bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility and refinement of a culturally tailored intervention to reduce financial strain among Latino caregivers using AI
Authors: Meyer Kylie , Dorai Chitra , Perales Jaime , Puga Frank , Zauszniewski Jaclene A , Benton Donna Marie
Published: January 2025

Background

Family caregivers to persons living with dementia are at risk of financial strain from the high out‐of‐pocket costs of care and reduced employment opportunities. Financial strain disproportionately affects U.S. Latino caregivers, who experience higher care costs proportionate to household incomes than non‐Latinos. In 2022, the authors presented the preliminary results of a pilot study to test a culturally tailored psychoeducational intervention (CONFIDENCE) to reduce financial strain; we summarize the results of this study and describe planned intervention refinements.

Method

We conducted a pilot study to test the feasibility of the CONFIDENCE intervention from May 2021 to September 2023. CONFIDENCE is a 5‐week group intervention delivered by Zoom by a community‐based organization in Los Angeles, CA. Caregivers could register to participate in CONFIDENCE, and, if eligible, enroll in an optional pre‐ and post‐test trial. Those in the trial completed a self‐administered online survey before the first session, post‐intervention, and 2‐ months post‐intervention. Surveys measured financial strain, and anticipated mechanisms (resourcefulness and self‐efficacy). Scores were compared using paired t‐tests.

Result

136 caregivers registered to attend CONFIDENCE, among whom 69 attended at least one session (51%). On average, the 69 attendees participated in 3.13 of 5 sessions (SD = 0.17). The 21 attendees who completed the satisfaction survey indicated they would recommend CONFIDENCE (Figure 1). Moreover, the 20 caregivers who enrolled in the optional trial reported lower levels of financial strain after participating in CONFIDENCE (p‐value = 0.013), as well as increased resourcefulness and self‐efficacy two months post‐intervention (p‐value = 0.015 and <0.001, respectively; Figure 2).

Conclusion

Assessed with Bowen et al.’s (2009) feasibility model, CONFIDENCE demonstrated high acceptability, adequate demand from end‐users, preliminary efficacy, and the ability to be implemented in a community setting. However, low attendance suggests the intervention may not be practical for end‐users to attend. CONFIDENCE is being modified to improve feasibility by consolidating sessions from 5 to 4 and integrating a digital application. This app, provided in partnership with Amicus Brian Innovations, includes text message reminders and access to interactive AI digital assistance (Figure 3). A second pilot is being conducted to examine the ongoing feasibility of the refined intervention.
Lateral Ventricle Volumes Predict Hippocampal Volume and Cognition
Authors: Chen Gengsheng , Doering Stephanie , Joseph‐Mathurin Nelly , Massoumzadeh Parinaz , Liu Jingxia , Wang Qing , Gordon Brian A. , Morris John C. , Benzinger Tammie L.S.
Published: January 2025

Background

The use of biomarkers for early detection of Alzheimer disease (AD) is crucial for developing potential treatments. As neurons die, brain structures, including the hippocampus, shrink and the cerebrospinal fluid spaces ventricles expand. However, due to its small size, hippocampal volumes can be challenging to measure. The lateral ventricles are larger and easier to reproducibly segment, even in low resolution scans. In this study, we investigated whether baseline and longitudinal changes in lateral ventricle volume could predict baseline and longitudinal changes in hippocampal volume and in cognition, assessed by the clinical dementia rating (CDR®) sum of boxes.

Method

We evaluated 518 participants enrolled in longitudinal studies at the Knight ADRC at Washington University in St. Louis (See Table 1). MRI and clinical data were obtained through OASIS (www.oasis‐brains.org). Lateral ventricular and hippocampal volumes were extracted and corrected for intracranial volume using FreeSurfer. Linear regression models were used to assess whether the baseline lateral ventricle volumes predict the baseline CDR sum of boxes or baseline hippocampal volume. A two‐step random coefficient model was used to assess whether the rate of change in lateral ventricle volume predicts the rate of change in the CDR sum of boxes or the rate of change in hippocampal volume.

Result

We found that larger baseline lateral ventricle volumes predict smaller baseline hippocampal volumes (estimate β =‐0.04, p<0.0001, Table 2, Figure 1A) and worse baseline CDR sum of boxes (estimate β =0.000007, p=0.0024, Table 2, Figure 1C). Additionally, the rate of change in lateral ventricle volumes predicts the rate of change in hippocampal volume (estimates β =‐0.0221, p<0.0001, Table 2, Figure 1B) and rate of change in CDR sum of boxes (estimates β =0.0001, p<0.0001, Table 2, Figure 1D).

Conclusion

Larger baseline lateral ventricles volumes predict smaller baseline hippocampal volumes and worse baseline CDR sum of boxes in an AD cohort. In addition, increased rates of enlargement of lateral ventricle volumes predict increased atrophy rates of the hippocampus and worsening CDR sum of boxes. Baseline and longitudinal lateral ventricle volumes could potentially be used to evaluate risk for AD in clinical populations.
Gamma‐secretase modulation: from bench to clinic
Authors: Gerlach Irene , Tortelli R. , Mueggler T. , Müller L. , Lindemann L. , Croney R. , Piosik P. , DeBuck S. , Vardar5 T. , Baumann K.
Published: January 2025

Amyloid β (Aβ) has been confirmed as a therapeutic target in AD by recent findings in Phase 3 trials with anti‐Aβ antibodies. Modulators of γ‐secretase (GSMs) are an emerging complementary approach to target amyloid. GSMs “modulate” the interaction between γ‐secretase and amyloid precursor protein (APP), leading to a reduced production of long, amyloidogenic Aβ42 and Aβ40 and to concomitantly increased levels of the shorter, non amyloidogenic Aβ37 and Aβ38. This change in processivity of γ‐secretase results in a reduced formation of soluble and insoluble Aβ aggregates and plaque deposits. Unlike inhibitors of γ‐secretase or BACE1, GSMs do not inhibit the activity of γ‐secretase and thus do not block the processing of APP and of other substrates. In addition, non‐clinical studies showed that GSMs may have beneficial effects on synaptic integrity and Aβ‐associated neuro‐inflammation.

The clinical relevance of higher Aβ37 and Aβ38 ‐levels for a reduced risk of cognitive decline have been described in observational cohorts (vonKienlin et al. 2018; Cullen et al. 2022). Nevertheless, to date the effects of GSMs on brain function and course of disease in people living with AD have not been investigated. Our novel orally available GSM RG6289 has completed the Phase 1 study in healthy young and elderly volunteers. Safety, pharmacokinetic and pharmacodynamic data from this study support the further clinical development of the molecule. The Phase 2 study in individuals with AD is expected to start this year. Challenges of developing in clinic a new mechanism of action, as well as considerations regarding how to best position this molecule for AD will be discussed in this presentation.
Structural Mechanism of γ‐secretase Cleavage and Regulation
Authors: Zhou Rui
Published: January 2025

Alzheimer’s Disease (AD) is characterized by the amyloid plaques in patient brain. The plaques are formed by β‐amyloid peptides (Aβs) that derive from the cleavage by γ‐secretase. Over 300 AD pathogenic mutations have been identified in presenilin1/2 (PS1/PS2), the catalytic subunit of γ‐secretase. Therefore, γ‐secretase serves as a potential drug target of AD. But inhibition of γ‐secretase suffers from severe side effect in clinical trials, which is thought to derive from unspecific inhibition towards its other substrates such as Notch. So, what is the molecular basis of γ‐secretase cleavage and how does the activity of γ‐secretase is regulated, especially in a substrate‐selective way?

To unravel the mechanism of substrate cleavage, we determined the cryo‐EM structures of γ‐secretase in complex with APP/Notch fragment, respectively. These structures reveal contrasting features of different substrates binding, thus providing valuable information for modulation of γ‐secretase cleavage in a substrate‐selective way. In addition, we solved structures of γ‐secretase bound to a number of inhibitors and modulator. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next‐generation substrate‐selective inhibitors. All these works lay the foundation for a better understanding towards the working mechanism of γ‐secretase and may facilitate related therapeutic intervention.
Neuronal viability/astrocyte activity ratio in the dorsolateral prefrontal cortex as a biomarker of Alzheimer’s dementia: A proton magnetic resonance spectroscopy study
Authors: Jha Shreya , Torres‐Carmona Edgardo , Iwata Yusuke , Ma Clement , Graff‐Guerrero Ariel , Fischer Corinne E. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Kumar Sanjeev
Published: January 2025

Background

N‐acetyl‐aspartate (NAA) and myo‐inositol (mI) are neurometabolites reflecting neuronal viability and astrocyte activity, respectively. These can be quantified in vivo using proton magnetic resonance spectroscopy (1H‐MRS). Previous studies have suggested that these metabolites could serve as biomarkers for Alzheimer’s disease dementia (AD). NAA and mI levels were compared in the dorsolateral prefrontal cortex (DLPFC) between AD and cognitively healthy control participants to assess for significant differences, assess if NAA/mI ratio can distinguish the two groups, and to explore the relationship between metabolites and cognition.

Method

Participants with AD and HCs over 55 years old were included. Bilateral NAA and mI levels were quantified in the DLPFC using 3T proton magnetic resonance spectroscopy (point‐resolved spectroscopy, echo time=35ms). NAA and mI levels were estimated using LCmodel version 6.3 and reported in H2O ratios i.e. NAA/ H2O or mI/H2O.

Result

The study included 64 participants, 41 with AD (mean (SD) age = 75.2 (7.2) years, females = 58.5%), and 23 HC (age = 72.2 (7.7) years, females = 60.1%). Bilateral NAA levels in the DLPFC were lower in AD vs. HC, (t(62)=‐2.5, p =0.02); however, mI levels in the DLPFC did not differ between the two groups t(62)=1.0, p=0.35. NAA/mI ratio was lower in AD vs. healthy (t(62)= ‐2.368, p =0.02). The NAA/mI ratio at a cut off value of 1.69 showed 59% sensitivity and 87% specificity at distinguishing AD from HC. NAA levels were associated positively with global cognition.

Conclusion

DLPFC NAA is decreased in AD and is associated with cognition. NAA/mI ratio shows good specificity in distinguishing AD from the control group, suggesting its role in complementing other biomarkers in ascertaining AD. Future studies should prospectively evaluate the clinical utility of NAA/mI ratio as a biomarker in AD.
Evaluating the use of eye tracking tasks as language‐ and culturally‐neutral assessments of cognition in a multi‐ethnic cohort of older adults
Authors: Yep Rachel , Nyman Alexander J , Gopinath Georgia , Alexander Madeline Wood , Marawi Tulip , Boshmaf Silina Z , Brien Donald C , Coe Brian C , Pople Christopher B , Munoz Douglas P , Ryan Jennifer D , Black Sandra E , Goubran Maged , Rabin Jennifer S
Published: January 2025

Background

Canada and the United States are both aging and becoming increasingly diverse. Despite this demographic shift, non‐White racial/ethnic groups remain underrepresented in research on cognitive impairment and dementia. A major barrier to inclusivity is the lack of cognitive assessments that are valid in individuals with diverse language and cultural backgrounds. Eye tracking tasks can potentially overcome this barrier since they do not require verbal responses and use culturally neutral stimuli. Here, we tested this hypothesis by comparing performance on standard neuropsychological tests and eye tracking tasks across individuals from White and underrepresented ethnic groups (UEG).

Method

Participants were cognitively unimpaired adults enrolled in the Canadian Multi‐Ethnic Research on Aging (CAMERA) study. Participants completed a battery of standard neuropsychological tests and two well‐characterized eye tracking tasks: the interleaved pro/anti‐saccade task (IPAST), which assesses executive function, and the visual paired comparison task (VPCT), which assesses visual memory.

Result

We included 54 participants (mean age=68.68±6.91, 70% female) with a Clinical Dementia Rating global score of 0. Among them, 22% of participants self‐identified as White (n=12) and the remaining participants identified as being from an UEG (n=42; 37% East Asian, 37% South Asian, 4% Other). Linear regression models assessed whether ethnic background (White vs. UEG) was associated with task performance after adjusting for age, sex, and years of education. We found that ethnic background influenced performance on several standard neuropsychological tests, including the MoCA (β=0.26, p=0.03), phonemic fluency (β=0.29, p=0.02), category fluency (β=0.38, p=0.003), and Benson Complex Figure delay (β=0.23, p=0.08), such that the UEG group had lower scores. There were no group differences on Trails A and B or the Symbol Digit Modalities Test (p‐values>0.1). Importantly, ethnic background did not influence performance on either eye tracking task (IPAST: β=‐0.17, p=0.17; VPCT: β=0.02, p=0.83).

Conclusion

Our preliminary results suggest that ethnic background influences performance on several standard neuropsychological tests, but not performance on the IPAST or VPCT. With further validation in larger samples, these eye tracking tasks may provide a brief and language‐free way to screen and monitor cognitive impairment in diverse samples currently underrepresented in dementia research.
Distinct CSF proteomic signatures are associated with cognitive decline in A+T+ and A+T‐ individuals with MCI due to Alzheimer’s Disease
Authors: Vromen Eleonora M. , van Harten Argonde C. , Teunissen Charlotte , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M.
Published: January 2025

Background

Individuals with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) show variability in cognitive decline. Little is known about the underlying mechanisms, but these are likely to depend on tau levels. Using untargeted proteomics in cerebrospinal fluid (CSF), we studied which processes were associated with cognitive decline in A+T‐ and A+T+ MCI individuals.

Method

We included 80 individuals from ADC (age 66±7.9 years, 28 (35%) women, 52 (66%) A+T+, 4.6±2 follow‐ups over 4.1±1.8 years). N=2323 CSF proteins were quantified at baseline using untargeted TMT LC‐MS/MS. We tested associations between each protein and 1) progression to dementia with Cox proportional hazard models and 2) decline over time on MMSE using linear mixed models with subject‐specific intercepts. All analyses were stratified for tau status and adjusted for age, sex and education. We performed enrichment analysis on proteins associated with cognitive decline.

Result

Both AT groups declined over time on MMSE, with steeper decline in A+T+ (A+T+ β±SE ‐0.99±0.08 p‐value<0.001, A+T‐ β±SE ‐0.39±0.09 p‐value<0.001, p‐valueA+T‐ vs. A+T+<0.001). Largely different groups of proteins predicted faster progression to dementia and steeper decline on MMSE in A+T+ (resp. n=119 and n=664, p‐values<0.05, Figure 1) compared with A+T‐ individuals (resp. n=88 and n=718, p‐values<0.05). In A+T+ higher levels of proteins associated with synaptic plasticity processes and extracellular matrix organization, and lower levels of proteins associated with immune system processes and lipid remodeling were associated with steeper cognitive decline. Conversely, in A+T‐ these processes were associated with slower cognitive decline. Furthermore, in A+T‐ proteins indicative of blood‐brain barrier (BBB) impairment were also associated with cognitive decline.

Conclusion

A+T+ and A+T‐ individuals with MCI show largely different proteomic signatures associated with cognitive decline. In A+T+ MCI individuals, higher levels of synaptic‐plasticity proteins and lower levels of immune‐related proteins were associated with faster cognitive decline, while in A+T‐ opposite effects were found. This suggest that treatments to slow cognitive decline in AD may need tailoring on tau status.
Amyloid‐PET disclosure in Subjective Cognitive Decline: patient experiences and outcomes over time
Authors: Hendriksen Heleen M.A. , de Rijke Tanja J. , Smets Ellen M.A. , Fruijtier Agnetha D. , van de Giessen Elsmarieke , van Harten Argonde C. , van Leeuwenstijn Mardou S. S. A. , van der Schaar Jetske , Trieu Calvin , Visser Denise , Visser Leonie N.C. , van der Flier Wiesje M.
Published: January 2025

Background

Communicating amyloid‐status and the subsequent risk of future cognitive decline to individuals with Subjective Cognitive Decline (SCD) is complex. Insight into how individuals with SCD evaluate the disclosure process and its impact could help optimize current practice. Therefore, the aim of our study was to examine experiences with, and outcomes of, amyloid‐PET disclosure in individuals with SCD over time.

Method

Fifty‐seven participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (66±8yrs, 21(37%)F, MMSE 29±1, 15(26%) amyloid positive (A+)) completed questionnaires one week prior (T0), one day after (T1) and six months after amyloid‐PET disclosure (T2). Questionnaires addressed patient‐reported experiences (satisfaction with the consultation, evaluation of the provided information, and decision regret) and outcomes (emotions and behavioral (intentions to) change). We analyzed open‐ended questions thematically and tested effects of amyloid‐status and/or time using Repeated Measures ANOVA, χ², Mann‐Whitney U, and Independent Samples t‐tests.

Result

Independent of amyloid‐status, participants were satisfied with the consultation (scale 1‐10; 7.9±1.7) and the provided information (scale 1‐4; T1:3.3±0.9, T2:3.2±0.8). After six months, A+ participants reported significantly more information needs (45% vs. 12%, p=.02), e.g. about drug research and advice on what can be done to slow down disease progression. Decision regret was low, independent of amyloid‐status (scale 1‐5; A+:1.5±0.9, A‐:1.4±0.6, p=.525). Participants mentioned to appreciate information about their own health status and the possibility to act on this information. After six months, A+ participants more often reported to have recorded their wishes for the future (scale 1‐7; median(IQR): A+: 5(4‐7), A‐: 3(1‐4), p=.023). Negative emotions remained low overall over the six‐month period, independent of amyloid‐status (negative affect: F(2, 82) = 1.884, p=.158, pinteraction=.997; uncertainty: F(2, 86) = 1.258, p=.289, pinteraction=.618; anxiety: F(2, 80) = 1.014, p=.368; pinteraction=.728).

Conclusion

Participants with SCD evaluated amyloid‐PET disclosure positively, regardless of amyloid‐status. Amyloid‐PET disclosure did not induce negative emotions and participants did not regret learning their result. The reported need for information after six months, especially among A+ individuals, underscores the importance of follow‐up.
Polygenic predisposition to white matter hyperintensities does not contribute to amyloid or tau progression in Alzheimer’s disease
Authors: Zheng Lukai , Frerich Simon , Franzmeier Nicolai , Malik Rainer , Ewers Michael ,   Alzheimer's Disease Neuroimaging Initiative
Published: January 2025

Background

White matter hyperintensities (WMH) are prevalent Alzheimer’s disease (AD). However, the role of WMH in the etiology of AD is debated. Specifically, a key question is whether higher WMH is predictive of higher beta‐amyloid (Aβ) and fibrillar tau accumulation. Here, we assessed whether a genetic predisposition to higher WMH (assessed via polygenic score [PGS] of WMH based on a large‐scale population‐based GWAS) is associated with higher rates of WMH volume and amyloid‐ and tau‐PET accumulation in elderly individuals.

Methods

We included 338 participants within the AD spectrum defined by amyloid‐PET positivity, encompassing 135 cognitively normal (CN Aβ+), 122 mild cognitive impairment (MCI Aβ+), 81 AD dementia, and in addition 287 amyloid‐negative controls (CN Aβ‐) from from ADNI. Flortaucipir‐PET was available in a subset of 92 Aβ+ & 85 CN Aβ‐ participants. WMH were segmented via a deep learning‐based algorithm on FLAIR images and partitioned into 5 lobar volumes. Based on GWAS in 35,000 individuals from the UKBiobank with global WMH volume as the dependent variable, we generated a PGS including 20 SNPs (p<5×10−8). Centiloids of global cortical amyloid‐PET and temporal‐meta ROI values of tau‐PET SUVR were computed. All linear regression analyses were stratified by group (CN Aβ‐ vs pooled Aβ+) and controlled for age, sex, education, systolic blood pressure, BMI, APOE e4 genotype, and population genetic components.

Results

A higher PGS was associated with higher cross‐sectional WMH volume in the frontal, parietal, and temporal lobes in both the CN Aβ‐ and the whole Aβ+ group (except for temporal WMH; Figure 1). Longitudinally, higher PGS was associated with faster increases in frontal WMH volume in CN Aβ‐ (β=0.18, p=.03) and in the temporal lobe in the Aβ+ group (β=0.18, p=.01, Figure 2) over 2.8 years on average. Conversely, neither PGS nor baseline WMH volume (or modifiable risk factors) predicted increase in amyloid‐ or tau‐PET (mean follow‐ups: 3.9 & 2.8 years).

Conclusion

Genetic predisposition to WMH was associated with higher WMH volume in a region‐dependent manner, but the increases in WMH were associated neither with Aβ‐ nor tau‐PET accumulation, suggesting that white matter lesions develop independently from AD pathologies.
A pandemic preparedness plan for common neurodegenerative diseases: a JPND advice report
Authors: Splinter Marije J. , Henderson Emily J. , Ben‐Shlomo Yoav , Wolters Frank J. , Darweesh Sirwan K.L. , Sowa Pawel , Velek Premysl , de Schepper Evelien I.T. , Ikram M. Kamran , Licher Silvan
Published: January 2025

Background

The expected seasonal recurrence of (new variants of) COVID‐19 and the emergence of other airborne infectious diseases underscore the need for a sustainable healthcare preparedness strategy. It is particularly essential to ensure equitable access to healthcare for individuals with chronic diseases, including dementia and Parkinson’s Disease. Moreover, it is vital to provide clinicians and researchers in the neurodegenerative disease fields with resources and infrastructure to ensure continuity of their work, even during a pandemic.

Methods

We established an international collaboration and invited not only researchers and clinicians, but also patient representatives from the Netherlands, Poland, and the United Kingdom. We co‐created a pandemic preparedness plan building upon insights and experiences from a total of 25.000 participants from four population‐based studies during the COVID‐19 pandemic. Between March and November 2023, we organized two hybrid meetings in Bristol (United Kingdom) and Rotterdam (the Netherlands), and two online meetings. Key aspects of the plan included lessons learned in healthcare provision, healthcare utilization, and conducting research that could be applied during future pandemics.

Results

During the group meetings, we outlined three fundamental elements of remote data collection during health crises: validated questionnaires, variated response options, and questionnaire testing within and beyond the research group. Additionally, we addressed the potential burden of participating in these studies for frail individuals, providing specific considerations about questionnaire length, readability, and the added value of supporting participants in completing a questionnaire. Finally, we made recommendations about data sharing, underlining the importance of legislative measures extending beyond the COVID‐19 pandemic, which are crucial for enabling successful integration and long‐term utilization of multiple data sources. Beside research‐related recommendations, we also shared clinical perspectives, including the risks of social isolation for individuals with dementia and Parkinson’s Disease, the dynamics of remote versus in‐person consultations, and the concept of moral injury among healthcare professionals who provided care for infected individuals during the pandemic.

Conclusion

In this pandemic preparedness plan, we provide research and clinical recommendations and insights specifically tailored to the neurodegenerative disease fields. This establishes an essential framework for setting up new studies and safeguarding research and clinical practices when a new pandemic emerges.
Sex‐ and lineage‐specific effects of cannabidiol in mouse models of Alzheimer’s Disease – a PET scan and behavioral study
Authors: Spelta Lidia Emmanuela Wiazowski , Righini Chiara Maria , Brizola Jean Marques , de Paula Faria Daniele de Paula
Published: January 2025

Background

Emerging preclinical studies show that cannabidiol (CBD) has neuroprotective and anti‐inflammatory effects that may have the potential to improve Alzheimer's disease (AD) therapy. Although much progress has been made in understanding the pathology of AD, its multifactorial nature can't be mimicked in a single preclinical model. In order to improve preclinical results and search for AD better interventions, the aim of this study is to compare the effects of CBD in two AD animal models in a sex‐dependent manner.

Method

Male and female Ts65Dn and 3xTg‐AD mice were used in this study (Ethical approval 1811/2022). At 7 months‐old animals received CBD (20mg/kg, ip) or vehicle (etanol:tween‐80:saline) for 30 days. At 8 months‐old, animal behavior was evaluated in the open field to access exploratory behavior and memory, through the novel object recognition test. Animals were also inject with [18F]FDG (5.5MBq, iv) and [11C]PK11195 (29.6–7.4MBq, iv) to evaluate neurodegeneration and neuroinflammation by positron emission tomography (PET).

Result

Exploratory behavior had significant influence of sex, animal lineage and treatment. CBD‐treated male and female 3xTg‐AD mice traveled less distance in the open field than the Ts65Dn ones (p=0.025 comparing females; p=0.004 comparing males), and had a smaller velocity (p=0.008 comparing females and p<0,0001 comparing males). Also, in male Ts65Dn mice, the velocity was higher in CBD‐treated than in vehicle‐treated group (p=0.023). Considering memory, there was an effect of sex and CBD in 3xTg‐AD mice, as the long‐term‐memory recognition index was higher in CBD‐treated females than in males (p=0.01). Regarding whole brain PET, [18F]FDG uptake was higher in 3xTg‐AD males compared to females, in vehicle‐treated (p=0.001) and CBD‐treated (p<0.0001) groups. Also, in male animals [18F]FDG uptake was higher in 3xTg‐AD than in Ts65Dn treated with vehicle or CBD (p=0.028 and p=0.008, respectively). Finally, in vehicle‐females [18F]FDG uptake was lower in 3xTg‐AD compared to Ts65Dn mice (p=0.048). Considering [11C]PK11195 uptake, the only significant difference was a higher uptake in 3xTg‐AD vehicle‐treated males compared to females (p=0.014).

Conclusion

Our study highlights the importance of studying sex in preclinical research, as well the development of different mouse models for AD research. This would strengthen the translational power of preclinical research.
Association of Long‐Term BMI Change with Alzheimer‐Signature Cerebral Glucose Metabolism in Non‐Demented Older Adults
Authors: Lee Seunghoon , Yi Dahyun , Byun Min Soo , Kong Nayeong , Jung Joon Hyung , Chang Yoon Young , Keum Musung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: January 2025

Background

Growing evidence suggests that low body mass index (BMI) or BMI decline from midlife is related to the risk of Alzheimer’s disease (AD) and related cognitive decline in later life. However, limited information is yet available regarding the underlying brain change that could explain such relationship. This study aims to investigate whether BMI and BMI change after midlife are associated with cerebral metabolism in late life.

Method

A total of 268 non‐demented (193 cognitive normal and 75 mild cognitive impairment) older adults from 55 to 90 years of age were enrolled from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). Current or late‐life BMI was calculated using the measured height and body weight. Midlife (40 ∼ 50 years of age) BMI was calculated using self‐recall based midlife body weight and height. Self‐recall past body weight in cognitively healthy older adults was well‐validated1. All participant received [18F] fludeoxyglucose (FDG)‐PET at baseline. General linear model analysis was performed to assess the association between BMI and BMI changers with AD‐signature cerebral glucose metabolism (AD‐CM).

Result

Midlife BMI had significant negative association with AD‐CM (p = 0.007). even after adjusting for age, sex, clinical deterioration rating (CDR) sum of box score, and apolipoprotein E ε4 positivity. Three strata of BMI change from midlife to late‐life (i.e., decreasing pattern: ≤ ‐4%, stable pattern: ‐4% < BMI change < 4%, increasing pattern: ≥ 4%) showed significantly different AD‐CM (p = 0.045). Post hoc comparison revealed that decreasing BMI pattern had significantly lower AD‐CM than increasing BMI pattern, while no difference was found between the decreasing pattern and stable pattern. Sensitivity analyses for cognitively normal participants showed similar results.

Conclusion

The findings suggest a close association between long‐term BMI decline from midlife and cerebral hypometabolism in late life. Such brain hypometabolism may serve as a potential neural substrate for BMI reduction‐related cognitive decline or increased risk of AD in older adults.

References

1. Kyulo NL et al. (2012) Validation of recall of body weight over a 26‐year period in cohort members of the Adventist Health Study 2. Ann Epidemiol 22, 744‐746.
Health related quality of life in an at‐risk population during an intervention study and extended follow‐up ‐ the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Lehtisalo Jenni , Ngandu Tiia , Mangialasche Francesca , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta , Tuomilehto Jaakko , Soininen Hilkka , Khalsa Dharma Singh , Kivipelto Miia
Published: January 2025

Background

The multidomain lifestyle intervention in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed positive effects on health‐related quality of life (HRQL) during the 2‐year intervention, particularly physical functioning. Our aim was to study how these benefits were maintained over an extended follow‐up.

Method

A total of 1259 older adults aged 60‐77 were randomized into multidomain intervention (n = 631) or control groups (n = 628). A validated HRQL scale RAND‐36 with 8 subscales was collected during the original 2‐year intervention (0,1,2 yrs) and during the 11‐year extended follow‐up (7,11 yrs). Emotional well‐being subscale was also available from a mail survey during the COVID19 pandemic (approx. 9 yrs). Changes over time and intervention effect on HRQL were analyzed using mixed‐effects regression.

Result

Altogether 1212 (96%) provided HRQL data at baseline, 1069 (85%) after the intervention, and 501 after 11 years (40%). During the follow‐up mean RAND total score decreased from 76.4 to 69.3 All subscales were below baseline after 7 years, and physical functioning subscales started to decline already after 2 years (physical functioning, role limitations due to physical health, and bodily pain). Intervention related improvement in general health perception at the 1st year was maintained up to 11 years (p‐value for difference in change between groups 0.002), but improvement in physical functioning subscales vanished over time. Emotional well‐being started to decline at the 7‐year visit, without group differences. It temporarily improved during the pandemic (p‐value for change from the 7‐year visit 0.001) but declined back at the 11‐year visit.

Conclusion

Overall HRQL declined over time, as expected with aging. A 2‐year multidomain lifestyle intervention among at‐risk older adults resulted in sustained difference in general health perception, which is an important marker of general health. Lesser decline in physical functioning observed during the intervention was not sustained during the extended follow‐up. In the whole group, emotional well‐being declined later than physical functioning. Temporary improvement during the pandemic could be explained by the timing of the questionnaire (right after lifting restrictions), but it indicates that rapid changes due to external factors have an impact on emotional well‐being of older people.
BACE1 expression in neurodegenerative and neurodevelopmental diseases
Authors: Talib Leda Leme , Cordeiro Augusto Magno Tranquezi , Gattaz Wagner Farid , Forlenza Orestes Vicente
Published: January 2025

Background

Beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) was first identified as the rate limiting enzyme of amyloid‐β‐peptide (Aβ) production. The catalytic activity of BACE1 favors the generation of Aβ peptides and overproduction and accumulation of Aβ in the brain triggers downstream neurotoxic events that pertain to the amyloid cascade, leading to the formation of neuritic plaques. Furthermore BACE1 acts in the synapse through processing substrates such as APP‐like proteins, Neuregulin‐1 (Nrg 1), and β2 and β4 subunits of voltage‐gated Na+ channels. Nrg1 is a major physiological substrate of BACE1 during early postnatal development and one of the most important proteins in myelin formation. The cleavage of Nrg1 by BACE1 is essential for synapse development, cell survival and remyelination. However, BACE1 knockout animals have many subtle phenotypic alterations, including deficits in long‐term potentiation, increased seizure susceptibility, and schizophrenic behavior. It is well known that elderly individuals with Down syndrome (SD) develop amyloid plaques similar to those found in Alzheimer's disease (AD).

Method

Taking this into account our objective was to confirm the BACE1 role in neurodegenerative diseases (23 AD), in 46 DS and 51 individuals with schizophenia (SCZ) and compare them to 79 healthy controls (HC). The enzyme BACE1 expression were determined by western blotting.

Result

The Kruskal‐wallis analysis show that AD patients present an increase in BACE1 in relation to the other groups (HC, DS and SCZ) (p<0.001). The DSCF pairwise comparasion show that SCZ present a decrease in BACE1 expression compared to HC (p=<0.001). SD present no diference related to HC and SCZ (p=0.515 and p=0.09 respectively) and no differences were observed in BACE1 between DS with cognitive decline and without cognitive decline. As well as no difference between SCZ resistant or not to treatment were noted.

Conclusion

Our hypothesis is that the amyloidogenesis observed in DS is not derived from the proteolytic action of BACE1 and that possibly the phisiological process of DS is closer to a neurodevelopmental disease as SCZ.
Links between cognition and multivariate brain white matter differences in individuals with family history of Alzheimer's disease
Authors: Tremblay Stefanie A , Spreng R. Nathan , Wearn Alfie , Alasmar Zaki , Pirhadi Amir , Tardif Christine L , Chakravarty M. Mallar , Villeneuve Sylvia , Leppert Ilana R , Carbonell Felix , Medina Yasser Iturria , Steele Christopher J , Gauthier Claudine J ,   The PREVENT‐AD Research Group
Published: January 2025

Background

Alzheimer’s disease (AD) is thought to result from a complex cascade of events involving several pathological processes. Recent studies have reported alterations in white matter (WM) microstructure in the early phase of AD, but WM remains understudied. We used a multivariate approach to capture the complexity and heterogeneity of WM pathologies and its links to cognition and AD risk factors in a more holistic manner.

Method

The MRI data of 134 cognitively unimpaired older adults with a family history of AD from the PREVENT‐AD cohort were analysed. Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (see Figure 1b‐c). We used the Mahalanobis distance (D2) to summarize the MRI metrics into a single score, indicative of the degree a voxel’s microstructure differs relative to a reference. Voxel‐wise D2 was computed for each subject relative to the group average of all other subjects using the MVComp tool and D2 maps were residualized for age (Figure 2). Partial Least Squares (PLS) analyses were then performed to relate WM D2 with cognition (RBANS) and AD risk factors, separately in each sex.

Result

In males, there was only one significant latent variable (LV 1). There were extensive brain WM regions associated with this LV pattern: higher white matter D2, was associated with higher BMI, lower total cholesterol (likely due to lower HDL) and worse cognitive performance in all cognitive domains except attention (Figure 2a‐b).

In females, only the first LV was significant. Higher D2 in several WM tracts, including the inferior and superior longitudinal fasciculus, and the parahippocampal cingulum, was associated with lower education, and worse cognitive performance in all cognitive domains except attention and visuospatial construction. Higher WM D2 was also associated with several metabolic risk factors in females including higher SBP, higher BMI, higher glycated hemoglobin (HbA1c) and lower cholesterol (Figure 2c‐d).

Conclusion

The different patterns of associations observed suggest there are sex‐specific risk profiles associated with WM microstructure differences in this population of older adults at risk of AD. The WM tracts affected in each sex were also associated with specific cognitive profiles.
Development of a Multidomain Composite Intervention Engagement Score in the U.S. POINTER Trial
Authors: Nouran Mina Ghadimi , Katula Jeffrey A. , Ventrelle Jennifer , Graef Sarah , Garcia Katelyn R , Lovato Laura , Wilmoth Sharon , Woolard Nancy , Leng Xiaoyan , Calandri Ismael Luis , Snyder Heather M , Baker Laura D
Published: January 2025

Background

Multidomain lifestyle interventions have shown promise to slow cognitive decline and possibly prevent dementia. However, challenges arise in analyzing and interpreting treatment response when participants vary in their adherence to intervention components. The U.S. POINTER trial, a phase 3, multicenter, randomized 2‐year clinical trial, is investigating the impact of lifestyle interventions on cognition in older adults at risk of cognitive decline.

Methods

Four composite scores are proposed to assess engagement in the POINTER multidomain intervention.

Results

Composite score one was based on the U.S. POINTER Prescription adherence goals for three intervention domains (physical activity, diet, brain training). For this composite score, values range from 0 to 1.25, where “1” signifies the adherence goal was met, and “1.25” indicates the goal was exceeded (Table 1). The composite score is the sum of values across domains.

Composite score two was constructed using Consistent Intervals, maintaining consistent scaling between the measurement of intervention domains and the values. The composite score is the sum of the values across the three domains, each ranging 0 to 1 (Table 1).

Composite score three employed a Proportional Approach, measuring engagement in the three intervention domains as a proportion of achieved U.S. POINTER prescription goals. The composite score is the sum of values across domains.

Composite score four utilized Exploratory Factor Analysis to identify optimal weighting for each domain’s adherence scores, aiming for a comprehensive assessment of participants' behavior.

Missing data are examined in two ways: (a) assume missing data indicates no adherence and assign zero, and (b) multiple imputation to predict missing values before composite calculation. Properties of the four composites are examined using simulated datasets in preparation for later use in U.S. POINTER. Distributions, central tendency, and variability of adherence values for each composite score will be presented.

Conclusion

Four possible multidomain adherence composite scores are proposed, reflecting intervention engagement in U.S. POINTER. In the future, we will explore sensitivity of each composite score to detect treatment‐related change in cognition. This study will lay the foundation for broader applications in other multidomain trials with quantifiable adherence metrics, such as FINGER and LatAm‐FINGERS.
Late‐onset Alzheimer’s disease and related dementia in Type 2 Diabetes: 20‐year Longitudinal matched cohort study
Authors: Jeong Sohyun , Pascual‐Leone Alvaro , Hsu Yi‐Hsiang
Published: January 2025

Background

Multiple studies report that patients with diabetes have an increased risk of Alzheimer’s disease and related dementia (ADRD). However, there are limited number of studies with a long‐term follow‐up and accounting for the strong genetic risk factor of APOE genotypes.

Method

We used UK Biobank First occurrences (FO) datasets (Category 1712) in Health‐related outcomes data. Among the 406,049 eligible individuals, 27,125 T2DM cases were 1:1 matched to non‐T2DM by age at first diagnosis, sex, cerebrovascular disease, ischemic heart disease, hypertensive disorders, lipid disorders, obesity, and mood disorders. We applied the Cox proportional hazard model and Fine and Gray competing risk model with mortality as a competing risk. These models were adjusted for years of education, Townsend deprivation score, APOE4 and APOE2 genotypes to assess the ADRD outcomes. Additionally, for subgroup analysis by sex, APOE4 and APOE2 genotypes, we conducted matching within the subgroups and applied the same statistical models to assess ADRD risk in T2DM. We performed additional matching with T2DM polygenic risk score (PRS) and evaluated the non‐genetic T2DM effects toward ADRD risk.

Result

The mean age at diagnosis was around 62 years old and female constituted 61% (Table 1). The ADRD risk was significantly increased in T2DM (HR:1.46, 95% CI: 1.23‐1.73). The Fine and Gray competing risk model presented 1.32 times increased risk in T2DM (95% CI: 1.12‐1.56). In the sex‐stratified analysis, a significantly increased risk was observed in males (HR:1.58, 95% CI:1.28‐1.95) but not in females with T2DM (HR:1.28, 95% CI:0.97‐1.69) (Fig. 1). In APOE stratified analysis, T2DM was not associated with ADRD risk in both APOE4 and APOE2 subgroups. T2DM PRS was negatively correlated with ADRD risk, but in T2DM PRS matched cohort, T2DM significantly increased ADRD (HR:1.52, 95% CI: 1.29‐1.80). Both male (HR: 1.62, 95% CI:1.31‐ 2.00) and female (HR:1.35, 95% CI:1.01‐1.79) subgroups presented elevated risks.

Conclusion

We demonstrated a 1.3‐1.5 times increased risk of ADRD in T2DM. This finding was confirmed in PRS matched cohort, suggesting non‐genetic T2DM effects could contribute to ADRD risk.
Can accelerometry identify/monitor neuropsychiatric symptoms correlated with motor activity in persons living with dementia? Results from a diagnostic test accuracy systematic review
Authors: Guseva Elena , Iaboni Andrea , Lanctôt Krista L. , Herrmann Nathan , Ismail Zahinoor , Burhan Amer M. , Gore Genevieve , Seitz Dallas , Kumar Sanjeev , Bruneau Marie‐Andrée , Lim Andrew , Wilchesky Machelle
Published: January 2025

Background

Wearable sensor technology shows promise for neuropsychiatric symptoms (NPS) identification/monitoring in persons living with dementia (PLWD). Accelerometry measures acceleration of body segments and physical activity. This study explores the diagnostic test accuracy (DTA) of accelerometry to identify the following 6 NPS associated with motor activity: aberrant motor behavior (AMB), aggression, agitation, anxiety, apathy, and wandering.

Methods

As part of a larger systematic review, we conducted an extensive literature search in nine health science and engineering databases. Meta‐analysis involved converting correlations to Fisher's Z scores, calculating 95% confidence intervals using the R Studio Metacor package, and assessing fixed effects, DerSimonian and Laird's random effects models, and heterogeneity.

Results

Out of 12,853 identified records, 84 reports were retained for analysis. Eight reports that provided 12 datasets assessed the DTA of accelerometry data for identifying/monitoring apathy (n=4), AMB (n=1), anxiety (n=2) agitation (n=5), aggression (n=2), and wandering (n=2). Studies included one single‐blinded trial, one non‐randomized trial, and ten observational studies. A random‐effect meta‐analysis yielded a pooled correlation across studies of r=0.61 (0.50; 0.70), heterogeneity I2=68%. When the wandering NPS subgroup was eliminated from analysis, heterogeneity fell considerably to I2=36%, with a pooled correlation of r=0.55 (0.47; 0.62).

Conclusions

These findings suggest that accelerometry consistently provides good to moderate DTA for identifying/ monitoring NPS associated with motor behavior in PLWD. Future research should prioritize standardizing the reporting of measurement procedures, signal thresholds, outcome measures, devices, and reference standards.
Retinal and brain imaging modalities for AD detection and monitoring
Authors: Martins Ralph N , Poudel Purna , Taddei Kevin , Eslick Shaun , Frost Shaun , Hone Eugene
Published: January 2025

Background

As an extension of the central nervous system (CNS), the retina shares many similarities with the brain and can manifest signs of various neurological diseases, including Alzheimer’s disease (AD). This study investigates the spectral features of the retina to develop a classification model for the differentiation of individuals with elevated brain amyloid levels.

Method

Participants (n=66) with varying brain Aβ levels, as determined by brain imaging, were non‐invasively imaged using a hyperspectral retinal camera at wavelengths of 450 to 905 nm. Multiple image features from the central view and superior view of retinas were selected and analysed to identify their variability among individuals with different brain amyloid loads. A machine learning classification model was trained to differentiate individuals with varying amyloid levels using the spectra of extracted retinal features.

Result

The retinal reflectance spectra between the wavelengths of 405–585 nm exhibited a significant difference between the individuals with raised brain amyloid levels. The performance of the spectral classification model was dependent on retinal region and showed 0.778–0.857 accuracy, 0.718–0.909 sensitivity, 0.778–0.912 specificity, and 0.758–0.878 AUC.

Conclusion

This study highlights the spectral variation of retinal features associated with brain amyloid load. It also demonstrates the feasibility of the retinal hyperspectral imaging technique as a potential inexpensive screening method to identify individuals in the preclinical phases of AD and as a complementary or alternative to brain imaging.