bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Obesity Paradox in Alzheimer’s: A Systematic Review
Authors: Delphus Daniela , Mittal Vaibhav , Karur Prasanna , Knight Alexander , Moussa Hadi , Khanna Deepesh
Published: January 2025

Background

Alzheimer’s Disease (AD) is a neurodegenerative disease that manifests as memory impairment, cognitive decline, and dementia. Of the preventive measures that exist for AD, research has been ongoing for modifiable risk factors, particularly obesity. The obesity paradox suggests that midlife obesity is a risk factor for AD, while later‐life obesity is a protective measure against AD. The purpose of this study is to examine the current literature on the obesity paradox for AD and determine its validity.

Method

Articles were found on EMBASE using relevant keywords related to “Alzheimer’s,” “obesity,” “body mass index,” and “obesity paradox.” Manual de‐duplication was done and 2,784 studies were screened using a blind review method. Inclusion criteria were established for primary articles, human studies, and relevant to obesity paradox. Articles not published in English, reviews, and animal studies were excluded. Ultimately, 44 articles were selected for full‐text review.

Result

Cerebrospinal fluid (CSF) biomarkers and brain structural changes were studied to evaluate the risk for AD in different patient groups. Multiple studies observed later life obese individuals had a decreased risk of AD. Compared to individuals with lower BMI, obese patients showed slower cognitive decline. Amyloid beta and tau protein are commonly associated with AD which several studies show vary among higher BMI individuals. These individuals showed lower loads of amyloid beta in the right hippocampus and decreased CSF tau protein. Higher BMI individuals showed increased total hippocampal and brain volume. A combination of these biomarker and structural changes shows the potential protective factor in obesity paradox.

Conclusion

This review highlights the potential protective effect of later life obesity, suggesting that various biomarkers and structural changes among individuals may decrease the risk of AD. We highly recommend raising awareness and conducting further research to better understand this paradox.
Surrogate Decision‐Making Regarding Life‐Sustaining Treatments for Older Adults with Dementia Admitted to Long‐Term Care Hospitals
Authors: Kim Hyejin , Cho Jeonghyun , Park Jongsun , Kim Sang Suk
Published: January 2025

Background

Long‐term care hospitals are the main healthcare setting for the growing population with dementia in South Korea. Despite various deficiencies (e.g., insufficient resources, impractical policies and regulations) in providing quality end‐of‐life care in this care setting, few studies have explored decision‐making practices in the context of dementia and end‐of‐life care planning. Thus, this study aimed to explore how decisions concerning life‐sustaining treatments were made for patients with dementia admitted to long‐term care hospitals, identify facilitators and challenges in the process, and suggest directions to improve the current decision‐making practices.

Method

This qualitative descriptive study included 24 healthcare providers—physicians, registered nurses, social workers, or oriental medicine doctors involved in dementia care for at least six months in their current long‐term care hospitals—and 7 surrogates—family members involved in medical decision‐making. We conducted individual, semi‐structured interviews with the participants regarding decision‐making approaches, facilitators and challenges to decision‐making, and suggestions to improve decision‐making practices. Data were analyzed using a directed content analytic technique.

Result

The analysis yielded 2 main categories, 7 categories, and 19 subcategories: How decisions about life‐sustaining treatments were made for patients with dementia?; and How to support decision‐making about life‐sustaining treatments for this patient population? Physicians, nurses, and surrogates were the key personnel in decision‐making about life‐sustaining treatments in long‐term care hospitals and played different but complementary roles. Although their primary goal of care was to maintain patients’ current functional status as long as possible while securing comfort, they showed three different views toward life‐sustaining treatments. When making decisions, they considered patients’ autonomy and best interests, surrogates’ interests, and other ethical factors. Various patient/surrogate/staff‐related factors facilitated or challenged decision‐making about life‐sustaining treatments. Individual/institution/policy/regulation‐level efforts were suggested to support such decision‐making.

Conclusion

The findings highlight the importance of open communication between healthcare providers and surrogates regarding end‐of‐life care for patients with dementia. Multi‐faceted strategies (e.g., the promotion of advance care planning, education to enhance healthcare providers’ competency in end‐of‐life care discussions, development of policies and regulations supporting life‐sustaining treatment‐related practices in long‐term care hospitals) are necessary to effectively assist surrogates in treatment decision‐making in this care setting.
Improving diagnostic accuracy: development of an artificial intelligence model to aid in the diagnosis of Alzheimer’s disease dementia
Authors: Espinosa Valeria Guerra , Maestre Juan Carlos Arbelaez , Zabaleta Daniela , Espinosa Mateo Ruiz , Lopera Francisco , Aguillon David Fernando , Espinosa Sofia Guerra
Published: January 2025

Background

Currently, the diagnosis of Alzheimer’s disease dementia (ADD) is determined based on clinical criteria, as well as specific imaging and cerebrospinal fluid (CSF) biomarker profiles. However, healthcare professionals face a variety of challenges that hinder their application, such as the interpretation and integration or large amounts of data derived from neuropsychological assessment, the importance attributed to each source of information and the impact of unknown variables, among others. Therefore, this research focuses on the development of a computerized diagnostic tool based on Artificial Intelligence (AI), to strengthen the capacity of healthcare professionals in the identification and diagnosis of ADD.

Method

During this research, all phases of the Cross‐Industry Standard Process for Data Mining (CRISP‐DM) methodology were applied. Specifically, seven types of machine learning (ML) classifier algorithms were trained with data derived from the medical and neuropsychological evaluation of 870 people with and without ADD. Additionally, genetic algorithms (GAs) were used to choose the hyperparameters of six of the models and the best performing model was deployed through a graphical user interface.

Result

A total of 147 ML models were trained to differentiate or classify between people with and without ADD. Using a random forest (RF) algorithm and 31 predictor variables we achieved a sensitivity of 98%, a specificity of 100% and an area under the curve (AUC) of 0,988.

Conclusion

We trained and evaluated a variety of ML models, highlighting the accuracy of a RF algorithm together with the use of GAs, to distinguish people with and without ADD. Additionally, we deployed the model with the best performance metrics through a graphical user interface in order to promote its future use in clinical settings.

Although these results are promising, the ongoing need to evaluate and re‐train the model, as well as the ethical considerations of its implementation, are well acknowledged.
Local disruptions in non‐rapid eye movement sleep expression are associated with cerebrovascular pathology and worse memory performance in older adults
Authors: Berisha Destiny E , Rizvi Batool , Chappel‐Farley Miranda G. , Dave Abhishek , Meza Novelle J , Sattari Negin , Lui Kitty K. , Chen Ivy Y. , Tustison Nicholas J. , Neikrug Ariel , Benca Ruth M , Yassa Michael A. , Mander Bryce A
Published: January 2025

Background

Aging is associated with disruptions in non‐rapid eye movement (NREM) sleep and memory decline. Cerebral small vessel disease (CSVD) increases with age and is associated with clinical sleep disturbance, but little is known about its relationship with local expression of NREM sleep. Here, we explore associations between CSVD burden, memory, and local electroencephalography (EEG) measures during NREM sleep in older adults.

Methods

Fifteen cognitively intact older adults (mean age 71.8±6.3 years, 10 female, Apnea Hypopnea Index (AHI)=7.82±7.95) underwent T2‐weighted fluid‐attenuated inversion recovery magnetic resonance imaging, an in‐lab overnight polysomnography with 128‐channel EEG, and a sleep‐dependent mnemonic discrimination task was administered. Lobar white matter hyperintensity (WMH) volumes were calculated using a validated semi‐automated toolbox. Topographical correlations were run with 5000‐permutation threshold free cluster enhancement.

Results

Older age was associated with lower absolute posterior total (all p<0.016, r>‐0.61) and slow sigma power (all p<0.018, r>‐0.60) and slow wave activity (SWA) (all p<0.017, r>‐0.61) over centro‐posterior EEG derivations. Age was also positively associated with frontal (τ=0.51, p<0.01) and parietal (τ=0.49, p<0.01) but not occiptal (τ=0.33, p=0.092) or temporal (τ=0.36, p=0.064) WMH burden. Occipital WMH burden was also not associated with AHI (τ=0.038, p=0.843). Occipital WMH burden was associated with global reductions in alpha activity (all p<0.043, τ>‐0.78), centro‐posterior reductions in SWA (all p<0.043, τ>‐0.63) and Delta (all p<0.009, τ>‐0.63), frontal reductions in total (all p<0.043, τ>‐0.71) and fast sigma power (all p<0.004, τ>‐0.57), global reductions in slow sigma power (all p<0.043, τ>‐0.71), and central reductions in theta activity (all p<0.042, τ>‐0.57). Better lure discrimination for low similarity lures was significantly positively associated with higher relative slow oscillation expression over fronto‐parietal regions, though this did not survive TFCE correction (all p<0.033, r>0.55).

Conclusions

Collectively, these findings indicate that WMH burden in older adults is associated with local disruptions in NREM sleep expression in multiple frequency bands, of which lower frequencies were particularly vulnerable. This in turn may explain weakened memory performance. Future studies should examine the role of NREM sleep expression in cognitive decline associated with CSVD burden.
Life‐course food insecurity is associated with cognition in later life: Evidence from the National Longitudinal Youth Survey 1979 Cohort
Authors: Esaryk Erin E , Vable Anusha M , Hebert Jillian , Pacca Lucia , Gaye S. Amina , Khadka Aayush , Singh Sonali , Wells Whitney M , Hill‐Jarrett Tanisha G , Martinez Suzanna
Published: January 2025

Background

Life‐course food insecurity may influence cognition through pathways of stress and poor health. Yet, few longitudinal studies examine whether life‐course food insecurity is associated with cognition among U.S. adults.

Methods

We performed a secondary data analysis using National Longitudinal Youth Survey 1979 data from 1979‐2016 (N = 7,320). Annual food security status was estimated between the ages of 22‐45 using 2008 Supplemental Nutrition Assistance Program eligibility requirements for household income and assets as a proxy. Sequence and cluster analyses were used to identify prototypical food security status trajectories. We identified seven trajectory groups ranging from persistently food secure to persistently food insecure. Trajectory groups varied by order, timing and duration of food security status. Cognition (ages 45‐59) was measured using five assessments, which were summarized into z‐scores (attention, memory, overall cognitive) and Langa‐Weir cognition score. We used linear regression to model associations between food security trajectory groups and cognition, while controlling for covariates.

Results

Most respondents were in the persistently food secure group (65%), with a Langa‐Weir cognition score of 15.84 (SD = 4.57, scale = 0‐27), and z‐scores as follows: memory, 0.00 (SD = 0.00); attention, 0.01 (SD = 0.76), overall cognitive, 0.00 (SD = 0.00). Compared to the persistently food secure group, the following groups were negatively associated with cognition after adjustment: persistently food insecure (β Langa‐Weir cognition: ‐2.08, 95% CI [‐2.64,‐1.52]), food insecure with bouts of food security in emerging and early adulthood (β Langa‐Weir cognition: ‐1.51,[‐2.19, ‐0.83]), food secure through middle adulthood and food insecure in later adulthood, (β Langa‐Weir cognition: ‐1.19, [‐1.73, ‐0.65]), and food insecure through middle adulthood and food secure in later adulthood (β Langa‐Weir cognition: ‐0.66, [‐1.17, ‐0.14]) Coefficients were consistent for z‐score outcomes.

Conclusions

We observed a dose‐response trend, such that cognitive ability decreased among groups with prolonged food insecurity exposure. Food insecurity is modifiable; therefore, strengthening policies to improve food access among Americans is imperative.
Gabapentin initiation and neurocognitive changes in older adults with cognitive impairment
Authors: Oh GYeon , Moga Daniela C , Fardo David W. , Harp Jordan P. , Abner Erin L.
Published: January 2025

Background

Gabapentin has been increasingly prescribed to older adults for off‐label indications, and accumulating evidence suggests potential for gabapentin misuse and related adverse events. However, the relation between gabapentin initiation and longer‐term neurocognitive changes is not well understood.

Method

A retrospective cohort study was conducted using the National Alzheimer’s Coordinating Center Uniform Data Set (2005‐March 2023). Participants with cognitive impairment at the visit of gabapentin initiation (i.e., index visit) were included. Using the incidence density sampling method, up to 9 non‐users were randomly selected for each initiator. Cognitive decline over one year was defined as any increase in Clinical Dementia Rating global score (CDR®GLOB) or a 1‐point increase in CDR® sum of boxes (CDR®SB). Functional status decline over one year was defined as at least a 3‐point increase in the Functional Activities Questionnaire (FAQ) sum or a 0.3‐point increase of mean of FAQ. Motoric decline over one year was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, joint stabilized inverse probability of treatment weights and censoring weights were used. Generalized estimating equations with an exchangeable working correlation structure were used to fit logistic regression models and account for the weighting, The confounders were selected using directed acyclic graphs. All analyses were conducted comparing index to index+1 and index+2 visits.

Result

For the study of cognitive and functional status decline, we included 505 initiators (mean age [SD]: 78.8 [7.4]; male = 45%) and 4,545 non‐users (79.2 [7.6]; 50.1%). For the study of motor decline, we included 353 initiators (78.3 [7.2]; 42.8%) and 3,177 non‐users (78.5 [7.4]; 48.1%). Gabapentin initiation was not statistically associated with decline on CDR®GLOB, CDR®SB, FAQ sum, or mean FAQ at the index+1 or index+2 visits. However, gabapentin initiation was significantly associated with increased odds of new falls at the index+2 visit (odds ratio [95% confidence interval]: 2.1 [1.1, 3.9]) (Figure 1).

Conclusion

Over 1 or 2 years of follow‐up, gabapentin initiation was not associated with decline in cognitive or functional status but was associated with increased odds of falling among research participants with cognitive impairment.
Comparing Research Attitudes in Down Syndrome and Non‐Down Syndrome Research Decision‐makers
Authors: Lu Thuy V , Campos Paola , Leader Sean , Lee Xavier , Xu Helena , Doran Eric , Gillen Daniel L , Grill Joshua D , Lott Ira T.
Published: January 2025

Background

Recruitment challenges in people with and without Down syndrome (DS) can delay research progress and risk sample bias. This study identified and quantified differences in research attitudes across populations of research enrollment decision‐makers for individuals with and without DS.

Method

We compared scores on the Research Attitudes Questionnaire (RAQ) of individuals enrolled in two recruitment registries: the UCI Consent to Contact [C2C (N = 4818)] and DS‐Connect (N = 976). We compared total RAQ scores using linear regression. We assessed item‐level RAQ differences using proportional odds regression.

Result

Mean total RAQ scores were not statistically different between DS (DS‐Connect) and non‐DS (C2C) decision‐makers, adjusting for age, sex, race and ethnicity, education, and COVID‐19‐time frame (Est. Diff = 0.11, 95% CI: ‐0.22, 0.43; p = 0.531) (see Table 1). In prespecified item‐level comparisons we did, however, find evidence of differential attitudes on item‐level RAQ scores (see Figure 1). Specifically, DS participants had an increased odds of a more favorable response to the question of responsibility to help others (DS vs non‐DS: OR = 1.26, 95% CI: 1.08, 1.48) and a decreased odds of a more favorable response to the question regarding belief that medical research would find cures for major diseases during their lifetime (DS vs non‐DS: OR = 0.77, 95% CI: 0.66, 0.90).

Conclusion

Our findings provide a framework for researchers to develop precise strategies for recruiting DS and non‐DS individuals into clinical research. The apparent differences in particular research attitudes across these two populations warrant further investigation to instruct these strategies.
PROGRESS‐AD: a phase 2 study to evaluate efficacy and safety of GSK4527226 (AL101), an anti‐sortilin monoclonal antibody, in patients with early Alzheimer’s disease
Authors: Machlitt‐Northen Sandra , Abdelkarim Azza , Bailey Christine , Budda Balasubrahmanyam , Bombois Stéphanie , Brew Bruce , Brintziki Dimitra , Burgess Brady , Cohen Sharon , Ganji Gopinath , Germani Massimiliano , Inman Dave , Jayabalan Tharaka , Mummery Catherine J. , Park Lovingly , Parker Christine , Romano Gary , Sadowski Martin , Salvadore Giacomo , Lai Robert Y. K.
Published: January 2025

Background

Progranulin (PGRN), a glycoprotein secreted by microglia and neurons, regulates lysosomal function, neuroinflammation, and has neurotrophic effects. Variants in the granulin gene (GRN) that cause a reduction of PGRN in plasma and cerebrospinal fluid (CSF) are associated with an increased risk of Alzheimer’s disease (AD). The sortilin receptor (SORT1) on neurons and microglia regulates PGRN degradation. GSK4527226 (AL101) is a human monoclonal immunoglobulin G1 antibody that inhibits SORT1 and increases extracellular PGRN levels in plasma and CSF. In Phase I studies, GSK4527226 was well tolerated with an acceptable safety profile in healthy volunteers, and showed dose‐dependent PGRN elevation in plasma and CSF (Ward et al. CTAD 2021; Germani et al. ACCP 2023).

Method

PROGRESS‐AD is a phase 2, parallel group, randomized, double‐blind, global study which aims to evaluate the efficacy and safety of GSK4527226 versus placebo in patients with early AD (N = 282) (EU CT: 2023‐505083‐11‐00; NCT06079190). Eligible patients are in the Alzheimer’s continuum, with amyloid positivity and clinical severity consistent with mild cognitive impairment or mild dementia, as defined by the 2018 National Institute on Aging and Alzheimer’s Association Research Framework (Figure). Patients (aged 50‐85 years) will be randomized to receive intravenous GSK4527226 (dose 1), GSK4527226 (dose 2), or placebo for 76 weeks, followed by a 12‐week safety follow‐up period (Figure). Randomization will be stratified by APOE4 status, AD stage and participation in the CSF sub‐study. The primary endpoint is change from baseline (CFB) in the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) score across Weeks 52, 64, and 76. Key secondary endpoints include CFB in the iADRS, ADAS‐Cog14, ADCS‐iADL component of ADCS‐ADL‐MCI, and ADCOMS. Safety endpoints include incidence of treatment‐emergent adverse events. Key exploratory endpoints include effect of GSK4527226 on pharmacodynamic and disease biomarkers, and pharmacokinetics of GSK4527226. The primary analysis will use a proportional MMRM (Wang, 2022) under a Bayesian framework with a non‐informative prior distributions. Three sub‐studies will be conducted to assess the effects of GSK4527226 on amyloid PET, tau PET, and CSF biomarkers.

Result

N/A.

Conclusion

This study of the anti‐sortilin antibody, GSK4527226, will comprehensively evaluate its efficacy, safety and effects on pathogenesis in early AD.
Investigating the effects of semaglutide in early Alzheimer’s disease using single‐cell transcriptomics and proteomics – rationale and design
Authors: Johannsen Peter , Bentsen Marie , Attfield Kate , Frederiksen Kristian Steen , Frisoni Giovanni B , Jeppesen Rose , Malik Ibrahim J , Knudsen Lotte Bjerre
Published: January 2025

Background

Evidence suggests glucagon‐like peptide 1 receptor agonists (GLP‐1RAs) may have therapeutic potential in Alzheimer’s disease (AD). Cumulative evidence has indicated a potential reduction in cognitive decline in people with AD, while real‐world evidence has shown decreased dementia risk in patients with type 2 diabetes. Non‐clinical data reveal that GLP‐1RAs impact neuroinflammation and other biological processes believed to be involved in AD pathophysiology, including effects on central and peripheral immune cells. The safety and efficacy of the GLP‐1RA semaglutide in early AD (Clinical Dementia Rating global score 0.5–1) is being investigated in two phase 3 trials (evoke [NCT04777396] and evoke+ [NCT04777409]). The aim of this exploratory study is to investigate the effect of semaglutide on central (cerebrospinal fluid [CSF]) and peripheral (blood) inflammation in a similar population using single cell transcriptomics (i.e., assessment of gene expression in individual cells) to complement and expand on the molecular understanding of semaglutide and AD.

Method

An interventional, randomized, parallel‐group, double‐blind, placebo‐controlled, multicenter, multinational study is designed to evaluate the effects of semaglutide versus placebo on central and peripheral inflammation in participants with early AD (NCT05891496; Figure). The 24 participants will be aged 55‐75 years and have established amyloid positivity. Central and peripheral inflammation will be investigated using single‐cell RNA sequencing, T‐cell receptor sequencing, and proteomics; AD‐related biomarkers (including glial fibrillary acidic protein and phosphorylated tau 217) will link cellular changes to AD pathology proxies. Cellular, protein, and biomarker changes will be assessed after 12 weeks of treatment.

Result

The study is expected to read out at the end of 2024.

Conclusion

Investigation of CSF and peripheral blood mononuclear cells at the single‐cell level in combination with protein and biomarker changes in the same individuals with early AD is an unprecedented opportunity to understand both the effects of semaglutide and the role of immune processes in early AD.
Characteristics of brain topological networks in posterior cortical atrophy: a hybrid FDG PET/MRI study
Authors: Wu Liyong , Chu Min , Nie Binbin , Liu Li
Published: January 2025

Background

Graph theory is an advanced method for analyzing the balance of brain networks. However, the changes in white matter (WM) and metabolic networks and their correlation with clinical features in patients with posterior cortical atrophy (PCA) require further investigation. This study aims to clarify the structural, metabolic, WM, and metabolic topological network in PCA, and explore their correlation with clinical features.

Method

Thirty‐four PCA patients and 34 healthy controls (HC) participated in the study and underwent hybrid FDG‐PET/MRI scans and neuropsychological evaluations. Voxel‐based morphometric analysis and Tract‐Based Spatial Statistics was used to assess gray matter volume and white matter integrity and standard uptake value ratio (SUVR) was calculated to evaluate the gray matter metabolism. Then, the topological network connectivity of 90 brain regions was computed using graph theory analysis.

Result

PCA patients exhibited gray matter atrophy and metabolic decline in the posterior regions (including the occipital, temporal, and parietal lobes), while white matter damage was more widespread, affecting the parietal, temporal and frontal to occipital tract. In both WM and metabolic topological network analyses, PCA patients displayed significant damage to global and local topological network properties. Particularly in local properties, including nodal centrality, degree centrality, nodal clustering coefficient, nodal efficiency, and nodal shortest path, the changes in the metabolic network were more significant than those in the white matter network. Not only were the posterior brain regions affected, but the frontal node was significantly impacted. PCA patients' WM and metabolic topological networks exhibited different centrality distribution patterns. Several network metrics were correlated with the clinical severity of PCA and the degree of visual impairment, notably the close association between the occipito‐frontal network and visual functional impairment.

Conclusion

The study revealed complex alterations in the topological brain networks in PCA patients, not only confined to the posterior brain but also involving the frontal nodes. In addition, the brain topological network characteristics can serve as important markers for assessing the severity of PCA, with potential value for earlier diagnosis and therapeutic intervention.
Cross‐cohort epigenome‐wide association study in Alzheimer’s disease risk and related traits
Authors: Milicic Lidija , Vacher Michael , Porter Tenielle , Dore Vincent , Bourgeat Pierrick , Doecke James D. , Shishegar Rosita , Maruff Paul , Masters Colin L. , Rowe Christopher C. , Villemagne Victor L , Laws Simon M.
Published: January 2025

Background

Epigenome‐wide association studies (EWAS) have identified multiple loci that are differentially methylated in Alzheimer’s disease (AD). However, for complex diseases such as AD, single methylation sites associated with disease and disease‐related traits have relatively low effect sizes. At the genetic level, measures of cumulative genetic risk, such as polygenetic risk scores, have yielded success in risk prediction as well as in association and interaction studies. Such approaches have the potential to be directly transferred to DNA methylation data.

Method

This study utilised data from two well‐characterised longitudinal cohort studies, the Australian Imaging, Biomarker and Lifestyle (AIBL) study (n=707) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n=620) and aimed to investigate the association between peripheral blood DNA methylation, at CpG sites across the epigenome, and eight AD‐related phenotypes: AD risk, MRI‐derived brain volumetric measures (hippocampal, ventricle, grey and white matter volumes), PET derived brain Aβ‐amyloid burden (as a continuous and binary (high/low) variable) and cognition (Pre‐Alzheimer’s Cognitive Composite (PACC)). Each trait‐specific EWAS was first undertaken in the AIBL cohort, and eight trait‐specific methylation risk scores (MRS) were then developed using summary statistics. An additional MRS was also developed using an elastic net machine learning method. MRSs were then validated within and across traits in the ADNI cohort.

Result

Nominally significant associations were observed between CpG sites within several of the EWAS that were performed; however, no individual CpG sites remained significant after FDR correction. Several MRSs were associated with AD risk after correction for the false discovery rate.

Conclusion

While this study adds to the growing literature supporting the role of MRSs in AD‐related traits, it suggests that there are limited associations of individual epigenome‐wide CpG sites with cognitive and neuroimaging traits using the methods undertaken in this study. Future studies with larger cohort sizes and phenotypically rich datasets will help to confirm these findings and potentially elucidate further associations.
Racial differences in neuropathology and cognitive abilities
Authors: Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Rodriguez Roberta Diehl , Justo Alberto Fernando Oliveira , Naslavsky Michel Satya , Zatz Mayana , Pasqualucci Carlos Augusto , Nitrini Ricardo , Ferriolli Eduardo , Jacob‐Filho Wilson , Grinberg Lea T.
Published: January 2025

Background

Racial differences in dementia prevalence and incidence were found with higher dementia burden in African descendants. Previous neuropathological studies were conducted mostly in white participants in convenience samples. Further studies in diverse populations are important to foster the understanding of race differences in dementia pathology. We aimed to compare the frequencies of neuropathological lesions between black and white participants and the association of cognitive abilities and race in an autopsy study.

Method

In a cross‐sectional community‐based autopsy study, samples were collected at the Biobank for Aging Studies from 2004 to 2023. A family member reported the deceased’s race. The frequency of neurodegenerative and cerebrovascular lesions was evaluated using immunohistochemistry and hematoxylin‐eosin staining in 13 selected cerebral areas. We also examined the association between cognitive abilities with the Clinical Dementia Rating Scale and race. Neuropathologists were blinded to cognitive outcomes. To examine the associations of race with neuropathology and cognitive abilities, we used regression models adjusted for age, sex, education, clinical variables, and apolipoprotein E genotyping.

Result

In 1,815 participants, the mean age was 74.0±12.5 years old, 50% were women, 34% were black, the mean education was 4.7±4.1 years, and 35% had cognitive impairment. Small vessel disease (SVD) (OR = 1.74, 95% CI = 1.29‐2.35, p<0.0001), siderocalcinosis (OR = 1.70, 95% CI = 1.23‐2.34, 0.001), and neuropathological comorbidity (OR = 1.35, 95% CI = 1.12‐1.63; p = 0.001) were more frequent in blacks compared to whites, while neuritic plaques were less frequent (OR = 0.61, 95% CI = 0.44‐0.83, p = 0.002). Likewise, AD diagnosis was more frequent in whites (Whites: 39%; Blacks: 33%), while vascular dementia was more common among black participants (Whites: 24%; Blacks: 32%). Race was not associated with cognitive abilities, nor was an effect modifier in the association between neuropathology and cognition.

Conclusion

In a large community‐based autopsy study, AD pathology was more frequent in whites, while vascular pathology and neuropathological comorbidity were more frequent in blacks. Cognitive abilities were similar between race groups, and race was not an effect modifier in the associations of cognition with neuropathologies. Further neuropathological studies in diverse samples are needed to understand race disparities in dementia burden.
Heritability of plasma biomarkers for Alzheimer’s Disease: A Nuclear Twin Family Design
Authors: Rousset Rebecca Z. , den Braber Anouk , Wilson David H , Teunissen Charlotte , de Geus Eco J.C.
Published: January 2025

Background

Plasma biomarkers may be a non‐invasive and cost‐effective tool for diagnosing Alzheimer’s Disease. Promising markers include amyloid‐β‐42/40 ratio (Aβ‐42/40), glial fibrillary acidic protein (GFAP), and neurofilament‐light (NfL). Not much is known about what genetic and environmental factors influence and potentially confound these biomarker levels. We aimed to determine the proportion of genetic (heritability) and environmental contributions on Aβ‐42/40, NfL, and GFAP plasma levels.

Method

Male and female twins, their parents, and up to two siblings were included (n=6516, Table 1). Plasma samples were analyzed on the Simoa HDx analyzer using the Neurology 4‐Plex E advantage kit (Quanterix). Biomarker levels were adjusted for age and sex. A twin‐only 5‐zygosities model was used to examine sex differences in genetic and environmental effects. A nuclear twin family design (NTFD) was used to estimate the proportional contributions of genetic, shared and unique environment. Shared environmental factors were broken down into environment shared by siblings, by twins only, or by parents and offspring.

Result

No sex differences in contributions to the variance in biomarker levels were found. The NTFD showed that 16% of the variance in plasma Aβ‐42/40 was explained by genetic effects and 84% by unshared environment. For NfL, 30% of variance in plasma levels was explained by genetic effects, 27% by sibling‐shared environment, and 43% by unshared environment. For GFAP, 45% of the variance in plasma levels was explained by genetic effects, 17% by sibling‐shared environment, and 38% by unshared environment.

Conclusion

The heritability of plasma Aβ‐42/40 was low, while the heritability of NfL and GFAP levels was moderate. The low heritability of Aβ‐42/40 is a mismatch with the high heritability of Alzheimer’s Disease (60‐80%), suggesting this plasma ratio might be susceptible to environmental confounding. The importance of sibling‐shared environment could be a reflection of a generational effect. If members of a generation (siblings) are collectively more exposed to a factor which influences their plasma levels, that would make them resemble each other more than they resemble the previous generation (parents). This findings are not definitive proof of confounding, but are a first step in identifying possible confounders.
Parental history of dementia does not confound the association between depression and decline in cognitive status
Authors: Guilliams Chad , Abner Erin L.
Published: January 2025

Background

Parental history of dementia may lead to participation bias and has been largely replaced in analyses with genetic markers such as APOEe4. We studied how the inclusion of parental history of dementia affects associations between depression and cognitive status.

Method

Participants without dementia were stratified by cognitive and depression status at their initial study visit (“baseline”): normal cognition without depression (n = 7,592), normal cognition with depression (n = 2,346), MCI without depression (n = 2,280), and MCI with depression (n = 1,525). Logistic regression and Fine and Gray models, with death of the participant treated as a competing event, were used to analyze whether parental history of dementia affects the association between depression and cognitive status at baseline (n = 20,796) and over time. Fine and Gray models were used for participants with normal cognition at baseline and then again for NACC participants with MCI at baseline to estimate associations for the conversion to MCI or dementia respectively. Models included APOEe4 dose, participant demographics (age, sex, race, and education), in addition to self‐reported depression and depressive symptoms.

Result

The adjusted odds of MCI were increased for those with depression at baseline, OR = 2.51 (95% CI: 2.36‐2.68), and inclusion of parental history of dementia in the logistic regression analysis slightly strengthened the association (OR = 2.55 [2.39‐2.73]). Selection bias was evident, as participants reporting both parents with dementia had the lowest adjusted odds of cognitive impairment (OR 0.65, 95% CI: 0.57‐0.73) compared to no reported parental history. In the competing risk analysis, among those with normal cognition at baseline, those with depression had an increased risk of converting to MCI or dementia, subdistribution hazard ratio (sHR) = 1.47 (95% CI: 1.31‐1.64). However, inclusion of parental history of dementia did not alter the estimates significantly in any of the Fine and Gray models.

Conclusion

There may be substantial heterogeneity among NACC participants with and without parental history of dementia. In our longitudinal analysis, parental history of dementia did not alter the association between depression and conversion to worse cognitive status. This suggests parental history of dementia may lead to differences in participation but may not confound longitudinal associations of interest.
Update on the current state of speech and language testing in Alzheimer's Disease
Authors: Dhareshwar Shloka , Mineur Ruby , Lewis Courtney , Kane Melissa , Maruff Paul , Vogel Adam P
Published: January 2025

Background

Screening and disease monitoring are two core challenges of disease management in Alzheimer's Disease (AD). Digital speech and language features have shown promise as clinical outcomes in related disorders.

Methods

We reviewed how speech digital markers are currently used in AD, focusing on how behaviours are connected to underlying disease pathology.

Result

The rate of cognitive decline can be predicted by poor performance on language tests. The capacity of current language tests to distinguish between those with mild cognitive impairment (MCI) and healthy controls is limited. In some cases, disease progression can only be detected when significant changes in severity occur. Poor standardisation and limited clinical data are currently restricting communication outcomes uptake in clinical trials. The potential advantages of speech analytics and mobile health technology lie in their cost‐effectiveness, accessibility (non‐invasiveness), and automated analytical protocols. They have the capacity to improve assessment procedures, enhance screening and provide meaningful outcomes in clinical settings.

Conclusion

High‐dimensional data can be collected by automatically and objectively analysing speech. Developments in machine learning, signal processing and natural language processing techniques will further optimise outcomes.
Care staff perspectives of clinically meaningful outcomes of supportive care programs for persons with dementia in Kentucky: A qualitative multiple case study
Authors: Reschke‐Hernandez Alaine E. , Vasil Martina , King Emma G. , Woolums Carson
Published: January 2025

Background

Emerging research suggests that complementary and supportive care programs, such as music therapy, show positive short‐term impacts (e.g., purposeful engagement, positive emotions) on persons with dementia who live in care facilities. However, barriers exist in understanding clinically meaningful outcomes (i.e., noticeable, valuable changes in a person’s life) in more advanced dementia and reliably documenting enduring outcomes within demanding care structures. This research aims to address these gaps by exploring clinically meaningful outcomes of such nonpharmacological programs from the perspective of clinical care staff.

Method

Because healthcare policies vary across the United States, this qualitative multiple case study is bound to Kentucky. This focus facilitates in‐depth analysis and description in the context of the state healthcare system. Care staff (e.g., certified nursing assistants) develop intimate knowledge of each person they care for, how they respond to various types of care, and the impact of such responses on the care environment. We are examining multiple cases (six) to reflect the care landscape within Kentucky and are using maximum variation sampling to ensure diverse identities and care experiences are represented. Data sources from each case are: (a) two interviews, (b) six weekly journal entries, (c) one site observation, and (d) publicly available facility information. Analysis involves rich case description, case‐wise thematic analysis, and cross‐case thematic analysis following Creswell’s (2013) data analysis spiral: (1) reading and memoing, (2) describing and interpreting data into codes and themes, (3) interpreting the data, and (4) representing and visualizing the data.

Results

To have transferability of results, readers must be able to gain an in‐depth understanding of each case. Therefore, planned enrollment (January to April 2024) is 6 care staff from non‐profit and for‐profit facilities across rural, suburban, and urban areas of Kentucky. Active data collection begins in February, and results are expected by July 2024.

Conclusion

The care needs of persons with dementia are high and require nonpharmacological options to maximize well‐being. Identifying ways to reliably document clinically meaningful outcomes without burdening caregivers is crucial to advance evidence‐based care. Results will provide insights into these challenges and transfer to the broader dementia care landscape.
Optimizing composite PET measurements for tracking longitudinal tau accumulation
Authors: Protas Hillary D. , Ghisays Valentina , Luo Ji , Sohankar Javad , Lee Wendy , Devadas Vivek , Chen Kewei , Reiman Eric M. , Su Yi
Published: January 2025

Background

Tangle burden, one of the hallmarks of Alzheimer’s Disease, is thought to accumulate and spread throughout the brain in a distinctive pattern starting from the entorhinal cortex following Braak stages as characterized in neuropathological studies. Longitudinal tau PET allows us to investigate in vivo the tau spread in an individual and substantial heterogeneity has been observed in the pattern of tau spread. In this analysis, we examine the statistical power of tau PET measurements in tracking disease progression using data from the ADNI cohort.

Method

The tau PET measures used in this study included conventional SUVR measures as well as graph theory based network strength measures as we previously reported (Protas 2023). We calculate the slopes of both regional SUVR and strength in 41 MCI and 71 CU participants who had one year, and/or two year follow‐up. Statistical power was assessed as the sample size needed to detect a 25% reduction in the rate of tau accumulation, and the power analysis was done for CU and MCI participants separately. The optimal composite measures (from combining up to 6 FreeSurfer ROIs) were determined based on two criteria: 1) having minimal tau accumulation (calculated sample size > 10000) in the A‐ group to ensure we are looking at AD related accumulation, and 2) having the smallest sample size in the A+ group.

Result

Strength in amygdala, entorhinal, fusiform, rostral anterior cingulate, frontal pole and transverse temporal regions gives optimal sample sizes of 172 in A+ CU. In CU A+, SUVR in amygdala, lateral occipital and middle temporal produced an optimal sample size of 230. In MCI, for strength, the sample size is 193(A+) in an optimized region including cuneus, inferior temporal, postcentral, rostral anterior cingulate, and superior parietal. With SUVR the optimal region in MCI was entorhinal and middle temporal with a sample size of 263(A+).

Conclusion

The optimal composite regional SUVR/strength measure varies depending on the target population and typically combines both early and late Braak stages. Further study is needed to confirm this finding using larger datasets.
Comparative analysis of clinical endpoint progression rates in sporadic Alzheimer’s disease and Down Syndrome‐related Alzheimer’s disease
Authors: Rafii Michael , Nicodemus‐Johnson Jessie , Hendrix Suzanne B. , Wagg Jonathan , Fournier Nicolas , Sol Olivier , Delpretti Saskia , Rongere Julien , Rudaz‐Kohler Claude , Kosco‐Vilbois Marie , Pfeifer Andrea , Streffer Johannes , Mendonca Nuno , Wassom Mitchell , Kirkham Zayne
Published: January 2025

Background

Clinical assessments utilized in trials to measure progression in sporadic Alzheimer’s disease (SAD) such as the MMSE, ADAS‐Cog, CDR‐SB and ADCS‐ADL are well established. Distinct assessments are utilized for Down Syndrome‐related Alzheimer’s disease (DSAD). Although these assessments are less well established, they probe comparable domains of cognition and function. We quantitatively compared progression rates for SAD assessments with comparable DSAD composite assessments and explored their utility in clinical trials.

Methods

The MMSE, ADAS‐Cog, CDR‐SB and ADCS‐ADL were mapped to comparable DSAD composite endpoints. Longitudinal data were sourced from the ADNI (SAD: n = 464) and ABC‐DS (DSAD: n = 393). Clinical endpoint progression rates were quantified as Mean to Standard Deviation Ratios (MSDR) of change across a unit time and derived using a model‐based approach. MSDRs were compared across populations and assessments. Clinical trial sample sizes were estimated to detect treatment effects using DSAD assessments.

Results

Sensitivity of progression rate (MSDR) to baseline Amyloid PET was apparent for many DSAD composite measures. Sensitivity to progression for DSAD composite endpoints in the total ABC‐DS population at 18 months for MMSE, ADAS‐Cog, CDR‐SB and ADCS‐ADL were ‐0.32, ‐0.29, ‐0.40, and ‐0.22, respectively. Individuals with higher baseline Amyloid levels had increased sensitivity to progression with MSDRs at 18 months of ‐0.45, ‐0.33, ‐0.49, and ‐0.36. Power calculations of the most progressive measure in the total ABC‐DS population at 18 months (CDR‐SB DS composite; MSDR 0.4) indicate that assuming a 1:1 active: placebo ratio, 60% slowing and a dropout rate of 20%, the total sample size needed to reach an alpha of 0.05 at 80% power would be 548 subjects. Sample sizes for detecting treatment effects were reduced markedly with higher baseline Amyloid; CDR‐SB DS composite MSDR ‐0.49 requires 352 and 200 individuals total assuming 60 and 80% slowing over 18 months, respectively.

Conclusions

Converging evidence demonstrates that DSAD progresses similarly to SAD. Here, we observe similar progression on composites of cognition and function between SAD and DSAD. Importantly, significantly smaller sample sizes will be required to detect treatment effects in DSAD populations when enriched for higher baseline Amyloid PET.
gamma‐secretase modulation: from bench to clinic
Authors: Rynearson Kevin
Published: January 2025

Cerebral beta‐amyloid accumulation is the key initiator of Alzheimer’s disease (AD) pathology. Most familial early‐onset AD mutations in the APP, PSEN1/2 genes increase the ratio of Abeta42:Abeta40, which drives beta‐amyloid accumulation in the brain. In 2001, the late Steve Wagner, Maria Kounnas, and I directed an agnostic high‐throughput screen for compounds that would reverse the Abeta42:Abeta40, ratio, and discovered the first non‐NSAID (second generation) gamma secretase modulators (GSM) at TorreyPines Therapeutics. Since then, in academia, we designed several novel structures similar to, but distinct from our original GSMs with predicted higher aqueous solubility. These compounds were then developed in the Wagner and Tanzi labs at UCSD and MGH, respectively with funding from the NIH and Cure Alzheimer’s Fund. Importantly, unlike gamma secretase inhibitors, our GSMs do not inhibit γ‐secretase activity, i.e. do not significantly inhibit NOTCH cleavage (up to 25 uM), but, instead, allosterically modulate gamma secretase activity, reducing generation of Aβ42 and to a lesser extent Aβ40, while enhancing production of Aβ37 and Aβ38, with IC50’s in the low nanomolar range. The preclinical development of our GSM’s evolved into four distinct chemical classes and involved testing over 1000 analogs, leading to our main clinical candidate, GSM776890, for which an IND has been submitted to the FDA (sponsored by Acta Pharmaceuticals, Boston). GSM776890 exhibits robust time‐ and dose‐dependent efficacy in both acute and chronic studies across various species, including a transgenic AD mouse model. GSM776890 displayed a >40‐fold safety margin in rats, with no observed adverse effects to the 50% effective AUC or AUC effective, which is needed to reduce Aβ42 levels by 50% in rat brain (Rynearson et al. JEM, 2021). Given the recent success of Abeta immunotherapy in clinical trials, GSM776890 represents an oral molecule alternate to managing beta‐amyloid levels as means for preventing and treating AD.