bluuebunny/crossref_metadata_2025 huggingface dataset:
Arterial calcification in the heart‐brain axis and cognitive performance over time: a population‐based cohort study
Authors: Streiber Anna M , van den Beukel Tim C , vom Hofe Ilse , Neitzel Julia , Vernooij Meike W. , Bos Daniel , Vinke Elisabeth J.
Published: January 2025

Background

Increasing evidence shows a link between arterial calcification in the heart‐brain axis and cognitive performance. However, how calcification relates to acceleration of cognitive changes, and which specific cognitive domains are mostly affected, remains unclear. We assessed the impact of calcification in major arteries between the heart and brain on cognitive decline and focused on different cognitive domains.

Method

We included 1863 participants from the population‐based Rotterdam Study (mean baseline age 67.9 ± 5.7 years, 53% female) who underwent a non‐contrast CT‐scan between 2003 and 2006 to quantify calcification in the coronary artery, aortic arch, extracranial internal carotid artery, intracranial internal carotid artery, and vertebrobasilar artery. Between 2002 and 2016, these participants also underwent two to three cognitive assessments (average follow‐up time: 9 years). The impact of arterial calcification at baseline on cognitive test performance over time was investigated using linear mixed models with a random intercept. The arterial calcification burden at baseline was transformed into age‐specific percentiles and cognition variables were log‐transformed in case of non‐normality. An interaction term was integrated between age‐specific calcification percentiles and follow‐up time, to allow for different slopes for different calcification percentiles. Non‐linearity of age and follow‐up time were taken into account by using natural cubic splines. All models were adjusted for follow‐up time, age, sex, education, APOE‐e4 carriership, and cardiovascular risk factors.

Result

The age‐specific percentile curves of arterial calcification for each artery are presented in Figure 1. We found that a higher calcification burden was associated with worse baseline cognitive performance across various domains, specifically psycho‐motor functioning. Figure 2 highlights the cognitive trajectories in different arteries, showing that cognition declines faster in participants with higher calcification volumes across all cognitive domains. Importantly, the effect of calcification on cognitive performance differs across the arteries. Both intercept differences and accelerated cognitive decline seem most pronounced for calcification in the vertebrobasilar arteries.

Conclusion

A larger amount of arterial calcification in the heart‐brain axis, is robustly associated with accelerated cognitive decline over time, specifically in the psychomotor domain. Our findings suggest that arterial calcification in arteries closer to the brain exerts most influence on cognitive decline.
Association of coffee and tea intake with the risk of dementia: A prospective study
Authors: Yan Minqing , Shen Jie , Huang Yuhui , Wu Minyu , Zong Geng , Zheng Yan , Yuan Changzheng
Published: January 2025

Background

The role of coffee and tea intake in dementia prevention remains inconclusive across studies.

Method

We included 6,001 Health and Retirement Study (HRS) participants (67.5±10.0 years old, 59.0% female) without dementia at baseline and followed them until 2020. Coffee and tea intake (including caffeinated and decaffeinated coffee and tea) was assessed using a 163‐item semi‐quantitative food frequency questionnaire (FFQ) in 2013. Dementia diagnosis was ascertained using the Langa‐Weir Classification strategy. Cox proportional hazard models were used to evaluate the associations of coffee and tea intake with dementia.

Result

During a median follow‐up of 7 years, 231 participants developed dementia excluding dementia cases within the first 2 years of follow‐up. Compared with participants who did not drink coffee, those drinking ≥2 cups/day were associated with lower risk of dementia (Hazards ratio [HR] = 0.62, 95% confidence interval [CI], 0.41, 0.94; P‐trend = 0.049). Associations were similar for caffeinated coffee (HR = 0.66, 95% CI = 0.46, 0.96) and decaffeinated coffee (HR = 0.49, 95% CI, 0.25, 0.99). Moderate intake of tea (>0 to < 2 cups/day compared with never) was also linked to a lower dementia risk (HR = 0.64, 95% CI, 0.47, 0.87 for >0 to <1 cup/day; HR = 0.55, 95% CI, 0.31, 0.98 for ≥1 to <2 cups/day). In addition, for caffeinated tea, drinking >0 to <1 cup per day was associated with a 43% lower risk of dementia (HR = 0.57, 95% CI, 0.43, 0.77), whereas no significant association were observed between decaffeinated tea and dementia.

Conclusion

Higher consumption of coffee and moderate tea intake were associated with lower risk of dementia.
Protective role of overweight in Alzheimer’s disease: New findings from Mendelian randomization study
Authors: Duan Hongzhe , Holmes Rachel , Wu Deqing , Feitosa Mary , Yashin Anatoliy I , Arbeev Konstantin , Ukraintseva Svetlana
Published: January 2025

Background

Weight loss has been associated with Alzheimer’s Disease (AD), suggesting the possibility that overweight may be protective against AD. Mendelian Randomization (MR) is a common method of revealing causal relationships in observational studies. Our recent MR analysis using the Health and Retirement Study (HRS) data found that overweight has a causal protective effect on late‐onset‐AD. Here we expand this strategy to two other cohorts, the Long Life Family Study (LLFS) and Framingham Heart Study (FHS), to examine causal role of overweight in AD in these data.

Method

For this MR study, we created two binary variables: ‘exposure’ (group‐1 “overweight” BMI 25‐30 vs. group‐0 “normal weight” BMI 18.5‐25, at ages 65‐75) and ‘outcome’ (group‐1 “no AD” vs. group‐0 “AD onset after age 75”), using FHS original cohort (N = 610) and LLFS (N = 1979) data on individuals who survived age 75. To identify instrumental variables (IVs), we implemented a recently developed new strategy. We selected SNPs in eight obesity‐related genes (ADIPOQ, FTO, LEP, LEPR, INSIG2, MC4R, PCSK1, PPARG) and paired them with each other, then summed their minor alleles to create new ‘composite’ SNPs as candidate IVs. This strategy improved the MR effectiveness due to the exponentially increased number of to‐be‐tested IVs. R‐package MendelianRandomization was used. Analyses were stratified by sex. The relatedness of samples was addressed by using mixed model to calculate statistics. Causal effect was evaluated using weighted median and Inverse‐Variance Weighted (IVW). MR‐Egger regression was employed to address potential pleiotropy.

Result

Being overweight at ages 65‐75 had significant causal protective effect on AD onset after age 75 in LLFS White females (N_IV = 61, weighted median causal estimate = 1.15, p‐value = 1.44E‐4; IVW causal estimate = 0.57, p‐value = 1.33E‐2) and FHS White males (N_IV = 12, weighted median causal estimate = 1.22, p‐value = 2.71E‐2; IVW causal estimate = 0.90, p‐value = 1.33E‐2). MR‐Egger regression intercepts in both cases were not distinct from the origin.

Conclusion

Our MR study found causal protective effect of overweight on late‐onset‐AD in White participants of FHS and LLFS, in line with previous findings in HRS data. To confirm these findings in other race/ethnic groups, MR study of datasets with larger numbers of individuals of diverse backgrounds is warranted.
Adherence to a lifestyle intervention ‐ self‐efficacy as crux of the matter?Analysis of AgeWell.de as multi‐domain lifestyle intervention against cognitive decline
Authors: Wittmann Felix Georg , Pabst Alexander , Zülke Andrea , Luppa Melanie , Wiese Birgitt , Hoffmann Wolfgang , Frese Thomas , Gensichen Jochen , König Hans‐Helmut , Kaduszkiewicz Hanna , Thyrian Jochen René , Riedel‐Heller Steffi G.
Published: January 2025

Background

Recent research on preventing cognitive decline has focused on lifestyle interventions, with first studies indicating cognitive benefits and suggesting a positive link between adherence to the interventions and their effectiveness. The purpose of this study was to analyse possible predictors of this very adherence to single components of a multi‐domain lifestyle intervention.

Methods

A total of n = 317 participants of the intervention group were included, characterized with an age ≥60 (mean age 68.9) and an increased risk of dementia (CAIDE score of ≥9). Generalized linear regression models were used to regress four predictor blocks (sociodemographic factors, cognitive and psychosocial predictors, lifestyle factors and chronic conditions, all assessed at baseline) on the adherence to each of four components of AgeWell.de (nutritional counselling, enhancement of social and physical activity and cognitive training). Adherence was operationalised as mean score of seven time points at which a study nurse assessed the degree of goal achievement per component. The goals were set individually at beginning of the intervention.

Results

Strengthening effects on adherence were found for higher education, unimpaired mental state and higher self‐efficacy. Increasing age, reporting depressive symptoms, smoking and partwise higher body mass index were instead negatively associated with adherence. No effect was found for chronic conditions.

Conclusion

The study has identified both strengthening and mitigating predictors of adherence. This is relevant to future intervention designs aimed at enhancing adherence as a pivotal aspect for effectiveness. While age or education remain non‐modifiable, self‐efficacy emerge as a promising predictor. In light of optimizing the efficacy of forthcoming lifestyle interventions, a reasonable approach may involve the incorporation of strategies for enhancing self‐efficacy within the study design.
Drug‐related problems among older adults with Mild Cognitive Impairment and dementia receiving care at Multi‐specialty Interprofessional Team‐based (MINT) memory clinic
Authors: Sharma Rishabh , Lee Linda , Chang Feng , Patel Tejal
Published: January 2025

Background

Up to 30% of hospitalizations in older adults living with Mild Cognitive Impairment (MCI) and dementia are attributed to drug‐related problems (DRPs), including adverse drug reactions, drug interactions, potentially inappropriate medication (PIM) use, and medication non‐adherence. This study categorizes the identified DRPs according to the Pharmaceutical Care Network Europe (PCNE) Classification for DRPs version 9.1.

Methods

A cross‐sectional study was carried out with older adults receiving care for MCI or dementia at an Interdisciplinary memory clinic over eight months. The study employed four tools: the Medication Appropriateness Index (MAI), and the Medication Review in Cognitive Impairment and Dementia (MedRevCiD) checklist, Beers Criteria 2023, and Screening Tool of Older Persons Potentially Inappropriate Prescription (STOPP) 2023 to conduct a medication review. Identified DRPs were categorized according to their types and root causes with the PCNE classification system, version 9.1.

Results

Forty‐four participants (45.5% female, n = 20) were enrolled. The average age of the study participants was 80.2 years (standard deviation (SD) 6.2). Most of the participants (61.4%, n = 28) had six or more comorbidities ((mean ± SD) 6.7 ± 3.4). A total of 375 medications were prescribed to the 44 study participants. The median number of medications per day was 7.5 (interquartile range (IQR): 6 per day). A total of 119 DRPs were detected in 36 patients, with an average of 2.7 DRPs per patient. The most common type of DRP was within the classification of treatment safety, accounting for 63% of the reported DRPs (n = 75), followed by treatment effectiveness (15.9%, n = 19). The most common cause of DRPs noted was inappropriate drugs according to guidelines/formulary (43.6%, n = 52), followed by an inappropriate combination of drugs, or drugs and herbal or drug‐drug interaction (21%, n = 25) from the drug selection category. A total of 53 recommendations were made by the pharmacist in the medical records for the study participants.

Conclusion

The high prevalence of DRPs, notably those involving treatment safety and inappropriate drug selection, emphasizes the importance of medication reviews and tailored interventions to improve medication management and safety in this at‐risk population.
Cross‐national harmonization of cognitive impairment and dementia diagnosis across US and Latin American populations
Authors: Llibre‐Guerra Jorge J. , Weiss Jordan , Li Jing , Soria Chris , Rodriguez‐Salgado Ana M , Llibre‐Rodriguez Juan J. , Jiménez‐Velazquez Ivonne Z. , Acosta Daisy M , Liu Mao‐Mei , Dow William H
Published: January 2025

Background

Cross‐national comparisons of dementia prevalence are essential for identifying unique determinants and cultural‐specific risk factors, but methodological differences in dementia ascertainment across countries hinder global comparisons. This study maps the 10/66 Dementia Research Group algorithm for dementia ascertainment, widely used and validated in lower‐ and middle‐income countries, to the U.S.‐based Aging, Demographics, and Memory Study (ADAMS), and validates it for use in the U.S.

Methods

We conducted pre‐statistical harmonization across the ADAMS and the 10/66 studies in Latin America to identify common measures, which were then utilized to develop a modified 10/66 algorithm. We computed dementia probabilities using the modified 10/66 algorithm and the optimal threshold for dementia ascertainment was established by maximizing sensitivity and specificity against ADAMS' clinical gold standard diagnosis. We then compared this algorithm to a TICS‐based algorithm developed in ADAMS and commonly used in the U.S. Health and Retirement Survey. Further analysis included an examination of the age‐adjusted educational gradients in predicted dementia prevalence, allowing for a comprehensive assessment of the modified algorithm’s validity and its comparative performance.

Results

The sample comprised 5,649 adults ages 70 and over (539 from ADAMS and 5,109 from 10/66 studies).10/66 participants had a lower education level (60% had primary school or less) relative to the ADAMS cohort (69.8% possessed at least a high school education). The modified 10/66 diagnostic algorithm performed similarly in the 10/66 data as compared to the original 10/66 algorithm. In the ADAMS data, the modified 10/66 algorithm outperformed the TICS algorithm across several metrics: it demonstrated higher sensitivity (90% vs 77%), specificity (90% vs 74%), accuracy (90% vs 75%), and Area Under the Curve (AUC) (90% vs 76%). The modest ADAMS sample size precluded statistically precise comparisons by education, but education gradients in predicted dementia were broadly similar across algorithms.

Conclusions

The modified 10/66 algorithm effectively classifies dementia in US studies and is suitable for cross‐national comparisons, supporting its use for international studies. This facilitates future harmonization efforts of dementia diagnostic tools and enhances cross‐country dementia research.
A digital twin technique using external observational data to reduce sample sizes in clinical trials on Alzheimer’s disease
Authors: Andrews Daniel , Collins D Louis ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Randomized placebo‐controlled trials (RCTs) are the gold standard to evaluate efficacy of new drug treatments for Alzheimer’s disease. For example, the United States FDA approved the brain amyloid‐targeting drug lecanemab following CLARITY AD, Biogen and Eisai’s Phase 3 RCT. However, recruiting enough participants for a high‐powered and demographically representative trial is difficult and expensive. Fortunately, historical patient data from existing external observational studies of a disease can help populate RCTs [Thorlund et al. (2020). https://doi.org/10.2147/CLEP.S242097]. We propose a new trial framework that uses an external study to source “digital twins” for each trial participant. Using computer‐simulated trials mimicking CLARITY AD’s demographics and 18‐month duration, we show that our digital twin trial (DTT) has increased power compared to a conventional RCT.

Method

A continuous time linear mixed model tracked CDRSB change‐from‐baseline (CDRSBΔbl) trajectories in 670 ADNI participants satisfying CLARITY AD inclusion criteria [clinicaltrials.gov/study/NCT03887455]. To simulate an RCT, we resampled and added noise to participants’ data, generating a desired sample size of “recruited” participants who we randomized 1:1 to “drug” and “placebo” groups. We calculated participants’ CDRSBΔbl scores at 18 months and simulated the drug effect as a 25% reduction in CDRSBΔbl. For each participant in our DTT, we used Gower’s distance on demographic and clinical baseline variables to identify 20 most‐similar real ADNI participants (the digital twins) from our original 670. Each original ADNI participant’s 18‐month CDRSBΔbl was calculated using the model. A z‐score was then calculated for each DTT participant’s 18‐month CDRSBΔbl relative to their digital twins. T‐tests were used to evaluate DTT drug vs. placebo group difference in mean z‐score and, separately, RCT group difference in mean 18‐month CDRSBΔbl. We simulated each trial 1,000 times. Power is the proportion of simulations with a statistically significant treatment group difference.

Result

Figure 1 shows that 90% power is reached with approximately 500 fewer recruited participants in simulated DTTs (∼1,600 participants) compared to RCTs (∼2,100 participants).

Conclusion

DTTs might require substantially fewer recruited participants to achieve the same power as conventional RCTs. This sample size reduction could facilitate recruitment for trials on Alzheimer’s and in rare diseases with low patient numbers.
Effectiveness of a Local Recruitment Registry
Authors: Birnbaum Adam I , Grant‐Freeman Zion T , Grill Joshua D , Hoang Dan , Gombosev Adrijana , Gillen Daniel L
Published: January 2025

Background

Recruitment registries are tools to decrease the time and cost required to identify and enroll eligible participants into clinical research. Despite their potential to increase the efficiency of accrual, few analyses have assessed registry effectiveness. We investigated the outcomes of study referrals from the Consent‐to‐Contact (C2C) registry, a recruitment registry at the University of California, Irvine.

Method

We categorized the outcome of study referrals as: (1) unable to reach, (2) declined to participate, (3) phone screened but ineligible, (4) consented but ineligible or (5) consented and enrolled. We assessed overall effectiveness of the registry via the empirical distribution of referral outcomes. To assess associations between participant characteristics and referral outcomes we used a binary logistic generalized linear mixed‐effects model with study‐specific random intercepts, restricting the analysis to the outcome of the first study referral for each participant in the subset of referrals for which we had complete subject‐level data (n = 3,238). We treated any referral leading to obtaining participant consent as a success. We tested for an association between the odds of successful first referral and score on the research attitudes questionnaire (RAQ) via a 2‐sided Wald test.

Result

The C2C made 9,696 referrals to 60 studies. 2,805 (28.9%) of these referrals were successful, leading to participant consent. In 40% of referrals, the participant did not respond to contact and in 23.7% of referrals the participant declined. We estimated that participants who scored 5 points higher on the RAQ had 13% higher odds of successful first referral compared to otherwise similar participants (95% CI: 1.02,1.25, p = 0.015). Other factors significantly associated with successful enrollment included older age (OR = 1.10 per 10 years, 95% CI: 1.01,1.2, p = 0.024), female sex (OR = 1.28, 95% CI: 1.07,1.53, p = 0.008), and higher education (ref≤12 years; 13‐16 years: OR = 1.68, 95% CI: 1.16,2.44, p = 0.006; >16 years: OR = 1.77, 95% CI: 1.21,2.58, p = 0.003).

Conclusion

These results suggest that the C2C is an effective tool in aiding accrual in ADRD clinical research and that the RAQ may be a meaningful predictor of referral outcomes.
Subjective Cognitive Decline is associated with blood‐plasma Neurofilament Light in cognitively normal older adults
Authors: Chapman Silvia , Cosentino Stephanie , Nosheny Rachel L. , Herman Mathieu , Brickman Adam M. , Simoes Sabrina
Published: January 2025

Background

Novel plasma markers are increasingly accepted as indicators of Alzheimer’s disease and related dementia (ADRD) pathophysiology. The extent to which these markers map with clinical symptoms of disease remains unclear. A proposed early clinical symptom of ADRD is subjective cognitive decline (SCD), the experience that cognition has declined despite normal performance on objective assessment. Mapping the association between ADRD plasma biomarker concentrations and SCD will shed light on the links between pathophysiology and symptomology in the earliest stages of disease. This pilot study examines how SCD (self and informant based) associates with plasma p‐tau181, Aβ42, Aβ40 and neurofilament light chain (NfL) concentrations.

Method

Forty‐four (mean aged=68 years) cognitively unimpaired individuals and 41 informants were recruited from the Columbia University Alzheimer's Disease Research Center. Levels of plasma ADRD biomarkers (Aß42, Aß40, p‐tau181 and NfL) were measured on the Simoa HD‐X platform. SCD was measured with two dichotomous variables indicating whether there had been a decline in memory relative to previous ability reported by the participant and their informant. Eight unadjusted linear regression models examined self and informant SCD as predictors of each plasma marker. Models were then adjusted for relevant covariates, and interactions with age and sex were considered.

Result

As reported in Table 1, unadjusted models showed that self‐reported SCD was associated with higher NfL. Informant‐reported SCD was also associated with higher plasma NfL as well as higher p‐tau181. Effect sizes were reduced after adjustment and only self‐reported SCD remained associated with higher NfL. Male sex was associated with greater levels of NfL in those who had SCD.

Conclusion

SCD had stronger associations with a marker of neurodegeneration than amyloid or tau burden. Findings are in line with previous studies showing that NfL has a close relationship with clinical impairments such as cognitive decline. Sample size and type of assay utilized in this study could have limited our ability to see associations with tau and amyloid burden. Futures studies should examine how the combination of plasma markers and early clinical symptoms can aid the predictive utility of plasma markers for onset and progression of clinical symptoms.
Engaging community stakeholders to develop a Dementia Risk Reduction Protocol for primary care settings assisting underserved mid‐aged and older adults
Authors: Souza‐Talarico Juliana Nery , Ashida Sato , Newman Larry
Published: January 2025

Background

Reducing dementia risk factors at mid‐life by 10‐25% can prevent an estimated 1‐3 million dementia cases worldwide. However, implementation of dementia risk reduction (DRR) is limited, particularly in underserved communities. Barriers include lack of awareness and access to appropriate services. Engaging community stakeholders is crucial for adapting and incorporating interventions that are feasible, acceptable, and sustainable into community care. We aimed to involve local stakeholders to develop a DRR protocol suitable for primary prevention in underserved communities.

Methods

Collaborating with a university‐affiliated Mobile Clinic (U‐MC) offering free health services, we reached out to middle‐aged and older adults in two underserved communities. A Stakeholder Advisory Board (SAB) was formed, comprising eight individuals, including community members, primary care providers/students, researchers, and aging organization representatives. Relying on the recommendations of the UsAgainstAlzheimer’s risk reduction workgroup, the SAB employed the ACTT framework (Actions, Context, Target, and Time) to delineate DRR strategies.

Results

Over five bi‐weekly meetings, the SAB designed an action plan for dementia risk screening (11 risk factors), education and follow‐up (Actions), involving students and primary care professionals (Actors) in community health assessments (Context) for individuals over 40 (Target). Culturally‐sensitive educational materials with local resources were designed to support detected risks, with annual monitoring (Time). Insights into the SAB operations like group dynamics and partnership efficacy were also evaluated to optimize collaborative efforts in healthcare delivery.

Conclusion

The active collaboration with community stakeholders facilitated the development of a tailored, evidence‐based DRR protocol, reinforcing the importance of local input in creating feasible and sustainable health interventions in underserved communities. This customized approach shows promise for wider adoption in similar communities, aiming to promote primary prevention and substantially decrease the incidence of dementia.
Sociodemographic and risk factor analysis of the SMRUTHI India: a cohort of at risk elderly Indians for primary prevention of dementia
Authors: Gupta Anu , Sinha Abhik , Sharma Varuna , Raina Sunil K , Roy Subarna , Baidya Subrata , Anand P K , Nehra Ashima ,   Nilima N , Khan MA , Vishnu Venugopalan Y , Srivastava MV Padma
Published: January 2025

Background

Around 40% of dementia cases can be prevented or delayed by modifying the risk factors. The SMRUTHI INDIA study will be conducted to establish a trial‐ready cohort of elderly Indians who are at high risk of developing dementia.

Method

The present study utilizes the design of “Cohort Multiple Randomized Controlled Trial” (cmRCT) with in‐built provisions to conduct multiple randomized controlled trials (Figure 1). A large cohort of the rural population (4 zones of India, through established Indian Council of Medical Research ‐ Model Rural Health Research Units) has been established aiming to explore risk factors for dementia and follow them systematically with yearly neuropsychological evaluation for 5 years. Active screening is ongoing at multiple sites of the project. Detailed neuropsychological testing and risk factor analysis are in progress. An ancillary study proposes to design a multimodal “care bundle” for the prevention of dementia, which is culturally tailored and context‐specific to the Indian population (Figure 2). This intervention will undergo testing for feasibility in the hospital setting at the central coordinating site, through a pilot randomized controlled trial (six months). The curated care bundle will be the first intervention tested in phase 2 of SMRUTHI INDIA cmRCT cohort.

Result

We have recruited 432 (South zone 236, East zone 130, West zone 42, North zone 24) participants so far. The mean age is 66.1 ± 7.6 years. 258 (59.7%) participants are females. 266 (69.1%) have no formal education. Only 109 (25.3%) are actively employed. 374 (86.6%) are married, with 259 (60.1%) living in a joint family. 104 (36.1%) are overweight or have grade 1 obesity. Hypertension is present in 136 (31.5%), active smoking in 131 (30.3%), diabetes in 59 (13.7%), current alcohol consumption in 52 (12%), uncorrected vision loss in 33 (7.7%), hearing loss in 7 (1.6%), known coronary artery disease in 2 (0.5%).

Conclusion

SMRUTHI‐India study intends to find the potential of sustainable multimodal interventions for the prevention of dementia among Indians with rural background. Low education is highly prevalent. Obesity, hypertension and smoking affect nearly one‐third of the participants and could represent important targets for dementia prevention in India. (CTRI/2014/01/061172)
Perceived adverse maternal control during childhood and striatal volume in healthy older adults: Differences between APOE ε4 carriers and non‐carriers
Authors: Gheorghe Delia A , Kuenzi Morgane , Bauermeister Sarah
Published: January 2025

Background

Early adversity has been reported as a risk factor for dementia. Adverse maternal control (MC) during childhood is believed to impact neural developmental pathways. Here we studied the associations between adverse MC and the volume of the dorsal striatum in older adults given evidence from the childhood adversity literature of structural reductions and altered reward processing. The contributing roles of APOE ε4 status together with multiple other known risk factors in brain aging were analysed.

Method

We analysed data from the MRC NSHD Insight 46 study on the Dementias Platform UK Data Portal (N = 394, 48% female, 70 years). MRI acquisition and APOE ε4 genotyping are described in published cohort papers. Bilateral volumes of the caudate nucleus and putamen were obtained using the FMRIB Software Library. MC was quantified using the Parental Bonding Instrument (PBI). Using k means clustering, participants were grouped in low, medium, and high MC groups. Analyses controlled for sex, age, socioeconomic status in late adulthood and childhood, speed of pubertal growth, birthweight, BMI and MMSE score at the time of brain scanning.

Result

Multivariate tests were followed up with Bonferroni‐corrected comparisons. Smaller bilateral caudate nuclei and reduced wellbeing were found in the high MC group compared to the low MC group. MC effects on the brain were not mediated by wellbeing. When considering the role of APOE ε4, Roy’s largest root revealed a significant interaction between MC and APOE ε4 status. Corrected follow‐up comparisons showed that in non‐carriers only, high MC was associated with smaller left caudate, left putamen volumes as well as reduced wellbeing, compared to the low MC group. Separately, in a smaller sample of APOE ε2 carriers (N = 51), the left caudate volume was smaller in high MC group.

Conclusion

Our study showed that regions implicated in reward processing are smaller in individuals who experienced adverse MC during development. These effects were present in APOE ε4 non‐carriers. APOE ε4 effects are detectable in the dorsal striatum in later life in preclinical populations. Whether genotype masks stress effects on the brain in APOE ε4 carriers is yet to be established.
Association of life course adiposity with risk of incident dementia: a prospective cohort study of 322,336 participants
Authors: Yue‐Ting Deng
Published: January 2025

Background

Cohort studies report inconsistent associations between body mass index (BMI) and all‐cause incident dementia. Furthermore, evidence on fat distribution and body composition measures are scarce and few studies estimated the association between early life adiposity and dementia risk.

Method

322,336 individuals of European ancestry were included in the main analysis after exluding people with baseline dementia, who are younger than 50 years old and who are non‐white. All participants joined the UK Biobank study from 2006 to 2010 and were followed up until December 31, 2020. Overall adiposity was comprised of birthweight (BW), childhood body size and adulthood body mass index (BMI). Other adiposity measures included central adiposity, body composition and fat distribution. Incident all‐cause dementia, ascertained through hospital inpatient, death records, and primary care.

Result

Among the 322,336 individuals (mean [SD] age, 62.24 [5.41] years; 53.9% women) in the study, during a median 8.74 years of follow‐up, 5083 all‐cause incident dementia events occurred. The risk of dementia was 22% higher with plumper childhood body size (P < 0.001). A strong U‐shaped association was observed between adult BMI and dementia. More fat and less fat‐free mass distribution on arms were associated with a higher risk of dementia. Interestingly, similar U‐shaped associations were found between BMI and four metabolites (i.e., 3‐hydroxybutrate, acetone, citrate and poly unsaturated fatty acids), four inflammatory cells (i.e., neutrophil, lymphocyte, monocyte and leukocyte) and abnormalities in brain structure that were also related to dementia.

Conclusion

In this large cohort study, adiposity in both childhood and adulthood were significantly associated with risk of dementia and a strong U‐shaped association existed between BMI and dementia. The findings that adiposity is associated with metabolites, inflammatory cells and abnormalities in brain structure that were related to dementia risk might provide clues to underlying biological mechanisms. Interventions to prevent dementia should begin early in life and include not only BMI control but fat distribution and body composition.
A framework for concepts of reserve and resilience in aging
Authors: Stern Yaakov
Published: January 2025

Background

This talk will review the Framework and discuss how it can be used to help conceive of and design research studies into cognitive reserve, brain maintenance and brain reserve. It will also highlight several funded pilot awards that emerged to implement the operational definitions. Finally, the talk will highlight the fourth Collaboratory workshop at which a set of collaborative research projects were initiated that make use of the Framework and address both human and nonhuman cognition.

Method

The Framework offers consensus operational definitions for three aspects of an overall concept of “resilience:” cognitive reserve, brain maintenance and brain reserve.

Result

Cognitive reserve is defined as a property of the brain that allows for cognitive performance that is better than expected given the degree of life‐course related brain changes and brain injury or disease. Brain maintenance was defined as the relative absence of changes in neural resources or neuropathologic change over time as a determinant of preserved cognition in older age. Finally, we define the concept of brain reserve to reflect the neurobiological status of the brain at any point in time. The Collaboratory funded 12 pilot awards that utilize these definitions. These awards are summarized in the supplement to the published Framework. At a fourth Collaboratory meeting, investigators gathered to initiate new collaborative research based on the framework. These include several projects that will be discussed at this talk. Additional projects will be described including evaluation of the interaction of physical activity and stress on cognitive performance, sociocultural factors and cognitive resilience, the contribution of molecular measures such as astrocytes and glia to cognitive reserve.

Conclusion

The framework defines three concepts developed to guide research. These operational definitions are also of use if researchers choose to use alternate names for concepts. The use of a common vocabulary and operational definitions will facilitate even greater progress in understanding the factors that are associated with successful aging. The studies we discuss demonstrate that the Framework can underline a broad range of human and nonhuman studies.
A shared behavioral framework for assessing preserved cognitive function in aging in rodent models
Authors: Branch Audrey E , McQuail Joseph , Kaczorowski Catherine C. , Foster Thomas C , Disterhoft John F. , Huentelman Matthew J. , Rapp Peter R. , Barnes Carol A
Published: January 2025

Background

Animal models provide a valuable basis for identification of conserved pathological substrates and processes underlying age‐related diseases as well as neurobiological features supporting cognitive resilience in the aging brain. Behavioral measures are a fundamental component in the assessment of cognitive processes but are rarely standardized across laboratories. Currently, there is a scarcity of centralized and standardized data infrastructure for behavioral experiment data collected across laboratories which presents a barrier for data sharing, hypothesis generation, and collaboration. A key goal of the Reserve and Resilience Collaboratory has been to create consensus approaches and definitions for the study of cognitive aging. We have designed a standard reporting framework and a centralized database across several labs.

Method

In rodent model studies of cognitive aging trajectories, the Morris water maze spatial learning paradigm is a widely used test for characterization of age‐ and disease‐related cognitive decline. The place learning version of this test depends on intact limbic and cortical systems which are key sites of dysfunction in both healthy aging and late life neurodegenerative diseases. Importantly, learning index and memory scores derived from Morris water maze testing in aged subjects replicate individual differences observed in human subjects and provide a basis for identifying covarying neurobiological changes supporting cognitive reserve and maintenance. Given the prevalence of this test for characterization of individual cognitive aging trajectories and preclinical intervention studies we have designed a standard reporting framework and centralized database housing Morris water maze behavioral data collected from rodent models across several labs.

Result

Four laboratories have committed behavioral measures to the database allowing meaningful comparisons to be made across rodent strains. Initial comparisons will include variables relating to sex differences, strain, and age of testing.

Conclusion

As we develop this resource, we intend to include access to biological measures, tissue banks, and additional behavioral measures taken from subjects in the database. Our goal is to provide a resource to enable collaborations and initiatives to advance the study of cognitive and brain reserve in aging, toward the prevention of Alzheimer’s disease.
Plasma β2‐microglobulin and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study
Authors: Huang Yi‐Ming , Tan Lan , Yu Jin‐Tai
Published: January 2025

Background

Previous studies have suggested a correlation between elevated levels of β2‐microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyse the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers, and cognition.

Method

To track the dynamics of plasma B2M in preclinical AD, 846 cognitively healthy individuals in the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups (suspected non‐AD pathology [SNAP], 2, 1, 0) according to NIA‐AA criteria. Multiple linear regression models were employed to examine plasma B2M’s relationship with cognitive and CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognition.

Result

We found that the levels of plasma B2M were increased in stages 1 (P=0.0007) and 2 (P< 0.0001), in contrast to stage 0. In total participants, higher levels of B2M were associated with worse cognitive performance (P = 0.006 for MMSE; P= 0.012 for MoCA). Moreover, a higher level of B2M was associated with decreases in Aβ1‐42 (P<0.001) and Aβ1‐42/Aβ1‐40 (P=0.015) as well as increases in T‐tau/Aβ1‐42 (P<0.001) and P‐tau/Aβ1‐42 (P<0.001). Subgroup analysis found B2M correlated with Aβ1‐42 in non‐APOE ε4 individuals (P<0.001) but not in APOE ε4 carriers. Additionally, the link between B2M and cognition was partially mediated by Aβ pathology (percentage: 8.6% to 19.3%), whereas tau pathology did not mediate this effect.

Conclusion

This study consolidated demonstrated the association of plasma B2M with CSF AD biomarkers as well as a possible important role of Aβ pathology in the association between B2M and cognitive impairment, particularly in cognitively normal individuals, particularly in cognitively normal individuals. The results indicated that B2M could be a potential biomarker for preclinical AD and might have varied functions throughout various stages of preclinical AD progression.
Aberrant resting‐state functional connectivity of the default‐mode network relates to cognitive decline in the earliest Alzheimer's continuum
Authors: Lizarraga Aldana , Kassinopoulos Michalis , González‐de‐Echávarri José María , Huguet Jordi , Sánchez‐Benavides Gonzalo , Brugulat‐Serrat Anna , Suarez‐Calvet Marc , Milà‐Alomà Marta , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Gispert Juan Domingo , Cacciaglia Raffaele ,   ALFA study
Published: January 2025

Background

Amyloid‐β (Aβ) pathology affects resting state functional connectivity (RSFC), even in cognitively unimpaired (CU) individuals. However, the impact of such an aberrant RSFC on cognitive decline is yet to be determined. Moreover, most prior research focused on fibrillary Aβ deposition to predict RSFC, while early Aβ dysmetabolism as reflected by cerebrospinal fluid (CSF) concentrations has received less attention. We assessed RSFC as a function of both CSF Aβ and p‐tau in CU individuals, and further analyzed the impact of biomarker‐dependent RSFC on the longitudinal cognitive performance.

Method

Analyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). RSFC was computed amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p<0.005. The effects of CSF biomarkers on RSFC were adjusted by age, sex, years of education and APOE‐ε4 status.

Result

Of the entire sample, 38.4% had positive CSF Aβ42/40 markers. Low CSF Aβ42/40 ratios were associated to a higher RSFC between visual areas and anterior as well as posterior subdivisions of the default‐mode network (DMN) (Figure 1). These results survived a family‐wise error rate p‐value<0.005. High levels of CSF p‐tau were related to a higher RSFC between inferior temporal areas and the anterior DMN, as well as a reduced RSFC between visual and the somatomotor network. The Aβ‐related higher RSFC significantly predicted longitudinal cognitive decline in PACC, episodic memory (EM) and executive control (EC), in models adjusted by CSF biomarkers (Figure 2), and further modulated the association between CSF Aβ42/40 and PACC longitudinal decline (Figure 3)

Conclusion

In CU individuals, CSF Aβ and p‐tau affect RSFC in networks relevant for cognitive performance. Low CSF Aβ42/40 was related to hyperconnectivity between the DMN and the visual system. Lack of DMN segregation as a function of CSF Aβ42/40 may represent a driving mechanism of cognitive decline in the earliest Alzheimer’s continuum.
The association between liver fibrosis and dementia risk: a nationwide retrospective cohort study
Authors: Schonmann Yochai , Yeshua Hanny , Zelber‐Sagi Shira , Weinstein Galit
Published: January 2025

Background

Liver fibrosis is a prevalent, most often clinically silent condition. Accumulating literature suggests that liver fibrosis may be related to brain health measures. However, its predictive role in assessing dementia risk is conflicting. Hence, we assessed the relationship of liver fibrosis with incident dementia in a large, nation‐based cohort.

Method

This retrospective cohort study utilized data from electronic health records of the Clalit Health Services (CHS), the largest health maintenance organization in Israel. We included dementia‐free CHS members aged 40‐69 years who were members for >1 year on January 1st, 2006 (baseline). All‐cause dementia was ascertained via ICD‐9 codes, hospital discharge letters and purchase of medications. Liver fibrosis was assessed from recent laboratory measures using the FIB‐4 index, a serum‐based algorithm. Cox regression models were used to assess the relationship between liver fibrosis and dementia incidence while adjusting for various sociodemographic, life‐style and comorbidities. Interaction of liver fibrosis with age, sex, socioeconomic status, ethnicity, obesity, smoking, prevalent diabetes, IHD and history of stroke were further assessed. Lastly, we conducted several sensitivity analyses, among them excluding dementia cases occurring at the first 5‐years of follow‐up.

Result

Of the 826,578 individuals included in the study (mean age 55±8y at baseline), 636,967 (77%) had no fibrosis, 180,114 (21.8%) had inconclusive fibrosis status and 9,497 (1.2%) had high risk for advanced fibrosis according to FIB‐4. Over a mean follow‐up of 15 years, 41,089 dementia diagnoses were recorded. After adjustment for potential confounders, individuals with inconclusive liver fibrosis range and those with advanced fibrosis had a 9% (Hazard Ratio (HR) 1.09, 95%CI 1.07, 1.11) and 18% (HR 1.18 95%CI 1.10, 1.27), respectively, higher dementia risk compared to those with no fibrosis (Figure). The association between liver fibrosis and dementia risk were stronger in those aged 45‐54y compared to other age groups and in persons with no history of diabetes, Ischemic heart disease and stroke. The results remained robust after exclusion of dementia cases occurring in the first years of follow‐up.

Conclusion

Liver fibrosis assessed through a non‐invasive serum‐based algorithm may serve as a novel risk factor for dementia in the general population.
Human iPSC‐based models of Alzheimer’s disease
Authors: Shi Yanhong
Published: January 2025

Background

Brain organoid models were generated from healthy control or Alzheimer’s disease patient iPSCs to facilitate our understanding of AD pathogenesis.

Method

ApoE3 and ApoE4 iPSCs were developed into brain organoids using our recently developed brain organoid platform that allows prolonged culture of brain organoids. Human iPSCs were also differentiated into microglia, which were then co‐cultured with brain organoids. These neuroimmune organoids were used to uncover mechanisms underlying neurodegeneration.

Result

We developed a long‐term brain organoid system that can undergo prolonged culture. Moreover, these organoids can support long‐term microglial co‐culture. Microglia can prevent neurons from degeneration in the long‐term brain organoids. ApoE4 microglia are less effective in reducing neuronal degeneration than ApoE3 microglia.

Conclusion

The microglia‐containing long‐term brain organoid platform generated in this study provides a promising human cellular model for studying brain‐immune interactions in brain development and pathogenesis of neurological diseases such as AD.