3 individuals, while we analyzed the new ADSP WES 20k subjects release and considered all APOE genotypes. We identified CHIP variants from joint‐called vcf files focusing on genes and variants provided in the previous study appendix. We further filtered variants requiring a median read depth above 30 among carriers and variant allele fraction below 40%. As in Bouzid et al., we restricted our analysis to European ancestry participants whose DNA was extracted from blood (Table 1). Using the generalized linear model implemented in the statsmodel Python package, we tested the association with diagnosis (Binomial family) and age‐at‐onset (Gaussian family) across and by APOE genotype. Analyses were adjusted for sex, and the first 3 principal components accounting for genetic ancestry. Additionally, the analyses considering all APOE genotypes were adjusted for ε2 and ε4 dosages.

Result

We confirmed CHIP association with reduced AD risk in ε3/ε3 individuals (OR = 0.68 [0.54; 0.86], p = 0.0016), and observed a similar direction of effect across APOE genotypes (OR = 0.77 [0.64; 0.93]; p = 0.0058), except in ε2/ε3 (Table 2). In addition, we found that CHIP was associated with 2.5 years delayed age‐at‐onset across APOE genotypes (b = 2.53 [1.27; 3.79]; p = 0.0001, Table 3), with a marked 7.7 years delayed onset in ε4/ε4 cases (b = 7.71 [2.66; 12.77]; p = 0.0028).

Conclusion

Taken together, these results provide stronger human genetic evidence that CHIP is associated with reduced AD risk and delayed age‐at‐onset, particularly in APOE‐ε4 carriers. These findings corroborate the notion that rescuing microglial phagocytic capacity during aging may be a therapeutic avenue for AD, most notably in APOE‐ε4 carriers.
The Relationship of Decision‐making capacity and the age of onset in Alzheimer´s Disease
Authors: Souza Natalie
Published: January 2025

Background

We investigated the relationship of decision‐making capacity in people with young‐onset Alzheimer´s Disease (YOAD) and late‐onset Alzheimer´s Disease (LOAD).

Method

Cross‐sectional study, with 169 (124 people with LOAD and 45 people with YOAD).

Result

People with YOAD (young‐onset Alzheimer´s Disease) were more cognitively impaired when compared with LOAD (late‐onset Alzheimer´s Disease), but more aware of their cognitive deficits and health condition, with moderate effect sizes. All people with AD (Alzheimer´s Disease) presented deficits in the domains of decision‐making capacity, with more impairment in understanding. The majority of participants were in the mild stage of teh disease (CDR 1). The YOAD group had more years of education than the LOAD group.

Conclusion

A higher decision‐making capacity is involved in a better understanding in the YOAD (young‐onset Alzheimer´s Disease) group. Clinically, our findings shed light on the need to consider the differences according to age at onset of AD (Alzheimer´s Disease).
Diagnosis of Alzheimer’s disease‐ Analysis of cross‐species biomarkers
Authors: Bathla Shveta
Published: January 2025

Background

Alzheimer disease (AD) is a heterogeneous multifactorial neurodegenerative disorder pathologically characterized by Aβ plaques, NFT, neuroinflammation, and synaptic and neuronal loss. The nature of most sAD cases strongly argues for an environmental link. The prominent pathological manifestations in AD patients are abnormal levels of Aβ 1‐42 (Aβ42), total tau (t‐tau) and p‐tau in brain and biofluids. Here, our goal is to find pathologically conserved phosphorylated tau signatures that are common to humans, non‐human primates and rodents, which may be utilized as biomarker candidates and/or therapy targets.

Method

In order to replicate the behaviors of AD in DKI mice (DKIhTau‐APPNL‐G‐F/NL‐G‐F), we employed a single‐step, antibody‐free method to extract tau from the prefrontal cortex, which was followed by quantitative phospho‐proteomics. We have further investigated p‐Tau changes in aged rhesus macaques which naturally develop amyloid and tau pathology at advanced ages. In the current study we have also tested whether chronic treatment with a GCPII inhibitor might also reduce tau hyperphosphorylation in aged rhesus monkeys with naturally‐occurring GCPII and tau pathology. Using an automated Lumipulse platform, we have further confirmed p‐tau (pT181 & pT217) changes in CSF (140) and plasma (∼200) in AD patients.

Result

A total of 40 and 39 phosphorylation sites were measured in human and mouse tau respectively. In DKI mice, significant increase were seen in pT181, pS202, pS214, pT217, and pT396, among other markers. The western blot analysis of entorhinal cortex (ERC) of monkeys revealed higher expression level of pS214 (P = 0.0012), pT181 (P = 0.0004) and pT217 (P = 0.0235) in aged monkeys as compared to young ones which captured p‐tau signatures at very earlier stage of AD. Moreover, pT217Tau levels in dlPFC and ERC were considerably reduced in elderly macaques treated with the GCPII inhibitor, 2‐MPPA. In AD patients compared to cognitively normal, the CSF p‐tau181 concentration is considerably greater ROC‐0.9299). However, compared to plasms p‐tau181(ROC‐0.7556), plasma p‐tau217(ROC‐0.8997) demonstrated noticeably greater diagnostic accuracy.

Conclusion

With the help of this study, which comprised two animal models as well as CSF and plasma from healthy and AD patients, we have developed a composite biomarker panel that shows great promise for early AD detection.
Bidirectional relation of depressive symptoms and cognitive function over 16 years follow‐up
Authors: Yin Jiamin , John Amber , Cadar Dorina
Published: January 2025

Background

Cognitive decline and depression often co‐occur among older adults, and they share several biological mechanisms. Despite that cognitive dysfunction has been linked to depression, the directionality of this association remains unclear. This study examined whether there is a bidirectional relationship between depressive symptoms and cognitive function in middle‐aged and older English adults over a 16‐year follow‐up period.

Method

The current analysis included 8,268 eligible participants from a nationally representative sample of community‐dwelling English older adults. These participants were examined longitudinally every other year from 2002 until 2018, resulting in a follow‐up period of up to 16 years. We used the bivariate dual change score models to estimate the multivariable associations between depressive symptoms and cognitive function, which are interchangeably used as exposures and outcomes. Cognitive measures include memory and verbal fluency tests, while the Center for Epidemiologic Studies Depression Scale evaluated depressive symptoms.

Result

The study population (n = 8,268) had an average age of 64 years at the study baseline, and 55% of the population was female. Higher depressive symptoms were cross‐sectionally correlated with poorer memory (β intercept = −0.018, standard error (SE) = 0.004, P < 0.001) and verbal fluency (β intercept = −0.009, SE = 0.004, P = 0.02) at study baseline. A steeper linear change in depressive symptoms was related to an accelerated memory change (β intercept = −0.253, SE = 0.079, P = 0.001), and a linear change in memory was associated with an acceleration in depressive symptoms over time (β intercept = 0.016, SE = 0.006, P = 0.005). This bidirectional change was not observed with verbal fluency.

Conclusion

Greater depressive symptoms were associated with poorer memory at baseline and steeper memory change over time. A gradual change in depressive symptoms contributed to accelerated memory loss and vice versa, suggesting that psychological mood and memory performance are intrinsically interrelated. In summary, these findings highlight the complex interplay between depressive symptoms and memory loss, underscoring the importance of integrated assessments and treatment approaches in clinical practice. Our work suggests that early intervention in depressive symptoms could provide a timely opportunity to slow down or delay memory decline in later life.
Examining Relationships Between Vitamin D Deficiency, Healthcare Access, Hispanic Ethnicity, and General Health Rating among Aging Rural West Texans: A Project FRONTIER Study
Authors: Morris Claudia , McCready Riley , McCrea Grace , Decourt Boris , Lawrence J. Josh
Published: January 2025

Background

Vitamin D (VD) deficiency is a risk factor for dementia and Alzheimer’s Disease (AD). Previously, we described health disparities in VD status, depression, and Hispanic ethnicity (HE) in an aging West Texas population from Project FRONTIER (Facing Rural Obstacles to Health Care Now Through Intervention, Education, and Research). Using the same sample, we examined relationships between VD status, health care access, and General Health Rating (GHR)

Method

Of 299 participants in which serum 25‐hydroxyvitamin‐D levels were available, we examined relationships between access to care, VD, HE, and GHR. Logistic and linear regression analyses were performed on binary and categorical variables, respectively. We used Mann Whitney U tests for between group comparisons.

Result

A significant negative association was found between the probability of health insurance and VD level (p = 0.0042). Lower VD levels were observed in uninsured (24.9 ± 1.4 ng/ml) compared to insured (29.4 ± 0.8 ng/ml) participants (p = 0.004). We found a significant negative association between VD levels and the probability of experiencing a time in the past 12 months when cost prevented seeing a doctor (n = 294, p<0.0001). We found a significant negative association between VD level and the length of time it had been since the participant had seen a doctor (p<0.0001). We found a significant negative correlation between VD level and GHR (p<0.0001). Lower VD levels were observed in HE (21.40 ng/ml) compared to non‐HE (34.00 ng/ml) participants (p<0.0001). Finally, we found a significant negative correlation between HE status and GHR (p<0.0001).

Conclusion

Our results reveal that insurance level, access to care, and length of time since seeing a physician likely impact VD status in this aging population. Additionally, our results reveal that VD status is negatively correlated with HE. Our results reveal that HE status and VD status likely impact GHR. Finally, the data highlights areas of healthcare in rural West Texas needing improvement, especially considering that studies show correlations between Vitamin D deficiency, dementia, and AD.
Systemic inflammation, lifestyle behaviours and dementia: A 10‐year follow‐up investigation
Authors: Hilary Leah , Frank Philipp , Cadar Dorina
Published: January 2025

Background

Lifestyle behaviours have been linked to dementia incidence, but their cumulative impact on dementia and the underlying mechanisms remain poorly understood. This study investigated the association of co‐occurring lifestyle behaviours with dementia incidence and the mediating role of systemic inflammation in this association.

Method

The sample comprised 3,131 participants (55.2% female) from the English Longitudinal Study of Ageing aged 52‐92 years at baseline (2008/09). Self‐reported baseline lifestyle behaviours (alcohol intake, fruit and vegetable consumption, smoking, physical activity, sleep duration, social engagement, and cognitive activity) were summed to derive an index of lifestyle behaviours, ranging from 0 to 7, with higher scores denoting a higher number of health‐risk behaviours. Incident dementia cases (n = 130, 4.2%) were identified through doctor‐diagnosed dementia, informant interviews, and health records between 2014/15 and 2018/19. Systemic inflammation was measured through fasting plasma concentrations of C‐reactive protein in 2012/13.

Result

Binary logistic regression models indicated that the odds of subsequent dementia increased by 1.19 for each additional health‐risk behaviour (95% confidence intervals: 1.04, 1.37, p = .014) after adjusting for age, sex, ethnicity, wealth, education, marital status, body mass index, coronary heart disease, hypertension, stroke, and depression. However, this association was not mediated by C‐reactive protein.

Conclusion

Co‐occurring health‐risk behaviours were associated with higher dementia incidence up to 10 years later, underscoring the importance of modifying health‐risk behaviours for the prevention of dementia. Systemic inflammation did not explain the association between behaviours and dementia.
Retirement and Healthy Lifestyle: Mediating Effects on Life Satisfaction
Authors: Yun Sohyeon , Park Hae Yean , Kim Inhye , An Hyunseo , Shin Jiwon , Yang Hyun , Nam Sanghun
Published: January 2025

Background

Retirement for elderly people marks a critical turning point in life, acting as a significant personal and social event associated with both positive and negative health impacts. Studies on elderly populations from the successful aging perspective suggest that individual efforts and external support are necessary for successful aging. The WHO emphasizes the importance of a healthy lifestyle in achieving health and well‐being in human life and indicates the need for professional programs.

Method

Data from 6,488 Korean adults, aged between 57 and 102 years, collected in the 2020 Korean data from the Korean Longitudinal Study on Aging (KLoSA), was used to analyze both direct and indirect effects of retirement status on life satisfaction. From the processed data, independent (retirement status), dependent (overall life satisfaction), mediating (lifestyle), and demographic characteristic variables were extracted for the mediation effect analysis. This process utilized the method of the mediating effect verification based on path analysis suggested by Baron and Kenny. To examine the statistical significance of the mediating role of lifestyle, a Sobel test was performed.

Result

Health behaviors accounted for a 14% partial mediation, while health status and social participation and activities demonstrated 70% and 96% full mediation effects, respectively. Additionally, the Sobel test results confirmed that the mediating effects of all subdimensions of lifestyle in the relationship between retirement status and overall life satisfaction were significant (p < .0001).

Conclusion

These results indicate that factors determining life satisfaction and successful aging at an individual level are significantly influenced not only by physical and psychological health but also by social competence, forming social relationships, and pursuing collective values, aligning with that of previous studies. To maintain optimal health status and behaviors, efforts to maintain health are required, namely, practicing successful aging. These findings imply the need for social prescription lifestyle programs to prepare for successful aging before retirement. A healthy lifestyle can be formed through various behavioral patterns and is shaped over the long term based on individualized contexts rather than showing short‐term changes. Therefore, a strategic approach focusing on both long‐term habit formation and new habits is necessary.
Studying the prevalence of ApoE Haplotypes in the Caribbean Hispanics from Puerto Rico
Authors: Maldonado Frances M Marin , Blondet Cristal Garcia , Duconge Ana S , Renta Jessica , Saez Jose Colon , Soler Jorge Duconge
Published: January 2025

Background

Among different ethnic groups, Hispanics rank second in Alzheimer’s disease (AD) prevalence. However, most studies on this condition have been conducted in Europeans. To address this bias in representation we interviewed and collected samples from Caribbean Hispanics living in Puerto Rico; to ascertain the prevalence of ApoE haplotypes and measure their association with the development of AD in this population.

Method

Initially, 150 Caribbean Hispanic adults participated in this study (females = 83, males = 68), divided into three groups (n = 50 each): cognitively normal (CN) participants, cardiovascular (CV) and Alzheimer’s disease (AD) patients. Given that heart disease is known to increase Alzheimer’s risk by ∼40%, we included the CV group because these patients will be at risk of AD by the vascular parameter. Clinical and demographic data were collected through questionnaires conducted during recruitments, while genetic testing for ApoE haplotypes was performed using the RT‐PCR‐based TaqMan SNP assay. Allelic and haplotype frequencies were determined.

Result

In the CN group, the ε3ε4 haplotype was detected in 43 subjects (91.4%). Conversely, the ε3ε3 haplotype was found in three subjects (6.38%), while the least common haplotype, ε2ε4, was present in only one subject (2.12%), 95% CI [0.871, 1.04]. Within the CV cohort, 48 subjects were identified as carriers of the ε3ε4 haplotype (96%). Only one subject had the ε3ε3 haplotype (2%), and similarly, one subject harbored the ε2ε4 haplotype, 95% [0.943, 1.056]. In the AD group, the ε3ε4 haplotype was the most prevalent, with 44 carriers (91.6%). In this group, both the ε3ε3 and ε2ε4 haplotypes were each observed in one subject, collectively accounting for 4.16% of the cohort, 95% [0.915,1.08].

Conclusion

Interestingly, our study revealed that the ε3 and ε4 alleles predominated across the various groups, while the ε2 allele emerged as the least common. Despite multiple reports linking the ε4 allele to an increased risk of AD, in our admixed population it seems that African ancestry enrichment at the ApoE locus potentially mitigates its effect. Further studies are warranted to elucidate the relationship between ancestry and AD risk.
Induction of Autophagic Pathways in Alzheimer’s Disease via SARS‐CoV‐2 Vaccination: A Deep Learning Analysis of Neurodegenerative Modulation
Authors: Fajar Rifaldy , Elfiany Elfiany , Putri Sahnaz V , Prihantini Prihantini
Published: January 2025

Background

Emerging research indicates that autophagy, a cellular degradation process, may be triggered by certain immune responses, including those by vaccines. This study aims to examine whether the SARS‐CoV‐2 vaccines, known to induce robust immune activation, can trigger autophagic pathways that facilitate the degradation of amyloid‐beta (Aβ), a pathological feature of Alzheimer’s disease (AD). By applying deep learning techniques to analyze complex immunological and neurological data, this study explores a potentially innovative therapeutic strategy for AD.

Method

In this study, we conducted a focused cohort involving 1,200 early to mid‐stage Alzheimer’s disease (AD) patients who received the SARS‐CoV‐2 vaccine, along with 1,200 matched controls who did not receive vaccination. Over a period of 24 months, we gathered and analyzed extensive datasets, which included genomic information related to autophagy‐related genes, longitudinal blood biomarker profiles emphasizing autophagy and amyloid‐beta (Aβ) markers, and detailed brain imaging data for quantifying Aβ deposition and brain morphology changes. Our analysis utilized deep learning models, specifically designed to process sequential and spatial data, to identify patterns that correlate vaccine response with changes in autophagic activity and Aβ levels.

Result

Preliminary analysis revealed that vaccinated AD patients exhibited a 24% increase in markers of autophagic activity (95% CI: 20%‐28%, p<0.001) and a corresponding 22% reduction in soluble Aβ levels (95% CI: 18%‐26%, p<0.001) compared to baseline and control groups. Cognitive assessments showed a deceleration in cognitive decline in the vaccinated group, with a statistically significant difference in the annual decrease in MMSE scores by 1.1 points (95% CI: 0.7‐1.5, p<0.001) relative to unvaccinated patients. Deep learning models identified a predictive interaction between specific autophagy‐related genetic variants and vaccine response, indicating higher efficacy in certain subgroups.

Conclusion

The study suggests that SARS‐CoV‐2 vaccination may improve autophagy in Alzheimer’s brains, aiding in amyloid‐beta breakdown. This has implications for treating Alzheimer’s and potentially other neurological conditions with vaccines or immunotherapies targeting autophagy.
Anti‐amyloid‐β treatment effects on dominantly inherited Alzheimer disease neuropathology: comparing autopsy findings with biomarker outcomes from the DIAN‐TU‐001 trial of gantenerumab or solanezumab
Authors: Chen Charles D. , Franklin Erin E. , Li Yan , Joseph‐Mathurin Nelly , Burns Aime , Hobbs Diana A , McCullough Austin A. , Schultz Stephanie A. , Wang Guoqiao , Benzinger Tammie L.S. , Bateman Randall J. , Perrin Richard J.
Published: January 2025

Background

Clinical trials of anti‐Aβ monoclonal antibodies in Alzheimer disease (AD) typically infer target engagement from Aβ positron emission tomography (PET) and/or cerebrospinal fluid (CSF) Aβ42/40 biomarker outcomes that measure Aβ deposits indirectly and/or incompletely. Assessment of postmortem tissue is needed to directly investigate treatment effects on Aβ deposits.

Method

From a clinical trial of anti‐Aβ monoclonal antibodies in dominantly inherited AD (DIAD), we measured Aβ immunohistochemistry area fractions (10D5 antibody) in 10 brain regions from 10 trial cases (representing gantenerumab (n = 4), solanezumab (n = 4), and placebo/no‐treatment (n = 2) arms) and 10 observational study cases. Gantenerumab, solanezumab, and control (placebo/no‐treatment/observational study) groups were compared on the basis of these Aβ area fractions, as well as their antemortem Aβ PET (11C‐PiB), and antemortem CSF (Aβ42/40, p‐tau181, and t‐tau) biomarkers. Five participants in the control group did not undergo PET imaging or CSF collection.

Result

Frontal, temporal, parietal, occipital, hippocampus, caudate, putamen, thalamus, cerebellar gray matter, and anterior cingulate Aβ area fractions were significantly lower in the gantenerumab arm versus control group. Temporal, caudate, putamen, and thalamus Aβ PET standardized uptake value ratios (SUVRs) showed significant decreases in the gantenerumab arm versus controls. When using cerebellar white matter as the reference region instead of cerebellar gray matter, anterior cingulate SUVR also showed significant decrease in the gantenerumab arm versus controls, and effect sizes were larger across all regions. CSF Aβ42/40 showed significant increase in the gantenerumab arm versus controls, CSF p‐tau181 showed no significant differences between groups, and CSF t‐tau showed significant decreases in the gantenerumab arm versus controls.

Conclusion

Neuropathological assessments, consistent with Aβ PET and CSF Aβ42/40 biomarkers, found that gantenerumab treatment in these participants reduced, but did not completely eliminate, Aβ deposits. Neuropathology also uniquely revealed lower levels of cerebellar gray matter Aβ in the gantenerumab group versus controls; this finding suggests that using cerebellar white matter as a reference region may improve the accuracy of Aβ PET in DIAD clinical trials. Both findings illustrate the value of neuropathological assessments to AD clinical trials. Future studies of these cases may provide insights into the downstream effects of antibody‐mediated Aβ removal in DIAD.