bluuebunny/crossref_metadata_2025 huggingface dataset:
A Cross‐Sectional Study to Evaluate the Impact of Dietary Patterns on Cognition in the Aging Urban Indian Population
Authors:   Amitha C M , Lingegodwa Abhishek Mensegere ,   Divya N M , Partha Ajith , Menon Meenakshi ,   Meghana R , Narayanasamy Rajitha , vishwanath Vindhya , HS Deva Kumar , Malo Palash K , Stezin Albert , Velavarajan Goutham , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Singh Sadhana , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

The impact of the pattern of daily food consumption on cognition is a less explored area. This study aims to identify the impact of dietary patterns on the cognition of the elderly population, specifically comparing absolute vegetarians and omnivores.

Method

It is a cross‐sectional analysis of the aging urban Indian population of 1237 participants recruited from the ongoing Tata Longitudinal Study of Aging (TLSA). The information on diet was obtained using a diet questionnaire. Cognition was assessed using COGNITO (Computerized Assessment of Information Processing), ACE (Addenbrooke’s Cognitive Examination) which includes memory, attention, fluency, language, and visuospatial span. Chi‐square test and multiple linear regression analysis models were used for statistical analysis.

Result

Results reveal a cohort of 824 absolute vegetarians and 413 omnivores, with the latter being comparatively younger, though literacy rates show no significant difference between the groups. There is a significant association between omnivores and in few cognitive domains such as visual attention (β: 0.451, p<0.001), and dual attention (β: 0.368, p<0.002).

Conclusion

The presented data suggests a noteworthy association between mixed dietary patterns, and cognitive function among aging urban Indians. Absolute vegetarians are recommended to consume more proteins in their preferred food forms to have a positive impact on cognition. Incorporating dietary recommendations with a focus on promoting a balanced diet has implications for public health interventions.
Loneliness and Alzheimer’s disease: Testing associations using univariable and multivariable Mendelian randomisation models
Authors: Desai Roopal , Zuber Verena , John Amber , Marchant Natalie L , Charlesworth Georgina , Stott Joshua
Published: January 2025

Background

Social isolation, encompassing factors like living alone and limited social contact, is associated with increased risk of Alzheimer’s disease (AD). One theory is that loneliness, which is the negative psychological affect often associated with social isolation, mediates the relationship between social isolation and AD. Mendelian randomization (MR) approaches that have thus far been used to investigate causal relationships between loneliness and dementia risk have not supported results from observation studies. However, loneliness has shared genetic overlap with other traits which are independently associated with dementia. The presence of these pleiotropic risk factors may obscure the results of univariable MR analysis. Therefore, the aim of the current study was to better understand possible causal pathways between loneliness and dementia by including multiple pleiotropic risk factors, specifically educational attainment, alcohol dependence, neuroticism, obesity and smoking, in a multivariable Mendelian randomization (MVMR) analysis.

Method

Publicly available genome‐wide association study data were used for the genetic instrument of loneliness and five pleiotropic risk factors and AD. A two‐sample univariable MR model was tested for loneliness and AD risk followed by a multivariable MR model to include the additional five pleiotropic risk factors.

Result

Univariable MR analysis indicated that genetic proxied risk of loneliness was not significantly associated with increased risk of AD (OR = 1.05, 95%CI: 0.72;3.65). In the multivariable model the estimate for loneliness (OR = 1.04, 95%CI:0.76;1.32) remained non‐significant. The pleiotropic paths of alcohol dependence (OR = 0.83, 95%CI:0.67;1.02), smoking (OR = 0.35, 95%CI:0.08;1.62), neuroticism (OR = 0.87, 95%CI:0.55;1.38), and education (OR = 0.56, 95%CI:0.21;1.54) were not significantly associated with increased risk for AD. However, higher body mass index (BMI) (OR = 0.41, 95%CI:0.19;0.87) appeared to reduce AD risk.

Conclusion

The null findings reported here should be interpreted within the context of limitations inherent to MR models including, weak instrument bias and construct validity. Specifically, the loneliness measure may lack validity. Survivor bias may account for the unexpected direction of results for BMI. While our results suggest that most of the tested pathways were not significant, further research aimed at addressing the limitations of MR is needed to better understand the nuanced interplay between loneliness, pleiotropic risk factors, and AD risk.
Mechanistic Model of Alzheimer’s Disease Progression: Linking Amyloid and Tau Pathologies
Authors: Duffull Stephen , Stone Julie A , Robey Seth
Published: January 2025

Background

Recent anti‐amyloid mAb trial results demonstrate slowing of Alzheimer’s disease progression, but to date do not fully halt or reverse this progression. Optimization of anti‐amyloid therapy (timing and duration of intervention, modality, combinations, biomarker guidance) is limited by incomplete understanding of the disease, such as relationship between amyloid and tau pathways. Mechanistic Alzheimer’s progression modeling investigated how amyloid and tau pathologies are connected in driving progression.

Method

Calibration data (amyloid PET, CSF Ab42, CSF p‐tau, tau PET) were obtained from a wide‐range of publications including observational trials and interventional trials with BACE inhibitors, anti‐amyloid mAbs, and anti‐tau antisense oligonucleotides. First, mechanistic representations of the key features of amyloid (monomer, oligomer, plaque) and tau (tau, p‐tau, NFTs with spatial spread in brain) pathology were developed separately. Next a broad empiric exploration of a large range of amyloid‐tau links was undertaken with an objective to identify a limited number of models that can describe all the available clinical data.

Result

Twenty eight variations on connecting models were considered; 12 were eliminated by review of their signature profiles, 3 due to redundancy of mechanisms, 6 due to implausible spatial mechanisms, 5 due to an inability to calibrate an amyloid component. The remaining 2 models (Amyloid plaque drives tau production or drives tau phosphorylation) could holistically describe all the available clinical data. Tau PET data from anti‐tau antisense trials were best described by a model with NFT loss (turnover 4‐times faster than amyloid plaque turnover). Further data is needed to fully characterize this process and related elements of the tau portion of the model. Simulations of early anti‐amyloid intervention (prior to emergence of tau pathology) suggested effects on progression would be enhanced relative to later intervention and emergence of tau pathology could be substantially delayed.

Conclusion

Modeling which combines mechanistic representation of understood aspects of disease biology and empiric explorations of less well‐understood aspects and is calibrated to human trial data only can yield important insights. Such approaches have an important role to play in optimizing therapeutic strategies as the field moves into complex questions of combinations or sequencing of multiple therapeutic interventions.
CSF biomarkers trajectories across the AD spectrum reveal the temporal dynamics of amyloid and tau
Authors: de Leeuw Diederick Martijn , Trieu Calvin , Vromen Eleonora M. , Verberk Inge M.W. , Blujdea Elena Raluca , Teunissen Charlotte , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , van Harten Argonde C. , Visser Pieter Jelle , Tijms Betty M.
Published: January 2025

Background

The Alzheimer’s disease (AD) research framework proposes a biological definition of the disease. Still, little is known about longitudinal dynamics of core AD biomarker trajectories and how they map to each stage on the clinical spectrum.

Methods

Participants with abnormal amyloid across the cognitive spectrum (i.e. preclinical AD, prodromal AD and AD dementia) and cognitively unimpaired controls with initially normal CSF markers were included from Amsterdam Alzheimer Center studies when they had at least one repeated CSF sample available. In all 452 samples, we measured Aß1‐42, Aß 1‐40, Aß1‐42/Aß1‐40 ratio, total tau (tTau), phosphorylated tau (pTau) with the Lumipulse multiplex. We tested longitudinal changes in all markers with linear mixed models including random intercepts and slopes, adjusting for age and sex. Each model included an interaction term of time and clinical stage. The Emmeans package in R was used to extract stage specific estimates.

Results

By definition, all controls had higher (i.e., normal) amyloid markers and lower tau markers compared to subjects with preclinical, prodromal and AD dementia at baseline (p<0.001; Figure 1). Prodromal AD and dementia had the highest levels of tTau and pTau (all p<0.001) and the lowest levels of Aß1‐42/1‐40 ratio (all p<0.001), but were similar between both stages. Over 4±1sd years, Aß1‐42/1‐40 ratios decreased in controls and preclinical AD (p<0.001 and p=0.01 respectively), but remained unchanged in prodromal AD and dementia. CSF tTau and pTau increased over time in controls, preclinical and prodromal AD (all p<0.05), but did not in the dementia stage. Increases in pTau levels over time were steeper in both preclinical and prodromal AD than in controls (p<0.05) with 10% of controls reaching abnormal levels. Increases in tTau levels were steeper in prodromal AD only compared to controls (p<0.05).

Conclusion

In this sample, we found that amyloid shifts towards abnormal levels in controls, becomes more abnormal in preclinical AD, and stabilizes in MCI and dementia. Tau markers become more abnormal in preclinical and prodromal AD only, suggesting that increase in CSF tau requires abnormal amyloid. This suggests that interventions targeting amyloid optimally happen before CSF amyloid becomes abnormal to prevent tau accumulation.
Synaptic dysfunction mediates the association between the CSF t‐tau and PACC change among cognitively unimpaired multiparous women
Authors: Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , López‐Martos David , Escalante Armand González , Milà‐Alomà Marta , Shekari Mahnaz , Ashton Nicholas J. , Kollmorgen Gwendlyn , Cacciaglia Raffaele , Grau‐Rivera Oriol , Quijano‐Rubio Clara , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Sundermann Erin E. , Gispert Juan Domingo ,   ALFA study
Published: January 2025

Background

CSF t‐tau is considered a marker of neuronal injury in AD and strongly correlates with cognitive impairment. Evidence suggests that women accumulate more tau pathology early in AD than men. However, how pregnancy influences this relationship is unclear. We explored association between the number of childbirths and t‐tau and the interaction of these factors on cognitive change in cognitively unimpaired (CU), middle‐aged women and tested whether late‐life biological pathways mediate these associations.

Method

We included 226 CU postmenopausal parous women and 144 men with children from the ALFA+ cohort (Table 1). As late‐life biological pathways we analyzed neuroinflammation (YKL 40, GFAP, and sTREM2), synaptic dysfunction (GAP‐43 and Neurogranin), and vascular dysregulation (sICAM1). All CSF biomarkers were measured using the NeuroToolKit and Elecsys® immunoassays (both Roche Diagnostics International Ltd), except GAP‐43 (ELISA). Cognitive change (3‐year follow‐up) was measured with a PACC‐like composite and individual cognitive domains. Independent linear models with t‐tau and cognitive change as dependent variables were constructed with age, education, APOE‐ε4, reproductive span, and age at first birth as covariates. We replicated the same models, adding Aβ42 as a covariate. Interaction terms between the number of childbirths and biomarkers were modeled. Causal mediation model stratified by number of childbirths was conducted to test whether late‐life biological pathways mediates t‐tau and cognitive change association.

Result

More childbirths were positively associated with higher CSF t‐tau. Number of childbirths interacted with CSF t‐tau to predict a steeper decline in PACC performance (Table 2, Figure 1A) with GAP‐43 levels mediating this relationship (Figure 1B). These results remained significant after covarying by CSF Aβ42. No significant associations among men were found.

Conclusion

A greater number of childbirths are linked to higher CSF t‐tau levels in CU middle‐aged women with a more deleterious effect on the change of PACC performance. This association was partially mediated by the effects of CSF GAP‐43, suggesting synaptic dysfunction in multiparous women in the context of early cognitive deterioration. These findings contribute to our understanding of the higher risk for AD observed in CU multiparous women, who show higher susceptibility and more adverse downstream consequences of tau pathology.
Plasma GFAP influences tau aggregation and cortical thickness thinning in Alzheimer’s disease
Authors: Guo Tengfei , Li Anqi , Sun Pan , He Zhengbo , Cai Yue , Lan Guoyu , Shi Dai , Lu Jie , Han Ying
Published: January 2025

Background

The thresholds of plasma β‐amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p‐Tau181) to detect Alzheimer’s disease (AD) pathophysiology in Chinese community older adults have not been well established. Besides, it is still unclear about the role of astrocyte reactivity in Aβ plaque deposition, tau tangle aggregation, and neurodegeneration in AD.

Method

In this study, we analyzed plasma Aβ42/Aβ40, p‐Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform in 470 Chinese older participants. Among them, 301, 195, and 70 individuals had MRI, Aβ PET, and tau PET images. The receiver operating characteristic curve analysis (Youden index) was conducted to define plasma Aβ42/Aβ40 (A) and p‐Tau181 (T) thresholds as £0.0609 and ³2.418 by comparing Aβ‐PET negative cognitively individuals and Aβ‐PET positive cognitively impaired patients. We compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal‐metaROI cortical thickness between different plasma A/T profiles and studied their association with each other using general linear models, controlling for age, sex, APOE‐ε4, and clinical diagnosis.

Result

We found that plasma A+/T+ individuals had the most astrocyte reactivity, Aβ plaque, tau tangle, axonal degeneration, hippocampal atrophy, and temporal‐metaROI cortical thinning (Figure 1). Lower plasma Aβ42/Aβ40 (p < 0.001) and higher plasma p‐Tau181 concentrations (p < 0.001) were associated with higher Aβ PET SUVR (Figure 2). Besides, higher plasma p‐Tau181 (p < 0.001) and plasma GFAP (p = 0.015) concentrations were associated with higher temporal‐metaROI tau PET SUVR, and they also showed significant interactive relation (p < 0.001) with higher tau PET SUVR (Figure 2). Higher plasma GFAP (p = 0.012) was related to more shrinking in temporal‐metaROI cortical thickness and showed significant interaction with plasma Aβ42/Aβ40 (p = 0.042) and plasma p‐Tau181 (p < 0.001) at predicting temporal‐metaROI cortical thinning (Figure 3). The voxel‐wise imaging analysis replicated these findings.

Conclusion

These findings offer significant reference for using plasma biomarkers to detect AD in the Chinese community older population and provide novel insights into understanding how astrocyte reactivity affects cortical tau aggregation and thickness thinning in AD. This study emphasizes the importance of controlling reactive astrogliosis to prevent AD progression.
Computerized decision support to optimally funnel patients through the diagnostic pathway
Authors: van Gils Aniek M. , Tolonen Antti , van Harten Argonde C. , Koikkalainen Juha , Barkhof Frederik , Herukka Sanna‐Kaisa , Hasselbalch Steen G. , Mecocci Patrizia , Remes Anne , Soininen Hilkka , Lemstra Afina Willemina , Teunissen Charlotte , Lötjönen Jyrki , van der Flier Wiesje M. , Meester Hanneke F.M. Rhodius‐
Published: January 2025

Background

The increasing dementia prevalence and potential introduction of disease‐modifying therapies (DMTs) highlight the need for efficient diagnostic pathways. Clear recommendations to guide the choice of diagnostic tests are lacking and may vary depending on different clinical scenarios. We used a data‐driven approach to identify efficient and effective stepwise diagnostic testing for three clinical scenarios: 1) syndrome diagnosis, 2) etiological diagnosis, 3) potential eligibility for DMT.

Method

We used data from two memory clinic cohorts (ADC, PredictND), including 504 patients with dementia (302 Alzheimer’s disease, 107 frontotemporal dementia, 35 vascular dementia, 60 dementia with Lewy bodies), 191 patients with mild cognitive impairment, and 188 cognitively healthy controls (CN). Tests included digital cognitive screening (cCOG), neuropsychological and functional assessment (NP), MRI with automated quantification, and CSF biomarkers. Sequential testing followed a predetermined order (Figure 1). Subsequent tests were conducted if the diagnosis remained uncertain. Diagnostic certainty was ascertained through a data‐driven clinical decision support system (CDSS) that generated a disease state index probability score (DSI, 0‐1), indicating the probability of each diagnosis. Diagnosis was confirmed if the DSI exceeded a predefined threshold, set based on sensitivity/specificity cutoffs relevant for each clinical scenario and step. We assessed correct diagnoses and the need for additional testing at each step.

Result

For syndrome diagnosis, stepwise testing (cCOG, NP, MRI) accurately identified 71% of the patients, with NP needed in 42%, and MRI in 31%. For etiological diagnosis, starting with cognitive testing to rule out dementia resulted in the need for MRI in 84% of cases, including 91% of dementia patients and 25% CN. Subsequent MRI reduced CSF required to 29%, ultimately diagnosing 81% of patients with 71% accuracy. In determining DMT eligibility, stepwise testing (cCOG, NP, MRI) correctly identified 91% of potential eligible patients for confirmatory CSF testing, while only 51% of ineligible patients.

Conclusion

Depending on the setting, alternative diagnostic pathways are accurate and efficient. As such, a data‐driven tool can assist clinicians in selecting tests of added value across different clinical contexts. This becomes especially important with DMT availability, where the need for more efficient diagnostic pathways is crucial to maintain accessibility and affordability of diagnoses.
Brain Health Services for the prevention of dementia: aligning pilot experiences for clinical deployment
Authors: Ribaldi Federica
Published: January 2025

Background

The European Task Force for Brain Health Services (BHS) has developed the concept for evidence‐based and ethical services targeting individuals with intact cognition and a high risk of dementia. BHS are complementary to current memory clinics and their missions consists of four pillars: risk assessment and profiling, risk communication, personalised risk reduction, and cognitive enhancement. Recommendations for the deployment of the four pillars have been published, and pilot BHS experiences are underway in European countries and the United States. The field is now ripe to draw lessons from these pilot experiences and move forward towards routine clinical deployment.

Method

Experts specializing in the four pillars are collaborating to assess the opportunities and challenges associated with implementing BHS in clinical practice, drawing on lessons from ongoing pilot programs. Additionally, experts in health economics are developing a business plan for the practical deployment of BHS in Geneva, along with a European business case. The BHS task force is actively formulating a comprehensive roadmap for clinical deployment, accounting for anticipated advancements over the next 3‐5‐10 years, including the incorporation of blood‐based biomarkers for risk profiling, personalized prevention and cognitive enhancement through pharmacological and non‐pharmacological interventions (e.g., non‐invasive brain stimulation).

Result

Practical programs and protocols for implementing BHS in different environments and countries will be presented ad AAIC 2024. Furthermore, we will present the roadmap for the clinical deployment of each service, along with expected timelines and the business plan for the setup of BHS as hybrid or stand‐alone services, emphasizing the progress made in aligning pilot experiences and the potential impact on dementia prevention.

Conclusion

The development and widespread diffusion of BHS in Europe and USA will contribute to fighting dementia and reduce its burden on patients, their families, and society.
Significance of plasma biomarkers in predicting long‐term dementia risk in community dwellings: insights from machine learning approaches
Authors: Xiao Zhenxu , Zhou Xiaowen , Zhao Qianhua , Cao Yang , Ding Ding
Published: January 2025

Background

The role of plasma biomarkers for predicting incident dementia in the general population is still undetermined.

Method

A total of 1857 baseline non‐demented older adults with follow‐ups within 10 years were included from a community‐based cohort. Consensus diagnoses of dementia and Alzheimer’s disease (AD) were based on clinical criteria. The Recursive Feature Elimination algorithm was used to select the important features from 90 baseline candidate predictors for developing dementia and AD prediction models. Area Under the Receiver Operating Characteristic Curve (AUC) was used to evaluate models’ performance. Models were further validated in the testing sets and subsets.

Result

During the follow‐up of 12,716 person‐years, 207 participants developed dementia (including 145 AD). The constructed Naive Bayes, Random Forest, and Bagged Trees models showed moderate‐to‐high AUCs predicting future dementia (AUCs = 0.700‐0.828) and AD (AUCs = 0.630‐0.844) in the testing sets. Age, neuropsychological tests, plasma p‐tau217, and neurofilament light chain (NfL) were the prioritized variables in all models. The models showed robustness in diverse subgroups.

Conclusion

Plasma p‐tau217 and NfL in combination with age and cognitive performance showed important values in predicting incident dementia and AD among community older adults. In the resource‐limited settings, these variables may be convenient‐collected and cost‐effective to identify participants with high risk of dementia in the general population.
Choosing wisely: Evaluating reference regions for improved longitudinal 18F‐AV‐1451 tau PET consistency
Authors: Saguer Isaac Llorente , Oxtoby Neil P
Published: January 2025

Background

Positron emission tomography (PET) can facilitate precise spatial and temporal measurement of Alzheimer's disease pathology in the brain. The default quantification measure is the standardized uptake value ratio (SUVR) of radiotracer uptake in a target region of interest normalised by uptake in a reference region. Evaluations of new radiotracers commonly assess test‐retest consistency in scans with no pathological changes, but rarely question the SUVR paradigm. Notably, even the Centiloid/CenTauR scales depend on SUVR. This study aims to quantitatively assess the impact of different reference regions on 18F‐AV‐1451 tau‐PET scans.

Method

We analysed SUVR data from 399 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) having at least two 18F‐AV‐1451 tau‐PET scans (199 CU, 149 MCI, 51 AD). Across multiple target regions of interest and common reference regions we compared SUVR longitudinal consistency for this radiotracer using median percent test‐retest (PTRT), average intraclass correlation coefficient (ICC), and average within‐subject coefficient of variation (WSCV). Target regions considered: cerebellum, brainstem, eroded subcortical white‐matter. Reference regions considered: inferior cerebellum grey‐matter, composite (cerebellum, eroded subcortical white‐matter, brainstem), and a data‐driven linear combination of these regions.

Four‐fold cross‐validation stratified by diagnostic group was used to train the linear model (optimizing the three metrics factored), using 75% of data for training and 25% for testing.

Result

Table 1 presents test‐retest performance across reference regions. The inferior cerebellum gray‐matter was the worst‐performing reference region with only 2.2% test‐retest consistency. The composite reference region produced 26% lower (better) PTRT, 33% lower (better) WSCV and 5% higher (better) ICC. Our data‐driven linear combination of reference regions outperformed inferior cerebellum gray‐matter by 32% PTRT, 37% WSCV and 3% ICC.

Conclusion

Longitudinal consistency varied based on the reference region chosen. The composite reference region and the linear model both outperformed the inferior cerebellum grey‐matter. This study emphasizes the importance of selecting an appropriate reference region for accurate assessment and tracking of Alzheimer's disease pathology in 18F‐AV‐1451 tau PET scans, in line with other studies (Young et al. 2021).
Alzheimer’s disease drug discovery centering on Hyperphosphorylated tau
Authors: Wang Kuang‐Wei
Published: January 2025

Background

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles (NFTs) which consist primarily of hyperphosphorylated tau protein. Abnormal phosphorylated tau has been considered as a pathogenic species that impairs cellular function and propagates from neuron to neuron. AD affects millions of people around the world, however, there’s no effective drug that can prevent or cure the disease to date. Drug development based on A‐beta plague has encountered a bottleneck in the past few decades. Thus, finding a drug candidate against hyperphosphorylated tau pathology becomes a key topic.

Method

With the use of recombinant hyperphosphorylated tau (p‐tau) which possesses several disease‐relevant characteristics, we have done a 100,000 – compound high‐throughput screening (HTS) based on p‐tau aggregation and cell‐based assays. The hits from the HTS were studied and modified with medicinal chemistry. The efficacy of synthetic compounds would be tested by our p‐tau cytotoxicity assay with SH‐SY5Y cells and then further verified with mice primary neurons and other functional assays.

Result

From the high‐throughput screening, 29 hits were selected to be verified in our lab. We then focused on two potential compounds, MSU‐45028 (C9) and MSU‐45031 (C13), which showed overall better molecular, chemical, and biophysical characteristics. Within C9 and C13 series, a few analogs with improved structure‐activity relationship (SAR) property also performed good or even better EC50 against p‐tau cytotoxicity.

Conclusion

The results showed that the hits identified from HTS could effectively inhibit p‐tau cytotoxicity. Our medicinal chemistry studies could improve the SAR while maintaining the efficacy of the compounds. The structural information of C9 and C13 analogs not only created potential AD drug candidates, but also provided hints for further drug development based on tau protein.
Clinical outcome assessments for LBD trials – Should we borrow?
Authors: Boeve Brad F.
Published: January 2025

Clinical outcome assessments (COAs) are an integral part of clinical trials. A fit‐for‐purpose COA with well‐selected endpoints can help determine the efficacy of a therapeutic intervention in the condition studied. The selection of the appropriate outcome measures depends not only on the condition but also on the disease stage and type of intervention studied.

In Alzheimer’s disease (AD) the clinical benefit of anti‐amyloid therapies has been assessed using outcomes that are specifically designed to measure the progression of Alzheimer’s disease during the early stages of the disease.

The enthusiasm to develop similar studies in Lewy body dementia (LBD) needs to be tempered with caution as there is no COA LBD that fully captures the progression of LBD, full symptom array, or impact of these upon function. This limitation has been partly met by the reliance on COAs developed for Alzheimer’s or Parkinson’s disease. However, these may not be valid or sensitive to treatment changes in LBD.

The impact of LBD on other domains beyond cognition including behavior, movement, and sleep represents one of the major challenges when considering the development of an LBD‐specific scale that encapsulates the severity of the disease as a whole.

During this presentation, we will discuss the limitations of the current outcome measures in LBD trials and what those developing a clinical trial focused on LBD in the near future need to be taken into consideration when deciding on a COA for disease‐modifying and symptomatic trials. We will also report on the current efforts to develop the Lewy Body Dementia‐Domain Rating Scale (LBD‐DRS), an LBD‐specific scale to be utilized in disease‐modifying therapy trials.
Objectively measured environmental features and the risk of dementia: a systematic review and meta‐analysis
Authors: Song Suhang , Jia Zimu , Myers Nicholas Gary Lamont , Sun Jin
Published: January 2025

Background

Existing evidence supports that living in a friendly environment is associated with lower risk of dementia, although the measurements of environmental variables are mixed. However, the type of environmental features reducing dementia risk has not been comprehensively identified and such associations have not been quantified. This systematic review and meta‐analysis aims to summarize the objectively measured environmental features associated with dementia and examine the pooled association between those features and dementia risk in older adults.

Method

We systematically searched PubMed, Web of Science, and EBSCO (Abstracts in Social Gerontology, AgeLine, APA PsycINFO, and CINAHL) databases on December 21, 2023, to identify the empirical studies assessing the role of objectively measured environmental features in the risk of dementia. The search yielded a total of 890 citations. According to the inclusion and exclusion criteria, ten studies were included in the systematic review and meta‐analysis. Among them, four articles included more than one environmental features, resulting in a total of 15 associations between environmental variables and dementia risk.

Result

This study summaries five environmental features that have been reported to be associated with lower dementia risk, including longer distance between residence and major roads (Hazard Ratio [HR] = 0.94, 95% Confidence Interval[CI] = 0.88‐1.00), larger green space (HR = 0.94, 95%CI = 0.88‐1.00), higher level of sidewalk installation (HR = 0.71, 95%CI = 0.52‐0.90), and less exposure to air pollution (i.e., NO2 [HR = 1.05, 95%CI = 0.96‐1.15], PM2.5 [HR = 1.03, 95%CI = 1.02‐1.05], and PM10 [HR = 1.13, 95%CI = 1.05‐1.21]). Pooled analysis showed that living in a friendly environment may reduce 7% of the risk of dementia (HR = 0.93, 95%CI = 0.90‐0.97) and exposure to air pollution may increase 5% of the dementia risk (HR = 1.05, 95%CI = 1.02‐1.08). There was heterogeneity in results across studies.

Conclusion

Even though a small number of studies included in this systematic review and meta‐analysis have examined the association between objectively measured environmental features and dementia risk, all existing investigations point to statistically significant associations in older adults. Whether those associations vary in different population subgroups and the mechanisms underlying those associations warrant further investigation.
Differential network‐based propagation of cortical thinning in atrophy subtypes in non‐demented individuals
Authors: Lorenzini Luigi , Tranfa Mario , Pieperhoff Leonard , ten Kate Mara , Pontillo Giuseppe , Alves Isadora Lopes , Shekari Mahnaz , Altomare Daniele , den Braber Anouk , Ritchie Craig W , Boada Mercè , Marquié Marta , Vandenberghe Rik , Luckett Emma S. , Hanseeuw Bernard J , Visser Pieter Jelle , Schöll Michael , Frisoni Giovanni B. , Birck Cindy , Mett Anja , Stephens Andrew W. , Gismondi Rossella , Buckley Christopher , Farrar Gill , Jessen Frank , Gispert Juan Domingo , Mutsaerts Henk‐Jan , García David Vállez , Wink Alle Meije , Collij Lyduine E. , Barkhof Frederik
Published: January 2025

Background

Different patterns of atrophy exist in the dementia stage of AD. However, little is known about the heterogeneity of atrophy patterns and the mechanisms that drive subsequent propagation of the disease in the preclinical stages.

Method

From the AMYPAD‐PNHS cohort, we included a total of 1323 non‐demented individuals, including 1094 amyloid‐negative, and 229 amyloid‐positive participants (Table 1). Gray matter thickness in 100 regions of interest was measured using FreeSurfer. Global cortical amyloid burden was derived from amyloid PET scans in Centiloids (CL).

Individuals were assigned to atrophy subtypes based on cortical thickness measures using Non‐Negative Matrix Factorization (Figure 1). Multinomial regression models were used to study differences between subtypes in age, sex, global CL and APOE E4 carriership. Linear regression models were used to investigate the effect of time on atrophy within each subtype. Coordinated deformation models (Figure 1, Shafiei et al. 2023) were used to estimate network‐based thickness changes in each region, by multiplying the effect of time in connected regions by the strengths of their connections. Connectivity strength was based on templates of functional, structural and morphometric similarity networks, and allowed us to evaluate differential mechanisms. Significance was tested using a permutation approach.

Results

Three significant subtypes of regional GM atrophy were identified:‘limbic predominant’, ‘typical AD’, and ‘diffuse cortical’ (Figure 2). Individuals assigned to the limbic predominant subtype were significantly older, while the typical AD subtype had more APOE E4 carriers compared to the others (all p<0.001). Both limbic predominant and typical AD subtypes had higher CL compared to the diffuse cortical atrophy subtype (all p<0.001). Significant longitudinal thickness changes per subtype are shown in Figure 2. In the typical AD subtype, all network architectures constrained longitudinal GM changes (p<0.001), while in the diffuse atrophy subtype, propagation was mostly determined by morphometric similarity (p<0.005). No significant prediction model was found for the limbic predominant subtype.

Conclusion

We show that atrophy subtypes can already be detected in non‐demented individuals. Progression of atrophy within subtypes is determined by network‐based mechanisms.
Multilingualism in use and white matter changes amongst healthy middle‐aged and older adults
Authors: Solé‐Padullés Cristina , Cattaneo Gabriele , Cabello‐Toscano María , Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Sánchez Javier Solana , Roca‐Ventura Alba , Alviarez‐Schulze Vanessa , Bargalló Núria , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: January 2025

Background

Bilingualism can stimulate brain plasticity (Jafari et al. Ann N Y Acad Sci. 2021;1505(1):8‐22) and is also associated with better executive function (Grundy. J Cult Cogn. Sci. 2020;4: 177–199). We investigated whether any feature of multilingualism (age of acquisition (AoA), proficiency or language usage) was related to change in white matter lesions and cognition amongst a cohort of middle‐aged to older adults.

Method

Healthy adults (N=267, age range: 45‐69, 53.56% women) from the bilingual Barcelona Brain Health Initiative cohort (BBHI, Cattaneo et al. Front Aging Neurosci. 2018 11;10) were assembled. Participants completed questionnaires of AoA for a third language (L3), level of proficiency in up to five languages and daily use of languages, up to three languages. Shannon Entropy was computed as an index measuring the proportion of languages used daily in different contexts and participants were classified as monolinguals, bilinguals or multilinguals based on this score. T1 and T2‐weighted acquisitions allowed extraction of volumes of white matter hypointensities (WMH) using Freesurfer at baseline and two years later (N=210). Stepwise regression models were conducted cross‐sectionally to investigate associations between the predicted variables (WMH and cognition) and the following predictors: age, sex, education, AoA, proficiency and Entropy levels. Linear mixed models explored changes in WMH, including fixed effects and a random intercept.

Result

Proficiency (high) and AoA of L3 (after puberty) were retained as factors linked to increased working memory (t=3.49, p=0.001; t=2,88, p=0.004, respectively). High proficiency was also associated with better episodic memory (EM, t=3.19, p=0.002). Multilinguals (high Entropy) presented increased WMH at baseline (t=2.39, p=0.024) and over time (F=4.41, p=0.013). Additionally, there was a slight WMH*Entropy interaction, with a steeper decline in EM amongst monolinguals, regardless of WMH changes, while multilinguals with a medium burden of WMH improved in EM (Figure 1 in green; F=2.39, p=0.065).

Conclusion

Multilingualism in use was linked to increased white matter change and a slightly better maintenance of EM when the burden of structural damage was low to medium. Language usage may provide the brain with an ability to cope with structural brain changes and may be considered a proxy of CR.
Comprehending Alzheimer’s Patient and Caregiver Needs
Authors: Stümpel Johanne , van Munster Marlena , Dörrhöfer Annika , Schmitz‐Luhn Björn
Published: January 2025

Background

Projected Alzheimer’s disease (AD) prevalence is expected to fourfold by 2050. With the escalating numbers of individuals affected by neurodegenerative diseases, including Parkinson’s disease (PD) and AD, associated challenges encompass increased burdens on individuals and families, societal and political implications and economic impacts. Integrating patient and caregiver perspectives is essential to creating comprehensive, patient‐centered care models that promote well‐being and resilience in the face of degenerative neurological diseases such as AD. This approach aims to contribute valuable insights into designing patient‐centered care interventions that can address common concerns across diverse neurodegenerative conditions.

Methods

Ten interviews and co‐design workshops were conducted with PD‐diagnosed individuals and their caregivers to explore future care perspectives. Participants selected cards from three domains (‘Resources,’ ‘Technologies,’ and ‘Interactions’) to envision their care. Most frequently named items were cross‐referenced with existing AD literature. Thematic analysis identified recurring patterns, and rigorous coding ensured a comprehensive exploration of various viewpoints. Synthesizing findings and extracting key themes, we contextualized results through an exploratory literature review. The integration of diverse data sources provided a robust foundation for understanding future neurodegenerative disease care needs.

Results

We identified needs and challenges throughout the disease trajectory, emphasizing emotional burden and daily life disruption. Recognizing similarities across neurodegenerative diseases, PD experiences may well be transferable to individuals with AD. However, existing AD literature proved inconclusive regarding patients’ and caregivers’ perspectives on future holistic care approaches. Our findings underscored interdependence of patient and caregiver experiences, highlighting the need for holistic support, also in AD. These address providers, administrators, and policy makers and call for tailoring technological advances, resource allocation, and strategies to the unique needs of each stakeholder group.

Conclusion

The findings underscore the need for tailored interventions and support services addressing the unique needs of individuals with neurodegenerative diseases and their caregivers. Given the increasing global prevalence of AD, understanding and meeting these needs are critical to improving the quality of life for affected persons. Moving forward, these findings contribute valuable insights for the development of holistic care models, fostering a supportive healthcare environment for those affected by neurodegenerative diseases.
Evaluating the interchangeability of blood‐based biomarkers and amyloid‐PET for identifying patients with Alzheimer’s pathology
Authors: Burnham Samantha C. , Harper Laura , Locascio Tricia , McPherson Holly E , Pontecorvo Michael , Wang Jian
Published: January 2025

Background

Presence of amyloid pathology is used to identify patients who would benefit from novel amyloid‐targeting therapies for Alzheimer’s disease (AD). Whilst PET tracers are considered the gold standard for establishing the presence of amyloid pathology, they are costly and not widely accessible. Blood‐based biomarkers, if interchangeable with PET, could help negate such an inequitable barrier to treatment. This study assesses the agreement and interchangeability between blood‐based biomarkers and amyloid‐PET.

Method

BioHermes participants with MCI or AD‐dementia and available amyloid‐PET evaluations as well as blood‐based biomarker results for PrecivityAD (C2N) and/or P‐tau217 (research use MSD, Lilly) were included. Agreement (PPA, NPA, OPA, PPV, NPV) between amyloid‐PET and blood‐based biomarker stratification as well as the non‐inferiority (Figure 1) of blood‐based biomarkers to amyloid‐PET for patient identification were evaluated. All thresholds and methods for stratification were pre‐specified. Two‐threshold stratification for the blood‐based biomarkers were implemented.

Result

537 participants with PrecivityAD and amyloid‐PET (mean‐age 73.2 years, 54.0% Female, 85.3% White, 47.3% amyloid‐PET positive) and 531 participants with P‐tau217 and amyloid‐PET (74.0 years, 53.9% Female, 85.3% White, 46.5% amyloid‐PET positive) were included. There was moderate to high agreement between the blood‐based biomarkers and amyloid‐PET visual read, Table 1. Higher agreement with amyloid‐PET visual read was achieved when participants between two‐thresholds were removed (and would require confirmatory CSF or PET evaluations). Generally, the P‐tau217 (MSD, Lilly) blood‐based biomarker demonstrated higher agreement with amyloid‐PET visual read in comparison to the Aβ blood‐based PrecivityAD test. Both blood‐based biomarkers, removing participants between the two‐thresholds, met criteria for non‐inferiority to amyloid‐PET clinical trial criteria for selecting patients with amyloid‐pathology, Table 2.

Conclusion

A clinically available plasma test (PrecivityAD, C2N) as well as a research use P‐tau‐217 assay (MSD, Lilly) were both able to rule in patients that would also be selected by amyloid PET (PPV 86% and 88%, respectively). New plasma diagnostics that incorporate P‐tau217 or other more sensitive markers may be more accurate than Aβ blood‐based tests for identifying amyloid pathology. Results support the hypothesis that blood‐biomarkers may be interchangeable with amyloid‐PET criteria for selecting patients who are suitable for and would benefit from treatment with amyloid‐targeting therapies.
Plasma pTau217, gender, and synaptic density
Authors: Yang Kao Lee , DiFilippo Alexandra H , Ma Yue , Wilson Rachael E , Thor Yer , Pasquesi Mary‐Elizabeth , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J. , Ashton Nicholas J. , Johnson Sterling C. , Christian Bradley T. , Zetterberg Henrik , Bendlin Barbara B.
Published: January 2025

Background

Synaptic loss is a key feature of Alzheimer’s disease (AD) dementia. In the entorhinal cortex (ERC) and hippocampus, phosphorylated tau (pTau) colocalizes with synaptosomes, and its presence may play a role in AD‐related synaptic loss. However, the relationship between pTau and synaptic density is not well understood. Plasma pTau represents secreted tau pathology and among the available epitopes, pTau217 has emerged as an accurate biomarker of AD pathology. Here, we tested the relationship between secreted pTau217 and synaptic density.

Method

Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention (N=38; Table 1). All participants underwent blood sampling for measurement of plasma pTau217 and [C‐11]UCB‐J PET to assess synaptic density in regions of interest (ROIs: hippocampus, ERC, and fusiform gyrus) known to show early AD tau accumulation. Synaptic density was quantified using [C‐11]UCB‐J DVR (LGA, whole cerebellar reference region) and ROIs were identified following FreeSurfer T1w‐MRI parcellation. Plasma pTau217 was determined using the ALZpath pTau217 Simoa assay on the Quanterix HD‐X platform. We utilized multiple regression analysis to examine the extent to which plasma pTau217 and gender predict synaptic density in ROIs controlling for age. All models were fitted in R and considered significant at Bonferroni‐corrected (.05/3) p<.017. During analysis we discovered one outlier; a cognitively‐unimpaired participant with pTau217 concentration >2.5 standard deviations above the mean and high UCB‐J DVR in all ROIs. Results with and without the outlier were considered.

Result

Plasma pTau217 (b=‐.07, p=0.01) and gender (b=‐.05, p=0.008) predicted UCB‐J DVR in the hippocampus, but not other ROIs (Table 2). The effect size of plasma pTau217 and gender, as measured by Cohen’s f2, was 0.23 and 0.34, respectively, indicating medium to large effects. Welch’s t‐test showed a significant gender difference in hippocampal UCB‐J DVR (Figure).

Conclusion

Our results indicate that higher levels of plasma pTau217 associated with lower synaptic density in the hippocampus. However, given the individual with high pTau217 and synaptic density, it is possible other processes unaccounted for in this analysis are impacting this relationship. Further examinations could give insight into early processes that confer neuronal injury in the AD pathological cascade.