bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline demographic, risk and cognitive characteristics of the final randomized sample enrolled in a decentralised multi‐domain lifestyle intervention trial (BetterBrains) to delay cognitive decline
Authors: Rosenich Emily , Pirotta Stephanie , Cummins Hannah , Norfolk Maya , Da Costa Gabrielle , Yassi Nawaf , Churilov Leonid , Sinnott Richard O. , Brodtmann Amy , Pase Matthew P. , Barton Chris , Bush Ashley I. , Maruff Paul , Ayton Darshini , Lim Yen Ying ,   BetterBrains Research Group
Published: January 2025

AbstractBackgroundThe BetterBrains Trial is a prospective behavior‐modification blinded endpoint randomized controlled trial to delay cognitive decline in middle‐aged adults (aged 40‐70) with a family history of dementia. The primary outcome is absence of decline on at‐least one out of four cognitive tests at 24‐months. We present trial recruitment and current participant completion statistics and baseline demographic, modifiable dementia risk factor (MDRF) and cognitive characteristics of the randomized sample, blinded to intervention arm.MethodParticipants completed online assessments (betterbrains.org.au), including assessment of vascular, sleep, mood, and social/cognitive engagement MDRFs. Participants with ≥1 MDRF were eligible. Participants also completed assessments of cognition, general health, medical history, and lifestyle factors at baseline, 12‐ and 24‐months. Unsupervised cognitive testing was conducted using the Cogstate Brief Battery (see Figure 2 for details). Subjective cognition was assessed using a modified Cognitive Function Instrument.ResultFrom August 2021 to July 2023, 1830 participants enrolled and 1053 (57%) were randomized (Figure 1). Randomized participants were on average 59.7 (±6.8) years, 83% women, 90% highly educated (≥12 years of education), 93% White, and 86% reported a first‐degree family history of dementia (Table 1). Importantly, 27% resided in regional or rural Australia (Table 1). Participants reported an average of 6.5 MDRFs (max = 18) and a mean Cardiovascular Risk Factors, Aging and Incidence of Dementia risk score (without APOE) of 6.3 (max = 15) (Table 1). Baseline cognitive performance scores are presented in Table 1 and Figure 2. Randomized participants required, on average, 19.2 days to complete baseline assessment. To date, 61% and 70% of randomized participants have completed the 12‐ and 24‐month assessments (respectively), with study attrition at 3% (Figure 1).ConclusionCompared to the general population, participants in this decentralised trial exhibit some increased risk of dementia, indicated by high prevalence of first‐degree dementia family history, female gender, and prevalent MDRFs. Participant characteristics are similar to those observed within other lifestyle intervention trials. The finding that 27% of the sample resides in a regional or rural area highlights that the BetterBrains methodology facilitates inclusion of hard‐to‐reach populations. Low attrition and high follow‐up rates suggest that the BetterBrains program is acceptable and feasible.
Hypothetical Midlife Lifestyle Interventions and Dementia Risk in US Older Adults: A Comparative Effectiveness Microsimulation Study
Authors: Nianogo Roch A , Churchill Nicola A , Barnes Deborah E 
Published: January 2025

AbstractBackgroundLifestyle and metabolic multi‐domain approaches targeting several risk factors at a time are increasingly being recognized as critical for dementia prevention since single‐factor approaches and one‐size‐fits‐all interventions often fall short in substantially reducing the dementia burden. Therefore, we compared the effectiveness of several hypothetical midlife lifestyle interventions considered singly and in combination across two health approaches: high‐risk subpopulations (targeted) and general population (untargeted).MethodData came from the combined 2006 and 2008 biomarker samples of the Health and Retirement Study (HRS, N = 12,219). High‐risk populations (47%) were defined as individuals who: i) were APOEe4 carrier, ii) had high allostatic load (i.e., being in the top decile of the sum of z‐scores for biomarkers including C‐reactive Protein, HbA1c, systolic blood pressure), or iii) had metabolic syndrome (defined according to the Joint Interim Statement specification for metabolic syndrome based on measured criteria). We used the parametric, simulation‐based g‐formula to project the risk of dementia among older adults under different scenarios compared to the natural course of no‐intervention. We simulated three hypothetical lifestyle interventions based on being the top three lifestyle risk factors from the literature and the availability of the variables in HRS.ResultFor single‐factor, untargeted interventions, only exercise was associated with significant reduction in dementia risk of 13% (95% CI: 2% to 21%) reduction. Increasing social support alone reduced the risk of dementia by 9% (95% CI: ‐4% to 20%) and smoking cessation alone by 8% (95% CI: ‐3% to 18%). When exercise was combined with smoking cessation and social support, there was a 32% (95% CI: 15% to 44%) reduction in dementia risk using the general population approach (untargeted) and a 23% (95% CI: 10% to 37%) reduction in dementia risk in the general population when targeting high‐risk individuals (targeted).ConclusionMicrosimulations suggest that midlife lifestyle interventions are likely to be marginally effective at reducing dementia risk when implemented individually with exercise being the most effective. Combined, multi‐domain approaches targeting several lifestyle factors at a time and targeting the general population regardless of risk factor distribution yielded a greater reduction in dementia risk than single lifestyle interventions or targeting only high‐risk individuals.
Predicting PET‐Based Amyloid and Tau Pathology Stages With Plasma Biomarkers in Alzheimer's disease
Authors: Kim Han‐Kyeol , Lee Jae Hoon , Chun Joong‐Hyun , Lee Jeong‐Ha , West Tim , Kirmess Kristopher M. , Verghese Philip B. , Braunstein Joel B. , Connell Daniel , Ryu Young Hoon , Lyoo Chul Hyoung , Cho Hanna 
Published: January 2025

AbstractBackgroundWe aimed to investigate whether the quantitative analysis of plasma biomarkers could distinguish the pathology stages indicated by positron emission tomography (PET)‐based Thal phase of amyloid and Braak stage of tau.MethodA total of 232 participants were enrolled, all of whom underwent 18F‐florbetaben (FBB), 18F‐flortaucipir (FTP) PET, plasma p‐tau217/np‐tau217 ratio, p‐tau217, and Aβ42/40 ratio. To differentiate between image‐based Thal phases and Braak stages, region‐of‐interests (ROIs) were constructed, and cut‐off points were established at each stage using Gaussian mixture modeling. Consequently, FBB PET was classified into Thal phase 0, I‐II, and ≥III groups, while FTP PET was categorized into Braak stage 0, I‐II, III‐IV, and V‐VI.ResultThe plasma biomarker that most accurately reflected both the PET‐based Thal phase and the PET‐based Braak stage was the p‐tau217/np‐tau217 ratio. P‐tau 217 was superior in reflecting the Braak stage, but inferior to the p‐tau217/np‐tau217 ratio in the Thal phase. The Aβ42/40 ratio exhibited a difference between Thal phase 0 and I‐II, ≥III, but failed to distinguish between I‐II and ≥III, and did not correlate with the Braak stage. The AUC for predicting Thal phase I‐II and Thal phase ≥III using the p‐tau217/np‐tau217 ratio was 0.965 and 0.848, respectively. The AUC for predicting Braak I‐II, Braak III‐IV, and Braak V‐VI using the p‐tau217/np‐tau217 ratio was 0.864, 0.925, and 0.889, respectively.ConclusionThe p‐tau217/np‐tau217 ratio demonstrates a strong correlation with the pathological stages based on amyloid and tau PET and exhibits the ability to predict the pathological stages of Alzheimer's disease through quantitative values, particularly reflecting the earlier stages more accurately.
Cardiovascular‐Kidney‐Metabolic Syndrome and Incidence of Dementia among Older Adults
Authors: Jiang Xiaqing , Bahorik Amber L , Dintica Christina S. , Yaffe Kristine 
Published: January 2025

AbstractBackgroundCardiovascular‐Kidney‐Metabolic Syndrome (CKM), a systemic interplay among metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD), has profound impacts on cardiovascular events and mortality, yet its association with dementia risk remains poorly understood. With data from the Health, Aging, and Body Composition study, we investigated the association between CKM and dementia risk among older adults.MethodWe studied 2,722 participants (mean age 74 ± 2.8, 53% female, 37% Blacks) who had measurements for CKM and were free of cognitive impairment at baseline (1997‐98). We defined incidence dementia over 15 years based on hospital records, prescription for dementia medication, or a decline ≥1.5 standard deviations below the mean on the Modified Mini‐Mental State (3MS) score. CKM staging, as defined by the American Heart Association, was based on constructs comprising dysfunctional adiposity, metabolic risk factors, CKD, and CVD. We used cause‐specific hazards models to assess the association between CKM, both as a linear term and dichotomously (CKM stage 3‐4 vs. 0‐2), and time to dementia diagnosis, treating death as censored. Models were adjusted for age, sex, race, education, and baseline 3MS.ResultParticipants with advanced CKM stages (3‐4) were prevalent at baseline: 3% stage 0 (no CKM risk factors), 4% stage 1 (excess or dysfunctional adiposity), 34% stage 2 (metabolic risk factors), 17% stage 3 (subclinical CVD in CKM), and 43% stage 4 (CVD in CKM). When modeled as a linear term, a greater CKM stage is significantly associated with an 11% increase in the risk of incident dementia (hazard ratio [HR] 1.11, 95% CI 1.02 to 1.21) after multivariable adjustment. Compared to participants with CKM stages 0‐2, those with CKM stages 3‐4 had a significant 24% increase in the risk of incident dementia (HR 1.24, 95% CI 1.03 to 1.50) after multivariable adjustment. Sensitivity analyses indicated no significant interaction between CKM and race, sex, or APOE ε4 (p‐values>0.05).ConclusionAmong community‐dwelling older adults, CKM is associated with increased risk of developing dementia. Older adults with CKM may need to be followed closely for adverse cognitive outcomes, and modifiable risk factors for CKM need to be managed adequately.
KLOTHO‐VS heterozygosity ameliorates the effects of APOE ε4 on longitudinal hippocampal atrophy
Authors: Zhang Linda , Alfayate Eva , Calero Miguel , Medina Miguel , Grothe Michel J. , Sanchez‐Juan Pascual , Strange Bryan A. 
Published: January 2025

AbstractBackgroundKLOTHO‐VS heterozygosity (KL‐VShet+) has been posited to be a protective factor against age‐related disease and cognitive decline, having been associated with increased cortical volumes and brain connectivity, as well as improved cognition in healthy elderly individuals. Conversely, the APOE‐ε4 allele is a primary risk factor for the development of Alzheimer’s disease (AD), with ε4 carriers more likely to have greater β‐amyloid burden, earlier age of AD onset, and accelerated rates of cognitive decline. Relatively few studies have investigated the interaction between these two genetic factors, with those that have presenting conflicting findings.Methods720 cognitively normal elderly participants (mean age: 74.7 years, range: 69‐87) with 3T T1‐weighted MRI, APOE and KL‐VS genotyping were selected for cross‐sectional analyses from the Vallecas Project cohort, a single‐centre 12‐year longitudinal study with annual follow‐ups. Of these participants, 443 had at least two visits and were included in longitudinal analyses (average follow‐up 4.7 years). Linear regression models were conducted to study the interaction between KL‐VS heterozygosity (KL‐VShet‐ vs. KL‐VShet+: n = 539 and 181, respectively) and APOE‐ε4 (carrier vs. non‐carrier: n = 135 and 585, respectively) on FreeSurfer‐derived hippocampal volumes, neuropsychological test scores, and plasma AD biomarkers (available for a subset, n=186), controlling for age, sex, education (in models with neuropsychological outcomes), and total intracranial volume (when considering hippocampal volume). Linear mixed‐effects models were used for longitudinal analyses of the same variables.ResultsNo significant interactions between genotypes were found for any cross‐sectional comparisons. A significant KL‐VShet+ by APOE‐ε4 interaction was observed in longitudinal right hippocampal volumes, where KL‐VShet+ ε4‐carriers had similar rates of hippocampal atrophy compared to ε4‐noncarriers, and slower rates compared to KL‐VShet‐ ε4‐carriers (β=52.94, SE=25.03, p=0.03). No significant interactions were found for neuropsychological scores or biomarker levels.ConclusionOur study provides additional evidence to suggest that KL‐VS heterozygosity attenuates the detrimental effects of APOE‐ε4 on brain structure in healthy elderly adults, although the effects are not apparent in cognitive performance. Plasma AD biomarker levels did not vary significantly as a function of genotype, although this may be due to the smaller sample size. Further analyses will be conducted as more samples continue to be processed.
Stavros Niarchos Park Walk for people with dementia: Memory and Senses
Authors: Blekou Patra , Zoi Panagiota , Leonti Antigoni Athina , Kalimniou Meropi , Sakka Paraskevi 
Published: January 2025

AbstractThere are 160.000 people living with dementia and 280.000 with Mild Cognitive Impairment (MCI) in Greece. Accordingly, more than 1.500.000 family carers are involved their care. COVID‐19 pandemic and social distancing measures caused significant decline, both in an overall aspect of the people with dementia and their carers, and in specific domains (mostly communication, mood and socialization).Rapidly aging global population increases the demand for programs activating elderly people in general and people with cognitive disorders in particular. Museums and cultural centers are well placed to provide such interventions. Many studies indicate that activities such as visiting museums and cultural centers, engaging in visual and performing arts, enjoying music, dancing etc., have positive impact on people with dementia and lead to alleviation of depression symptoms and improvement of cognitive functions.In order to dismantle barriers and provide equal opportunities to people with dementia in engaging in cultural activities in Greece, Alzheimer Athens with the support of the Stavros Niarchos Foundation Cultural Center (SNFCC) has designed a guided walking tour in the Stavros Niarchos Park, where the largest public Mediterranean garden in the world is located. On a monthly basis, during an 1,5 hour tour, people with MCI and dementia are acquainted with a rich variety of flora, trees, shrubs, as well as an extensive selection of indigenous Greek aromatic plants accompanied by two health professionals from Alzheimer Athens. Later on, they visit a temporary art exhibition located at the SNFCC Esplanade. The walk ends with specially designed dual task activities using the information provided in the tour. With an average of 25 participants per tour, more than 300 people with cognitive deficits have participated since January 2023.Overall, this intervention aims to combine physical and mental activation using the senses (touch, smell, sight and hearing), to improve mood and to promote socialization of elderly participants through an interactive, educational and relaxing journey.
Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia
Authors: Zelek Wioleta M , Bevan Ryan J , Morgan Bryan Paul 
Published: January 2025

AbstractBackgroundNeuroinflammation is a critical factor of Alzheimer’s Disease (AD). Dysregulation of complement leads to excessive inflammation, direct damage to self‐cells and propagation of injury. This is likely of particular relevance in the brain where inflammation is poorly tolerated and brain cells are vulnerable to direct damage by complement. Membrane attack complex (MAC) is highly pro‐inflammatory product of the complement cascade killing cells by lysis and/or causing ‘bystander’ damage initiating NLRP3 inflammasome activation and provoking other immune damaging responses leading to death of the vulnerable nerve cells.MethodThe role of MAC in AD was investigated in MAC‐deficient animals and by using a newly developed anti‐C7 monoclonal antibody (mAb) that efficiently inhibits formation of the MAC in vitro and in vivo. Impact of C7 deficiency on brain complement dysregulation, synapse loss, amyloid load and cognitive decline was examined by comparing APPNL‐G‐F mice back‐crossed to C7 deficiency (APPNL‐G‐FxC7) with unmodified APPNL‐G‐F mice. To assess the effect of therapeutic C7 blockade, unmodified APPNL‐G‐F mice were treated systemically (for four weeks) with anti‐C7 mAb or control IgG and the same set of parameters of complement dysregulation, pathology and cognition measured.ResultC7 deficiency in AppNL−G−F mice reduced levels of complement activation markers, reduced amyloid load and increased synapse density with a commensurate improvement in cognitive test performance. Systemic treatment of AppNL−G−F mice with a blocking anti‐C7 mAb reduced brain levels of complement activation markers, amyloid load and increased neuronal spine density in treated mice in peri‐plaque areas when compared to controls. in AppNL−G−F mice. APPNL‐G‐FxC7 performed significanlty better in behavioural cognitive tests.ConclusionWe demonstrate that complement dysregulation occurs in brain in mouse models of AD. C7 deficiency reduced brain complement dysregulation, improved pathological parameters and cognitive function; systemic anti‐C7 therapy reduced complement dysregulation and protected from synapse loss in the model. Modification for brain delivery of the anti‐C7 mAb will enhance efficacy in the model. The findings highlight the potential for complement inhibition at the level of MAC as a therapy in AD.
Targeting novel anti‐complement drugs to the brain reduces complement activation and synapse loss, and improves cognition in a mouse model of dementia
Authors: Zelek Wioleta M , Bevan Ryan J , Nimo Jacqui M , Dewilde Maarten , De Strooper Bart , Morgan Bryan Paul 
Published: January 2025

AbstractBackgroundIn the brain as in other organs, complement contributes to immune defence and housekeeping to maintain homeostasis. Sources of complement may include local production by brain cells and influx from the periphery, the latter severely restricted by the blood brain barrier (BBB) in healthy brain. Dysregulation of complement leads to excessive inflammation, direct damage to self‐cells and propagation of injury. This is likely of particular relevance in the brain where inflammation is poorly tolerated and brain cells are vulnerable to direct damage by complement.MethodWe have developed novel anti‐C7 antibodies (mAb) that efficiently inhibit formation of the pro‐inflammatory membrane attack complex (MAC) in vitro and in vivo. Here we describe recombinant fusion proteins (FP) that replicate the MAC‐blocking action of the mAb, and are designed to access the brain utilising “Trojan horse” shuttles. The Alzheimer model APPNL‐G‐F mice were treated systemically with native mAb to swamp peripheral C7 followed by the FP. Immunohistochemistry and ELISA were used to demonstrate FP entry into brain and show impact on the disease pathology.ResultThe recombinant FP showed complement inhibitory activity in vitro equivalent to their parent mAb and were able to cross an artificial BBB in transwells. The presence of the FP in brain homogenates of peripherally dosed animals was confirmed by ELISA. Treatment with the FP caused reduced levels of complement activation products C3b and terminal complement complex (TCC) in brain. Diolistics analysis showed significant increased neuronal spine density in treated mice compared to controls, demonstrating a protective effect of the FP on synaptic function. Mice treated with the drug showed significant improvements in cognition.ConclusionThe FP described are able to cross BBB and are potent inhibitors of complement in brain; impact on brain pathology was detected after just one week of treatment. The findings highlight the potential for complement inhibition as a therapy in Alzheimer’s disease.
Aging and ADRD social media programs for outreach and recruitment: Longitudinal outcomes
Authors: Teano Anthony L. , Scott Ashley , Gipson Cassandra , Albert Marilyn S. , Pettigrew Corinne 
Published: January 2025

AbstractBackgroundSocial media may be a useful method for research centers to deliver health messaging, increase their visibility in the local community, and recruit study participants. There are, however, few studies evaluating the outcomes of social media in this setting. The objective of this study was to describe one Alzheimer’s Disease Research Center’s social media activities for community education on topics related to aging, memory loss, and dementia, and evaluate their impact on recruitment into clinical research studies.MethodSeveral social media platforms were used, including: Facebook, Twitter/X, and YouTube. Objective assessments quantified monthly, based on each platform’s native dashboard, included: number of posts, number of followers, post reach and engagement, and post impressions. The number of participants volunteering for research during this period was also tracked using a RedCap database, with many entries reflecting individuals who indicated that they learned about Center research through social media when completing a “Participate in Research” webform. Educational material posted to social media most frequently included content developed by Center staff, content from partner organizations, and news articles/resources featuring Center researchers. Multiple educational programs were developed, including social media series, virtual talks, Twitter chats, and webinars. Facebook content was occasionally boosted to increase visibility in the local geographical region.ResultMetrics over four years demonstrate growth in reaching social media audiences, as indicated by increases over time in the numbers of likes/followers on Facebook and Twitter and video views on YouTube (growth trajectories). Overall, Facebook reach rates and Twitter impression rates were respectable, although Facebook engagement rates were more modest (Table 1). Months that included boosted Facebook posts resulted in a greater change in page Followers and page Likes, and higher reach and engagement rates (all p£.002). Recruitment of participants into Center‐affiliated research studies increased during this time frame, particularly when Facebook posts were boosted.ConclusionThese data demonstrate that social media activities can provide increased educational opportunities focused on Alzheimer’s disease and related dementias and have a measurable impact on recruitment of participants into research studies. Additionally, this study highlights the importance of tracking outcomes to maximize return on investment.