bluuebunny/crossref_metadata_2025 huggingface dataset:
Fosgonimeton attenuates amyloid‐β‐induced autophagic impairments in primary cortical neurons
Authors: Reda Sherif M , Wu Wei , Berthiaume Andrée‐Anne , Setti Sharay E. , Taylor Robert W , Johnston Jewel L , Church Kevin J.
Published: January 2025

Background

Accumulating evidence highlights impairment of autophagy as a key pathological feature of neurodegenerative diseases including Alzheimer’s disease (AD). Autophagy is a highly dynamic, lysosome‐based degradation process that promotes the clearance of degenerative factors to maintain cellular functions, preserve metabolic integrity, and ensure survival. Impaired autophagic function leads to the abnormal accumulation of autophagic vesicles (i.e., autophagosomes, lysosomes), build‐up of toxic protein aggregates, dysregulated homeostasis, synaptic dysfunction, and neurotoxicity. We have previously demonstrated that fosgonimeton, an investigational small‐molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, is neuroprotective and reduces pTau levels in amyloid‐beta (Aβ)‐driven preclinical models of AD. Herein, we investigate the effect of fosgonimeton on autophagic function in cortical neurons following Aβ injury to further characterize the neuroprotective effects of fosgonimeton treatment.

Method

To evaluate potential effects on autophagic function, primary rat cortical neurons were treated with the active metabolite of fosgonimeton (fosgo‐AM), challenged with Aβ1‐42 (15 µM) for 24 hours, and immunostained for microtubule‐associated protein‐2 (neuronal marker), phospho‐tau, LC3 (autophagosome marker), and LAMP2 (lysosomal marker). Immunofluorescence analyses were used to determine neuronal survival, neurite network integrity, pTau levels, and expression/co‐localization of LC3 and LAMP2. Beclin‐1 (autophagy initiator) expression was also measured via western blot.

Result

Fosgo‐AM treatment promoted neuronal survival, preserved network connectivity, and reduced levels of pTau following Aβ1‐42 challenge. Application of Aβ1‐42 significantly decreased the expression of Beclin‐1, led to the abnormal accumulation of autophagic vesicles (LC3, LAMP2, and LC3‐LAMP2 co‐localization), and increased the co‐localization of pTau within LC3‐autophagic vesicles, all of which are indicative of impaired autophagic function. Such effects were significantly attenuated in the presence of fosgo‐AM, suggesting that the neuroprotective effects of fosgonimeton are associated with improved autophagic function.

Conclusion

The data presented demonstrate the ability of fosgonimeton to potentially address autophagic impairment in AD, which may have important implications regarding the attenuation of pTau pathology. These effects of fosgonimeton, in addition to the neurotrophic and neuroprotective effects previously demonstrated in preclinical models, highlight the therapeutic potential of the HGF system for neurodegenerative disorders, wherein autophagic impairment is a key pathological hallmark.
Characterization of Social Isolation and Perception of Loneliness in a Group of Chilean Older People post‐pandemic
Authors: Gierke Christine , Navarro Carlos F. , Martinez Melissa , Delgado Carolina , Delano Paul H , Medel Vicente , Leiva Alexis , De Gatica Cristina , Vidal Victor , Martin Simon San , Garcia Ximena , Cerda Mauricio , Vergara Rodrigo C. , Farías Gonzalo
Published: January 2025

Background

During the pandemic, Social Isolation (SI) and the perception of loneliness emerged as critical factors associated with significant psychological and physical impacts (Tyrrell, C. & Williams, N., 2020; González, D., 2021).

This study examines gender differences and explores the impact of social isolation and the perception of loneliness on self‐sufficient older people in Santiago, Chile, in the post‐pandemic period (March to November 2022). The focus is on understanding the relationship between these factors and psychiatric symptoms, utilizing specific scales to evaluate these variables.

The pandemic introduced three main variables that affected older individuals: the severity of the disease and the fear of contagion; the effects of social isolation, and the perception of vulnerability, which was amplified by the media (NCHS, 2020; CEVE‐UC, 2022; Smith, B. & Lim, M., 2020; Ayalon et al., 2020; Monahan et al., 2020; Vervaeke & Meisner, 2020).

Method

A descriptive cross‐sectional study included 150 participants (ages 60‐87). Surveys administered were the Steptoe Social Isolation Index, Three‐Item UCLA Loneliness Scale, Yesavage Geriatric Depression Scale (GDS‐15), current concern about the pandemic (Likert Scale, 1‐10), and gender differences in these variables. JAMOVI software version 2.36 was utilized for data processing and statistical analysis.

Result

From March to December 2022, 150 older adults were surveyed (Mean = 69.5, Median = 69, SD = 5.93, Variance = 35.11). The sample comprised 68% women and 32% men (Women = 102, Men = 48). Of the variables analyzed, 42% of the sample experienced Social Isolation (Chi‐square = 3.2, p = 0.696 / U = 2395.0, p = 0.825). 26% perceived Loneliness (Chi‐square = 6.10, p = 0.412 / U = 2210.0, p = 0.290), 30% indicated depression (Chi‐square = 7.94, p = 0.848 / U = 2270.0, p = 0.470), and 91% expressed concern about the pandemic (Chi‐square = 0.10, p = 1 / U = 2442, p = 0.980).

Conclusion

The results suggest that, although there are no significant gender differences in individual variables, there are significant correlations between all combinations of the variables (Social Isolation, Loneliness, GDS‐15, and Pandemic Concern). Among men, significant correlations were found between Social Isolation and Loneliness (rho = 0.432, p = 0.002), Loneliness and GDS‐15 (rho = 0.299, p = 0.03), and Loneliness and Age (rho = 0.381, p = 0.008). In women, all correlations were significant, except with age, between Social Isolation and Loneliness (rho = 0.419, p≤0.001), Social Isolation and GDS‐15 (rho = 0.279, p = 0.005), and Loneliness and GDS‐15 (rho = 0.474, p≤0.001).
Association between everyday perceived discrimination and cognitive function as mediated by depression in diverse populations: A HABS‐HD Study
Authors: Mendoza Edna Patricia , Nolan Emma , Phillips Nicole , Barber Robert , O'Bryant Sid E. , Zhou Zhengyang
Published: January 2025

Background

Previous research suggests that perceived discrimination is associated with cognitive function impairment, and such association is mediated by depression. With minority populations continuously growing, it is crucial to investigate such relationships in diverse populations. This study aims to examine and compare the above relationships among non‐Hispanic white (NHW), Mexican American (MA), and African American (AA) participants.

Method

A sample size of 1,129 participants (640 AAs, 248 NHWs, 241 MAs) aged 50+ came from the Health and Aging Brain Study – Health Disparities (HABS‐HD). Multiple linear regression was conducted to explore the direct association between perceived discrimination, measured by the Everyday Discrimination Scale mean score, and cognitive function, measured by the Mini Mental State Examination (MMSE) Score. The mediation effect of depression, measured by the Geriatric Depression Scale total score, was evaluated by the indirect effect estimate and confidence interval through Monte Carlo simulations.

Result

Everyday perceived discrimination negatively influenced cognitive function, and the effect was fully mediated by depression across the three populations (estimate for indirect effect = ‐0.16, 95% CI = [‐0.24, ‐0.09]). When stratified, the mediation effect of depression on the association between discrimination and cognitive function remained significant for NHW (estimate for indirect effect = ‐0.37, 95% CI = [‐0.63, ‐0.16]) and MA (estimate for indirect effect = ‐0.42, 95% CI = [‐0.74, ‐0.16]). However, such mediation effect was not observed for the AA population.

Conclusion

Depression mediates the link between everyday discrimination and cognitive decline, but differences between racial/ethnic groups underscore the need for further research into underlying mechanisms among minority groups, including Mexican American and African American populations. Depression interventions may mitigate negative cognitive effects from discrimination. Tailoring such interventions by race/ethnicity and targeting at‐risk groups could optimally promote cognitive health.
Caregiving experience and service utilization of informal caregivers for community‐living older adults with neurocognitive disorders: preliminary findings in Hong Kong
Authors: Huo Zhaohua , Lee Allen TC , Yip Benjamin HK , Lin Cuichan , Ma Suk Ling , Wong Samuel YS , Lam Linda CW
Published: January 2025

Background

Caring for people with dementia in communities inevitably brings heavy burden for their family caregivers. Senses of positive aspects from caring and proper service support may help shape a healthy care journey for carers. This study aims to evaluate the caregiving burden, positive aspects, and service utilization of informal caregivers for community‐living older adults with neurocognitive disorders (NCDs).

Method

448 informal caregivers of older adults aged ≥60 (major NCD/ dementia: 68, mild NCD: 254, normal cognition: 126) were recruited from in a community‐based prevalence survey in Hong Kong. Caregivers’ subjective burden was measured by Zarit Burden Interview (ZBI), while their gain was measured by positive aspect of caregiving scale (PACS). Caregivers’ use of medical and social service was also recorded. Differences in measures across three disease groups were examined by analysis of variance and t‐test. Correlations between measures were estimated by Pearson coefficient.

Result

Nearly 60% of interviewed carers were female, spouses of care recipients, and not in employment. Over 75% of them cohabited with care recipients and take the major responsibility for caring. Compared to normal controls, carers of major and mild NCD had higher scores in caring burden, and over one in ten dementia carers were suffering moderate to severe degree of burden. Regarding positive aspects, carers of major and mild NCDs also have higher scores, mainly in items of “feel needed”, “feel appreciated”, and “feel important”. As for service utilization, dementia carers used more psychological and home help services. Finally, caring burden was positively correlated to positive gain (r = 0.233, P<0.001), psychological (r = 0.186, P<0.001) and social services (r = 0.146, P<0.001). The sense of positive aspects was uncorrelated to psychological services (r = ‐0.064, P = 0.174) but positively correlated to social services (r = 0.149, P = 0.002).

Conclusion

Informal caregivers of major and mild NCD are experiencing heavier caring burden. They also have higher sense of positive aspects from caring and more utilization of psychological and social care. Relationships between positive and negative experience of caregivers and their service utilization need further investigations.
Impact of AI‐based segmentation on PET analyses
Authors: Bracoud Luc , Cajgfinger Thomas , Rousset Olivier , Ingalhalikar Madhura , Conklin Chris , Lehmann Manja , Schaerer Joel , Scott David , Suhy Joyce ,   the Alzheimer's Disease Neuroimaging Initiative
Published: January 2025

Background

Brain MRI segmentation is required for quantitative PET analysis, in order to derive regional uptake and calculate uptake ratio relative to reference regions. FreeSurfer has been a popular method but is being supplanted by faster and more robust AI‐driven methods. The objective of this work is to confirm that the use of Clario’s novel AI segmentation method, whose impact was assessed towards various MRI endpoints, is also valid in the context of PET quantification.

Method

507 subjects from ADNI were selected, including normal controls, subjective memory complainers, early/late MCI and AD subjects. Besides, 210 were selected with available test/re‐test data. For each, a pair of good quality 3DT1 MRI and Amyloid PET scans were available.

3DT1 data were segmented with both FreeSurfer v6 (FS) and Clario’s AI method (AI), and registered to PET space for calculation of Standard Uptake Value (SUV) in a set of cortical regions (frontal, posterior cingulate, lateral parietal and lateral temporal) and reference regions (cerebellar grey and whole cerebellum). SUVR (ratio to reference region) was calculated for both. Results were also converted to Centiloid (CL) units.

SUV and SUVR values were compared across segmentation methods via Bland‐Altmann plots and correlated with Pearson’s coefficient. The ability to distinguish between disease severity stages was assessed by ROC analysis using global AUC. Finally, classification as amyloid (Aβ) positive or negative was assessed by setting a cut‐off of 20.1 CL and looking at Cohen’s Kappa.

Results

SUV and SUVR values were highly and significantly correlated between FS and AI methods (r>0.99, p<0.001) and for test/re‐test, for all regions investigated, with a difference that did not exceed 0.41% on average (SD<1.38%). Global AUC was comparable for both methods and for test/retest (average gAUC=0.62). Aβ classification was near‐perfect across methods (κ=0.98) and between test/retest data (κFS=0.97, κAI=0.99).

Conclusion

Comparing FreeSurfer and Clario’s AI‐based MRI segmentation method, no impact was found on subsequent PET analyses and test/retest performance was equivalent. These results support the use of either method for PET quantification. For future trials, the AI method could either be used as the primary method, or as a back‐up when traditional FS segmentation fails.
Exploring Neighborhood Level Socioeconomic Status and Volumetric MRI Results in Patients with Memory Impairment
Authors: Stamos Hannah M , Achitoov Mia , Zia Nadia , Sadatsafavi Hessam , Niknejad Bahar , Okhravi Hamid
Published: January 2025

Background

This study addresses the impact of neighborhood‐level socioeconomic disadvantage, as measured by the Area Deprivation Index (ADI), on individuals with mild cognitive impairment and dementia. Our primary outcome aimed to explore associations between ADI and hippocampal volume in cognitively impaired individuals from a comprehensive memory center.

Methods

We conducted a retrospective, cross‐sectional analysis of patients over 50 from Virginia and North Carolina, with visits between January 1st, 2014, and July 1st, 2022. Normative percentile of hippocampal volume, total hippocampal occupancy scores (HOC), superior lateral ventricular volume, and inferior lateral ventricular volume of patients living in census block groups at the top and bottom 20th ADI percentiles were compared. We fitted a linear regression model on propensity‐matched data in the two ADI groups, with multiple covariates. We performed g‐computation in the matched sample and included the interaction of ADI category with covariates and the matching weights in the estimation.

Results

A total of 310 patients were included in the analysis, with 8% of the subjects in the high‐ADI category. The actual sample size slightly varied for each outcome after excluding missing records, thus full matching was utilized. The estimated average treatment effect for high versus low ADI groups only reached statistical significance for hippocampal volume with the difference of 13.9% (SE = 5.83, p = 0.01). The difference of 0.7% (SE = 2.11, p = 0.75) for HOC, 0.5% (SE = 4.13, p = 0.90) for superior lateral ventricular volume, and ‐0.2% (SE = 7.18, p = 0.90) for inferior lateral ventricular volume were not statistically significant.

Conclusions

Contrary to expectations, high versus low ADI groups only showed a difference in hippocampal volume, but in the reverse direction. This finding may suggest global effects of the ADI on the brain health, rather than focal effects on hippocampus. Due to the limited size of our sample in the top 20th percentile, further validation of this discovery is necessary through studies employing larger sample sizes.
Changes to Medicare Advantage Risk Adjustment and Dementia Diagnosis in Older Adults
Authors: Haye Sidra , Jacobson Mireille , Joyce Geoffrey , Zissimopoulos Julie M
Published: January 2025

Background

Diagnosing dementia supports patients’ access to treatment options and social services. The addition of dementia to the risk adjustment model for Medicare Advantage (MA) plan payments, affecting claims beginning in 2019, provided an incentive for MA plans to improve the detection and diagnosis of dementia among their enrollees. The objective of this project is to examine the changes in annual incident dementia diagnoses rates associated with the inclusion of dementia diagnoses in risk adjustment models for Medicare Advantage.

Methods

We conducted a retrospective study using 2017‐2020 data for community‐dwelling beneficiaries enrolled in TM and MA. We estimated difference‐in‐differences (DiD) models to examine changes in incident dementia diagnosis rates in MA relative to TM before and after 2019. The rate of incident dementia diagnosis in each year among beneficiaries without any dementia diagnosis in the year prior to the year of interest.

Results

There were 84,997,374 beneficiaries. In regression models that adjusted for beneficiary characteristics and time trends, we find that in response to the payment change, the annual incident dementia diagnosis rates in MA increased by about 0.282 percentage points or 11.5% relative to TM. We further find that the increase in incident dementia diagnosis was concentrated among beneficiaries who were more likely to have undiagnosed dementia, specifically, beneficiaries who were Hispanic or Black, who were ages 85 and over, and who were dual‐eligible/low‐income subsidy. Sensitivity analyses excluding 2020 data and allowing beneficiaries to switch between TM and MA during our sample years finds similar results.

Conclusion

Financial incentives to detect dementia resulted in more dementia diagnoses, particularly among persons at high risk of dementia and of undetected dementia but also raises concerns about diagnostic upcoding and the potential for over‐diagnosis.
Predicting future Biomarker changes in Alzheimer's Disease, Brain Aging and Comorbidities
Authors: Tassopoulou Vasiliki
Published: January 2025

Background

The Spatial Pattern of Abnormality for REcognition of Alzheimer's Disease (SPARE‐AD) index ∖citep{davatzikos2009longitudinal} is one such marker that robustly discriminates between early brain changes observed in cognitively normal aging (CN), mild cognitive impairment (MCI), and Alzheimer's Disease (AD) phenotypes. The adoption of such markers to the clinical setting combined with the ability to forecast their future trajectories would be of great value during clinical assessment, and could improve clinical trial design through targeted risk stratification.

Method

Subjects scanned using the same scanner with more than four longitudinal MRI acquisitions from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Baltimore Longitudinal Study of Aging (BLSA) study cohorts were used for method development. T1 structural MRIs were preprocessed and segmented into 145 gray (GM) and white matter (WM) regions of interest (ROIs) using previously described methods. The output of the model is the temporal function of the biomarker score, which in this work is the SPARE‐AD and the SPARE‐BA, seperately. The core of our methodological advancement revolves around the concept that the progression of each biomarker can be represented by a temporal function, f, which is approximated with a Gaussian Process (GP). The learned temporal function is a function of the baseline acquisition of the subject, which means that on inference time, we need only the first scan of the subject so as to get the temporal function of the biomarker

Result

The Temporal Deep Kernel GP (TempDKGP) model achieves higher predictive performance on both SPARE‐AD and SPARE‐BA model. Our model had lower MAE averaged across all participants per K‐fold when compared to ithe LMM. MAEs were also lower when the cohort was subgrouped by their longitudinal cognitive status (i.e., stable vs progression), and by short‐term (less than 5 years ahead of baseline) or long‐term predictions (more than 5 years ahead of baseline). Longitudinal trajectories predicted using baseline features by TempDKGP more closely followed the ground truth trajectories than the LMM as illustrated.

Conclusion

The TempDKGP model is a predictive model that extrapolates biomarker trajectories along with uncertainty intervals.
Uptake of Medicare’s Annual Wellness Visit and Cognitive Screening: Evidence of Urban‐Rural Disparity from a National Survey
Authors: Liu Ying , Mattke Soeren
Published: January 2025

Background

Early‐stage cognitive impairment remains severely under‐detected. In the U.S., Medicare covers an Annual Wellness Visit (AWV) that includes assessment of cognitive state, but it remains under‐utilized: only 55% of beneficiaries reported having had AWV, of whom only 26% were given a structured cognitive test in 2019. We obtained updated estimates and analyzed association with beneficiary characteristics.

Method

We used a nationally representative survey, the Understanding America Study, to collect data on uptake of AWV and whether the visit included a formal cognitive test or simple questions about memory complaints in December 2023. The survey also collects data on demographics (age, sex, race/ethnicity, education, and yearly household income) and urbanicity of the participant’s residence. Logistic regression was used to predict a beneficiary having an AWV or been probed for cognitive state during the AWV using the beneficiary’s characteristics.

Result

Table 1 shows the logistic regression results. Among 1,885 respondents, 81% reported having had an AWV, higher likelihood among older, female, and higher education beneficiaries. During AWV, 51% were probed for their cognitive condition: 31% with formal screening and 35% being asked about subjective memory complaint.

Despite no urban‐rural difference in AWV’s uptake (compared to urban residents, Odds Ratio [OR] = 1.29 for rural and OR = 1.04 for mixed, p>0.05), conditional on the uptake, residents of rural (OR = 1.83, p<0.001) and mixed (OR = 1.68, p<0.001) areas were more likely to undergo formal screening than their urban counterparts, with adjusted probabilities of 36% for rural, 34% for mixed, and 24% for urban (Figure 1). Results are similar on being probed about memory complaints.

Conclusion

AWV uptake is increasing, despite a lesser increase in cognitive screening. Female, older, and higher educated beneficiaries are more likely to use the AWV. The unexpected finding of urban residents being less likely to be probed for cognitive impairment deserves further investigation. Potential explanations include clinicians’ awareness of higher disease burden in rural populations, and greater familiarity with their patients. Also, limited access to specialists could cause clinicians to offer a greater range of diagnostic services themselves and become more experienced in cognitive testing.
The Synergistic Effect of Sleep and Physical Activity on Memory in Cognitively Normal Older Adults
Authors: Callies Lana S. , Chen Coty , Lee Shannon Y. , Diaz Valentina E. , Tucker Miwa , Hallgarth Savannah R. , Lo Carina , VandeBunte Anna M. , Pandher Natalie , Li Esther , Song Felicia , Coppola Quentin , Saloner Rowan , Watson Caitlin Wei‐Ming , Dutt Shubir , Neylan Thomas C. , Kramer Joel H. , Walsh Christine M , Casaletto Kaitlin B. , Paolillo Emily W.
Published: January 2025

Background

Modifiable risk factors are important for prevention of age‐related cognitive decline. Prior research has linked both physical activity (PA) and sleep with better memory outcomes. To better understand their potential synergistic effects, we examined independent and interactive effects of actigraphy‐based PA and total sleep time on cognitive functioning in cognitively unimpaired older adults.

Method

Participants included 40 cognitively unimpaired older adults (age = 71.1 ± 10.8yrs; 52% female; 75% White; mean education = 18.2yrs) enrolled in studies at the UCSF Memory and Aging Center. All participants completed in‐person neuropsychological assessments and 30 days of FitbitTM Inspire 2 monitoring, which tracked average nightly total sleep time and average daily step count. Average sleep time was dichotomized into optimal sleep (6‐8hrs) and sub‐optimal sleep (<6hrs, >8hr) based on previous literature, and average daily step count was dichotomized by median split (high PA ³ 8490 steps). Composite cognitive z‐scores were calculated for memory and executive functioning. Multiple linear regression models examined the interaction between sleep and PA on cognitive domain z‐scores, controlling for age, sex, and education.

Result

Neither sleep nor average daily steps were independently related to memory (sleep:b = ‐0.58, 95%CI [‐1.36, 0.20], p = 0.141; steps: b = ‐0.27, 95%CI [‐0.86, 0.32], p = 0.357) or executive functioning (sleep:b = ‐0.68, 95%CI [‐1.46, 0.10], p = 0.087; steps: b = ‐0.21, 95%CI [‐0.82, 0.40], p = 0.487). In combination, however, sleep significantly moderated the effect of PA on memory (b = 1.47, 95%CI [0.03, 2.92], p = 0.046) such that higher PA related to better memory performance only among participants with optimal sleep times. The interaction between PA and sleep on executive functioning was not significant (b = 0.49, 95%CI [‐1.06, 2.03], p = 0.528).

Conclusion

Using unobtrusive objective monitoring of modifiable lifestyle factors via wearable actigraphy, we found a beneficial synergistic relationship between sleep and PA on memory. Results highlight the clinical relevance of supporting multi‐domain improvements in modifiable lifestyle factors, including optimal sleep time and higher PA in older adults.
Sex Differences in Comorbidity Patterns and the Associations with Risk of Alzheimer’s Disease and AD‐Related Dementias among Adults Aged 65 and Older: Findings from the United States Medicare Current Beneficiaries Surveys, 2018‐2020
Authors: Liu Longjian , Gracely Edward J , May Nathalie S , DiMaria‐Ghalili Rose Ann Rose Ann , Eisen Howard J
Published: January 2025

Background

To provide a nationally representative estimate of the burden of multiple comorbidities (MCM) among community‐dwelling Medicare beneficiaries with Alzheimer’s disease (AD) and AD related dementias (ADRD).

Method

We analyzed national sampling data in Medicare beneficiaries aged ≥65 (n = 34,318) from the 2018‐2020 Medicare Current Beneficiaries Surveys. AD/ADRD and twelve chronic comorbidities (hypercholesterolemia, hypertension, diabetes, coronary heart disease, heart failure, stroke, depression, mental disorder, chronic kidney disease, chronic obstructive pulmonary disease, arthritis, and osteoporosis) were examined. A novel age‐adjusted regression weighted MCM index was developed by taking into account the relative impact of each comorbidity on the risk of AD/ADRD. Logistic regression models estimated adjusted odds ratios (AORs) of commodity and the MCM index for AD/ADRD, adjusting for sociodemographic, body mass index and behavior factors.

Result

A total of 1,802 AD/ADRD cases (5.3%) were identified, representing an estimated 5,580,421 AD/ADRD cases in the nation’s Medicare beneficiaries. In the 65‐74 age group, the prevalence of AD/ADRD was 1.8% in males and 1.4% in female (p = 0.11), while in those aged ≥75, it was 6.1% in males and 7.6% in females (p = 0.001). AD/ADRD individuals more often had ≥4 comorbidities than those without AD/ADRD (52.6% vs. 30.9% in males, and 58.3% vs. 34.8% in females). In males, of the 12 comorbidities, depression exhibited the highest AOR (95%CI) at 4.62 (3.70‐5.78) for AD/ADRD risk, followed by mental disorder at 4.36 (2.88‐6.59), and stroke at 3.19 (2.51‐4.06). The same disorders were the top three in females, but in a different order, namely mental disorders at 4.79 (3.44‐6.68), stroke at 3.50 (2.79‐4.39), and depression at 2.92 (2.41‐3.54). An increase in MCM index score was associated with 2.13 (1.92‐2.37) higher AD/ADRD risk in males, and 1.65 (1.52‐1.80) higher risk in females.

Conclusion

The study highlights that AD/ADRD poses a substantial public health burden in the nation, with older females experiencing a significantly higher prevalence of AD/ADRD. The association of sex and specific comorbidity profiles on AD/ADRD risk is evident, emphasizing the need for further studies of the disease mechanisms and the potentially targeted prevention strategies by addressing these factors.
Health Coaching Intervention Retained ANU‐ADRI Scores Over a 2‐year period in APOE e4 Carriers Among Older Adults at Risk for Alzheimer’s Disease
Authors: Gray Michelle , Campitelli Anthony , Urbina Ray G , Jones Megan
Published: January 2025

Background

The Apolipoprotein epsilon 4 allele (APOE ε4) gene is known as the most prevalent genetic risk factor for Alzheimer’s disease (AD). However, many lifestyle risk factors that are modifiable influence the development of AD. Reducing the prevalence of risk factors can prevent or delay up to 33% of AD cases. Health coaching is known to improve health over time in older adults by using a motivational interviewing technique resulting in positive behavior modification. The purpose of this study was to determine if a 2‐year health coaching intervention improves AD risk score among older adults at risk for AD aged 60 and 75 years of age.

Method

Adults between the ages of 60‐75 (n = 106) were randomly assigned to a health coaching (HC) or health education (HE) control group. HC met with a health coach once every 4‐6 weeks and HE received biweekly educational emails addressing AD risk factors. Each participant tested at 4 time points: 0 (baseline), 4, 12, and 24 months. At baseline the participants had blood drawn to test for APOE ε4 (carrier and non‐carrier). At each time point the participants completed the Australian National University‐Alzheimer’s Disease Risk Index (ANU‐ADRI), a validated tool to predict AD. To determine significant differences between time points for each group and apoe ε4 carrier status a mixed factorial ANOVA (α = .05) was used.

Result

Among both carrier groups the HE and HC interventions had no significant mean difference between baseline and 24 months (Non‐carriers HE p = .936, HC p = .123; Carriers HE p = .109, HC p = .832). No meaningful difference between non‐carrier HE (‐.881) and HC (‐1.513) or Carrier HC (‐0.333) interventions. Overall, HE risk scores increased over time.

Conclusion

HC intervention retained risk scores among APOE ε4 carriers over 2 years among older adults. Within carrier group, HE risk scores had a meaningful change leading to an increased risk of AD. Though HC did not result in an improvement in AD risk, there was not a decline, as we expected. Health coaching has been shown to have a positive effect on AD risk reduction.
Objective sleep characteristics and cognitive performances: the role of race/ethnicity
Authors: Cavaillès Clémence , Leng Yue , Stone Katie L , Peltz Carrie B. , Yaffe Kristine
Published: January 2025

Background

A growing body of literature suggests that poor sleep has a negative effect on cognition. However, most prior research has predominantly used subjective sleep data and focused on non‐Hispanic White (NHW) populations. Our goal was to explore the associations between objective sleep characteristics and cognition in a racially/ethnically diverse cohort.

Method

We studied 855 participants from the Health and Aging Brain Study‐Health Disparities (HABS‐HD)‐Dormir study. Objective sleep characteristics, including nighttime sleep duration, wake after sleep onset (WASO), sleep efficiency, and sleep fragmentation index, were assessed by 7‐day wrist actigraphy. Using a battery of cognitive tests, we created four cognitive composite z‐scores for executive function, attention, language, and memory. We used multivariable linear regressions to examine the associations between sleep characteristics and cognitive function, adjusting for age, race/ethnicity, sex, education, marital and cognitive status. Stratified analyses based on race/ethnicity were performed in the presence of interaction.

Result

We studied 370 (43.3%) NHW, 292 (34.2%) Mexican American (MA), and 193 (22.6%) Black participants, with an average age of 66.7 (±8.4) years, and 65.1% female. Compared to NHW participants, both MA and Black participants had shorter sleep duration (7.5, 7.2, and 7.1 hours, respectively, p<0.0001), higher WASO (44.5, 57.0, 61.0 min, p<0.0001), lower sleep efficiency (91.0, 88.0, and 87.0%, p<0.0001), and higher sleep fragmentation index (24.0, 27.2, and 31.9, p<0.0001). Across the sample, longer sleep duration (per 1 hour; β = ‐0.048; p = 0.01) and higher WASO (per 30 min; β = ‐0.041; p = 0.06) were associated with worse executive function. Better sleep efficiency (per 5%; β = 0.080; p = 0.02) was associated with better executive function whereas higher sleep fragmentation index (per 10%; β = ‐0.074; p = 0.06) was associated with worse executive function in Black participants (p interaction = 0.07 and 0.008, respectively). Moreover, higher WASO (per 30 min; β = 0.075; p = 0.04) and higher sleep fragmentation index (per 10%; β = 0.072; p = 0.05) were associated with better attention function in Black participants (p interaction = 0.07 and 0.06, respectively).

Conclusion

These findings indicate associations between poor sleep and both executive function and attention; and highlight evidence for racial/ethnic disparities across these relationships.
Subclinical Vascular Risk Composites and Dementia Imaging Biomarkers 17‐20 years later in the Multi‐Ethnic Study of Atherosclerosis (MESA)
Authors: Rudolph Marc D. , Tanley Jordan E. , Ding Jingzhong , Chen Haiying , Hayden Kathleen M. , Liu Yongmei , Bryan R. Nick , Nasrallah Ilya M. , Dolui Sudipto , Habes Mohamad , Luchsinger José A. , Heckbert Susan R. , Lockhart Samuel N. , Hughes Timothy M.
Published: January 2025

Background

Vascular risk factors captured in midlife represent modifiable features of cardiovascular disease (CVD), stroke, dementia, and dementia‐related neuropathology. Subclinical measures of CVD may help identify specific structural and function aspects underlying vascular contributions to cognitive impairment and dementia over and above conventional dementia risk scores.

Method

The MESA study followed a diverse cohort of 6,814 adults aged 45‐84 years over 6 clinical examinations and annual follow‐up calls since baseline, 2000‐2002. We evaluated relationships between subclinical cardiovascular assessments collected at baseline (Table 1) and neuroimaging biomarkers (Table 2) acquired ∼17‐20 years later in a subset (N = 1420) of older adults free from clinical CVD at baseline with MRI data (Table 2). Factor analyses identified four subclinical composites of arteriosclerosis, atherosclerosis, cardiac function, and blood pressure. Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk (CAIDE) composite scores comprised of age, sex, education, systolic blood pressure, body‐mass index, total cholesterol, physical activity and APOE‐ε4 genotype were calculated. Adjusted general linear models and Random Forest modeling paired 5‐fold 10x‐repeated cross‐validation were used in all analyses.

Results

Baseline subclinical factors were differentially associated with MRI measures at long‐term follow‐up. Subclinical composites of arteriosclerosis and atherosclerosis exhibited the strongest associations with lower global and hippocampal gray matter volume, greater white matter hyperintensity burden, and with higher Aβ‐PET deposition in unadjusted (not shown) and adjusted models (Figure 1, panel A; all p < .05). A composite of cardiac function was modestly associated with MRI measures. Blood pressure was more strongly associated with measures of white matter brain health. Cross‐validated prediction models utilizing individual subclinical measures best predicted measures of global and regional GM volume (Figure 1, panel B). Subclinical measures representing arteriosclerosis (e.g., small artery elasticity, systemic vascular resistance, carotid distensibility) and atherosclerosis (e.g., common carotid intimal‐media thickness, maximum intimal‐media thickness) were most predictive across imaging outcomes assessed. Baseline coronary calcification and carotid distensibility were most strongly associated with MRI measures indexing global GM atrophy (Figure 1, panel C).

Conclusion

Ultimately, our findings may highlight specific subclinical vascular pathways to dementia. Extending this work, we aim to develop trajectory‐based prediction models to better assess vascular aging.
INTERCEPT‐AD: A Gender Analysis of the Phase 1 Experience Among Trial Participants with Early Alzheimer’s Disease and Their Study Partners
Authors: Johnston Kelly , Presnall Carrie , Merikle Elizabeth , Cline Stephanie , Moxon Robyn , Feaster Todd , Siemers Eric
Published: January 2025

Background

Qualitative patient interviews are increasingly conducted alongside clinical trials; interviews administered early in drug development can yield insight into the patient journey. Examination among patient subgroups may identify factors that influence the patient experience, including trial participation. As part of the INTERCEPT‐AD phase 1 study evaluating the safety and tolerability of the Aβ oligomer‐targeting monoclonal antibody ACU193, we conducted semi‐structured qualitative interviews among a subset of participants with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD) and their study partners to obtain feedback on their trial experience and the decision‐making process preceding trial enrollment; results were compared between study participant genders.

Method

A subset of study participants and study partners completed qualitative interviews following the final study visit. Topics included referral source, motivations for participating, enrollment decision‐making, concerns regarding study medication and procedures, and positive and negative aspects of participation. Study participant/study partner dyads were defined as female or male according to the gender of the study participant as it was captured in the main study protocol; study partner gender was not obtained. Transcripts were coded and analyzed using principles of qualitative thematic analysis and grounded theory. Differences in concepts mentioned between genders were reported when >20%, and when sample size was sufficient (≥5 dyads reporting a concept with a difference of >2 mentions between genders).

Result

Twenty‐eight participants (64.2% female) and their study partners were interviewed, representing 43% of the total randomized trial population (n = 65; 53.8% female). Female dyads accounted for 62% and 70% of those who first heard about INTERCEPT‐AD from social media or physicians, respectively. More female dyads desired additional information about AD (86% of all dyads reporting this concept), to benefit others (75%), and to benefit self (65%) by participating. Regarding the decision to enroll, those who decided independently were exclusively female dyads; female dyads accounted for 71% among those who had pre‐trial concerns about side effects. More female dyads expressed dislike for cognitive tests (83%) and blood draws (78%).

Conclusion

Certain factors of trial participation differed by participant gender, including motivations for participation and perceived burden of some study procedures.
Conditions prior to age 16 are associated with incident dementia status among older adults in the United States Health and Retirement
Authors: Cockell Scarlet M , Wang Herong , Benke Kelly S , Ware Erin B , Bakulski Kelly M.
Published: January 2025

Background

Dementia is a prevalent neurodegenerative disease with risk attributed to both genetic and environmental factors. Multiple factors contribute to the etiology of dementia, and the relevant exposure window of susceptibility is likely before symptom onset. Conditions and the environment in the early life period have not yet been comprehensively tested for association with later‐life dementia.

Method

In the United States Health and Retirement Study (HRS) (n = 16,509; 2008‐2014 waves) 31 exposures occurring before age 16 were assessed via retrospective questionnaire among those with normal cognition (baseline measure). Incident dementia status (dementia, cognitively impaired non‐dementia, cognitively normal) was assessed over up to ten years of follow‐up. In this exposure‐wide association study, we tested for associations between exposures and cognitive status relative to normal cognition using parallel multivariable logistic models, adjusting sex, age at baseline, follow up time, race/ethnicity, personal education, and parental education.

Result

In the analytic sample, participants were an average of 63 years of age at baseline. Over an average of 10 years of follow‐up, 5.3% of participants had incident dementia and 14.5% cognitive impairment. Depression before age 16 was associated with 1.71 (95% CI: 1.28, 2.26) times higher odds of incident cognitive impairment, relative to those with normal cognition. Headaches or migraines before age 16 were associated with 1.63 (95% CI: 1.18, 2.22) times higher odds of cognitive impairment, relative to normal cognition. Learning problems before age 16 were associated with 1.75 (95% CI:1.05, 2.79) times higher odds of cognitive impairment, relative to normal cognition. Self‐rated health as a child of “fair” (1.856 95% CI: 1.27, 2.64) and “poor” (3.39, 95% CI: 1.91, 5.82) were associated with odds of developing dementia, relative to self‐rated “good” childhood health.

Conclusion

Conditions and exposures originating in early life may be important risk factors for later onset of cognitive impairment or dementia, extending the relevant window of susceptibility. Longitudinal research may be subject to challenges related to recall of information and differential survival and follow‐up studies are needed.
Living alone, medial temporal tau pathology, and loneliness in cognitively normal older adults during the COVID‐19 pandemic
Authors: Zide Benjamin S , Gagliardi Geoffroy Pierre , Jacobs Heidi I.L. , Gatchel Jennifer R. , Quiroz Yakeel T. , Marshall Gad A , Johnson Keith A , Sperling Reisa A , Vannini Patrizia , Donovan Nancy J
Published: January 2025

Background

Social restrictions during the COVID‐19 pandemic raised acute concerns about the impacts of loneliness on older adults’ well‐being, particularly for those who live alone. Loneliness is a perceived state of isolation from others that is only partly determined by quantities of social ties and interactions. Drawing a subsample from the Harvard Aging Brain Study, we measured self‐reported loneliness in older adults living alone and those living with others during the pandemic. We leveraged pre‐COVID‐19 loneliness and neuroimaging data to evaluate whether Alzheimer’s disease (AD) pathology contributed to rising loneliness levels in community dwelling older adults living alone during the pandemic.

Method

One‐hundred and six cognitively unimpaired older adults underwent clinical assessments of self‐reported loneliness (UCLA Loneliness scale), cognitive performance (Preclinical Alzheimer’s Cognitive Composite [PACC]), depression (Geriatric Depression Scale), anxiety (Hospital Anxiety and Depression Scale), PiB‐PET measurements of cortical Aβ and FTP‐PET measurements of entorhinal cortex (EC) and inferior temporal (IT) tau prior to the pandemic. In May 2020, participants completed online surveys to determine living circumstances (alone vs. with others) and to re‐assess loneliness. Linear regressions with backward elimination estimated the interactive effect of living alone and either PiB, unilateral EC FTP, IT FTP, or PACC with change in loneliness (Δ Loneliness), adjusting for age, sex, time since pre‐COVID‐19 assessment, and pre‐COVID‐19 depression, anxiety, and loneliness.

Result

Table 1 presents sample characteristics. Before May 2020, pre‐COVID‐19 loneliness levels did not differ between participants living alone or those living with others (t [103] = ‐1.77, P = 0.08). Participants living alone during COVID‐19 reported greater increases in loneliness compared to those living with others, adjusting for covariates (β = 1.22, P = 0.024). Greater right EC and IT FTP binding in individuals living alone was associated with greater increases in loneliness (for living alone*EC FTP: β = ‐4.31, P = 0.044; R2 = 0.18; for living alone*IT FTP: β = 7.45, P = 0.019; R2 = 0.20; Figure 1). Interactions of PiB and PACC with living alone predicting change in loneliness were not significant.

Conclusion

Greater tau pathology compounded the association of living alone with increases in loneliness in cognitively unimpaired older adults during the COVID‐19 pandemic. AD pathological brain changes may be an unrecognized factor which contributes to late‐life loneliness.
Bridging Oral Health and Alzheimer’s Risk: The “Mouth to Mind” Project
Authors: Chamut Steffany , Dye Bruce A. , Igwe Akwaugo , Low Spencer , Rahman Salman , Tabkhi Hamed , Au Rhoda
Published: January 2025

Background

Global health is increasingly burdened by oral diseases (ODs) affecting 3.9 billion people, and Alzheimer’s disease with related dementias (AD/ADRD), impacting 46.8 million globally. Both are expected to increase due to aging populations and greater tooth retention. With soaring dental costs highlighting economic implications and complexities in access to care, there is an urgent need for early diagnosis and preventative low‐cost and accessible interventions. The “Mouth to Mind” project aims to develop and validate a comprehensive oral‐jaw health assessment tool that identifies early signs of cognitive impairment, focusing on the impact of jaw‐occlusal dysfunctions and exploring the intersection of oral health with neurodegenerative risks, malnutrition, and equity.

Method

A questionnaire, part of an oral‐jaw health assessment tool, is being validated with a cohort of participants aged 40 and above (n = 23) who are part of a larger study providing feedback on different health technologies. Qualitative analyses are being used to evaluate the tool’s feasibility and clinical utility. Key outcomes include participant burden, measured by questionnaire completion time, and suggestions for improving questions and answers to enhance clarity and usability.

Results

The study presents 20 females and 3 Males across diverse ethnic and racial groups (n = 8 Whites; n = 4 Hispanics; and n = 11 Black or African American) from the Greater Boston area. Anticipated results will be supportive of a validated questionnaire with insights into its administration, informing the design of a non‐invasive, user‐friendly tool for non‐dental settings.

Conclusions

This study lays the groundwork for the “Mouth to Mind” tool, aimed at early detection of oral diseases and jaw‐occlusal dysfunctions. By integrating oral health into the broader spectrum, it addresses cognitive decline risks. The next phase involves linking jaw‐occlusal dysfunction data with malnutrition and AD/ADRD risks, fostering the development of a transformative digital oral‐cognitive health tool. This tool is expected to advance early detection and preventive care, enhance life quality across populations, and drive significant policy and economic improvements in healthcare management.