bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlates of missed or late versus timely diagnosis of dementia in healthcare settings
Authors: Chen Yi , Power Melinda , Grodstein Francine , Capuano Ana W. , Lange‐Maia Brittney S , Moghtaderi Ali , Stapp Emma K , Bhattacharyya Joya , Shah Raj C. , Barnes Lisa L. , Bennett David A. , James Bryan D
Published: January 2025

Background

Previous research suggests dementia is undetected in healthcare settings for more than half of those with dementia. Most research on underdiagnosis of dementia has focused on the presence or absence of a clinical diagnosis in claims or the medical record without addressing differences in the timeliness of a diagnosis. Little is known about factors that may be related to the timeliness of clinical dementia diagnosis.

Method

In five longitudinal cohorts at Rush Alzheimer’s Disease Center, we identified participants with incident dementia based on annual research assessments from 1994 to 2019 and examined the timing of dementia diagnoses in Medicare claims. Receiving a claims diagnosis within three years prior to or one year following incident dementia was considered a “timely diagnosis”; the remaining were categorized as “underdiagnosis”, including late or missed diagnosis. We assessed correlates of timely versus under‐ diagnosis, including sociodemographic characteristics, health, and psychosocial factors, using bivariate analyses and adjusted logistic regressions.

Result

Of the 710 participants with incident dementia, 54% (n = 385) received a timely diagnosis. In logistic regressions adjusting for demographic characteristics, we found Black older adults had twice the odds of underdiagnosis versus timely diagnosis (OR = 2.15, 95% CI: 1.21‐3.82). Higher mid‐life income (on 10‐level scale) was related to 11% lower odds of underdiagnosis (OR = 0.89, 95% CI: 0.81‐0.97). Better cognitive function (OR = 1.48, 95% CI: 1.10‐1.98 for one standard‐deviation higher cognitive function), and fewer comorbidities (OR = 0.94, 95% CI: 0.89‐0.98 for one‐unit increase in Elixhauser Comorbidity Index) at the time of dementia onset were associated with diagnostic delay. The number of encounters with the healthcare system, disability, frailty, social network, psychosocial factors, and APOE‐4 genotype were not associated with diagnostic timing.

Conclusion

When considering the timeliness of dementia diagnosis, two socio‐demographic characteristics (Black race and lower income) and two health characteristics (better cognitive function and fewer comorbidities) were related to receiving a late/missed diagnosis. Observed correlates of timeliness may have implications for improving dementia diagnosis and care.
T1/T2 weighted ratio mapping to assess intracortical myelination in autosomal dominant Alzheimer's disease
Authors: Sgalia Alessia , Ocal Dilek , Veale Thomas , Ferguson Damien , O'Connor Antoinette , Malone Ian B. , Cash David M , Fox Nick C , Weston Philip SJ
Published: January 2025

Background

Identifying early pathological changes in Alzheimer’s Disease (AD), and accounting for variability in progression between individuals, is crucial for timely and effective intervention. While Amyloid‐b, tau, and neuronal loss are core pathological processes in AD with established biomarkers, myelin alterations have been shown to occur but remain under‐investigated. The T1/T2w ratio represents an accessible MRI‐based marker, providing a potential proxy measure of myelin integrity. Autosomal dominant AD (ADAD) provides a unique opportunity to investigate AD‐related changes across its continuum, estimating time to/from symptom onset from family history. This study examines the T1/T2‐weighted ratio as an indicator of extra‐neuronal AD pathology in ADAD.

Method

Seventy‐two ADAD family members were included: 28 presymptomatic mutation carriers, 20 symptomatic mutation carriers and 24 non‐carrier controls (Table 1). Volumetric T1 and T2‐weighted MRI sequences were acquired. Whole brain preprocessing and T1/T2w ratio were calculated for each participant using MRtool in SPM12 (bias correction, rigid registration, calibration, ratio), followed by tissue segmentation, DARTEL, normalisation and smoothing. Voxel‐wise analysis compared T1/T2 across 1) presymptomatic mutation carriers vs. non‐carriers and 2) symptomatic mutation carriers vs. non‐carriers, adjusting for age and sex. In mutation carriers only, we assessed correlations between T1w/T2w ratio and 1) estimated years to/from onset (EYO), and 2) Mini‐Mental State Examination (MMSE) scores.

Result

Symptomatic ADAD mutation carriers had lower T1w/T2w ratios than non‐carriers in the medial parietal lobe (t = 7.06, p <0.001 family‐wise error (FWE) corrected) (Figure 1), likely reflecting altered myelin integrity. After FWE correction, no significant differences were observed between presymptomatic mutation carriers and non‐carriers. Across all mutation carriers, there was a positive correlation between T1w/T2w and EYO (i.e. lower T1/T2 was associated with less time to symptom onset), with significant clusters in the praecuneus (p < 0.05 FWE‐corrected) (Figure 2). There was a positive correlation between T1w/T2w and MMSE (t= 5.82, p <0.05 FWE‐corrected) (Figure 3).

Conclusion

T1w/T2w ratio is reduced in ADAD, suggesting reduced myelin integrity, and is associated with measures of disease stage (EYO) and severity (MMSE). T1w/T2w ratio could therefore provide a feasible biomarker of myelin integrity, potentially enhancing early AD prognostication, monitoring and treatment development.
Childhood attention‐deficit hyperactivity disorder (ADHD) and cognitive function in later life: Analysis of HRS data
Authors: Stinchcombe Arne , Hanes Douglas William
Published: January 2025

Background

Attention‐deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition marked by cognitive deficits (e.g., challenges sustaining attention, distractibility). Symptoms of ADHD typically manifest in childhood and can interfere with engagement in school activities, chores, and interpersonal relationships. In many cases, symptoms endure into adulthood and older adulthood. ADHD in adulthood and mild cognitive impairment (MCI) share many overlapping cognitive (e.g., impaired executive functions) and non‐cognitive (e.g., depression, poor sleep) symptoms, complicating differential diagnosis. Currently, the association between ADHD and cognitive impairment associated with aging, such as MCI, remains unclear. The purpose of this present study was to examine differences in cognitive function by ADHD status in an aging sample.

Method

Data were drawn from the Health and Retirement Study, a longitudinal survey of U.S. residents aged ≥51 years. Waves 4‐14 (1998‐2018) were used in the present analysis. Of the 10,804 participants included for analysis, 99 participants (i.e., 0.9% of the sample) reported having an ADHD diagnosis in childhood. Cognitive function was measured on a 27‐point scale. The primary analysis consisted of a series of multiple linear regression models, treating cognition as the outcome, and adjusting for age, sex/gender, wealth, education, and race.

Result

Descriptive analysis showed that participants with ADHD reported lower levels of education and were more likely to have experienced homelessness and depression. Participants with ADHD showed lower cognitive scores at baseline (m = 14.52) compared to non‐ADHD peers (m = 17.01, t = 5.90, p<.001). Multivariable analysis revealed that after adjusting for covariates, ADHD status was associated with lower cognitive scores in the study (B = ‐1.88, p<.001). ADHD participants showed a similar slope of decline to non‐ADHD peers over time; however, cognitive scores were consistently lower at each time point for ADHD participants.

Conclusion

Individuals with self‐reported childhood ADHD diagnoses demonstrated lower cognitive scores compared to their non‐ADHD counterparts, suggesting a persistent impact of ADHD on cognitive function in later life and potential risk for cognitive impairment. These findings emphasize the need for further research to elucidate the complex relationship between ADHD and cognitive impairment and underscore the importance of considering ADHD in the broader context of cognitive health throughout the lifespan.
Cognitive and Brain Structure Correlates of Plasma Biomarkers in Traumatic Encephalopathy Syndrome
Authors: Emanuel Olivia M , Matusz Emily F , Lee Shannon Y. , Bove Jessica , Smith Karen , Kramer Joel H. , Rabinovici Gil D. , Asken Breton M.
Published: January 2025

Background

Traumatic encephalopathy syndrome (TES) is a proposed framework for the clinical syndrome resulting from chronic traumatic encephalopathy and other neurodegenerative effects of repetitive head impacts (RHI). TES symptoms can mirror Alzheimer's disease (AD) despite absence of hallmark AD pathology. We investigated whether GFAP, NfL, and IL‐6 correlated with cognition and brain volume changes within TES relative to AD.

Method

We studied 96 participants from the UCSF Memory and Aging Center (N=35 RHI/TES; 24 of whom were AD biomarker‐negative, TESAD‐; N=61 biomarker‐confirmed AD phenotype, no RHI; Table 1). Plasma was analyzed for GFAP, NfL, and IL‐6 (age‐ and sex‐adjusted). Cognitive measures included composite memory and executive functioning scores (demographically‐adjusted). MRI was obtained concurrent to blood draws and several regions of interest were analyzed (demographic‐ and total intracranial volume‐adjusted): frontal, temporal, parietal, occipital, hippocampus, subcortical. Spearman’s rho assessed associations between plasma biomarkers, cognition, and brain volume. A priori alpha was p<.05, but associations with at least medium effect size (rho ≥0.3) were interpreted as potentially meaningful given small N in TES and TESAD‐ subgroups.

Result

In TES, higher GFAP was associated with lower hippocampal volume (rho=‐0.33, p=.09) and worse memory (rho=‐0.44, p=.02). Results were similar in TESAD‐ subgroup (GFAP‐hippocampus: rho=‐0.45, p=.07; GFAP‐memory: rho=‐0.42, p=.07). IL‐6 appeared most related to brain volume in the TESAD‐ subgroup, where higher IL‐6 correlated with lower volumes in all regions (rho’s ‐.43 ‐ ‐.63, p’s=.004 ‐ .06), but not with cognition. In AD, both higher NfL and GFAP were associated with lower brain volume in several regions and with worse cognition but, notably, neither related to hippocampal volume (NfL: rho=‐.11, p=.47; GFAP: rho=.02, p=.91). IL‐6 did not relate to brain volume or cognition in AD (Figure 1).

Conclusion

Plasma biomarkers reflect different regions of atrophy and cognitive change in TES vs. AD. Inflammation (IL‐6) may play a distinctive role in the pathophysiology underlying atrophy in TES. While recent work highlights astroglial activation (GFAP) is a putative AD‐related biomarker, it may uniquely relate to hippocampal changes in TES. Ongoing work is needed to unravel the clinical utility of plasma biomarkers for characterizing the neurodegenerative effects of RHI and underlying TES symptoms.
Comparison of dementia incidence and risk factor associations in All of Us against the nationally representative Health and Retirement Study
Authors: Wang Jingxuan , Chen Ruijia , Hayes‐Larson Eleanor , Mayeda Elizabeth Rose , Choi Minhyuk , Ackley Sarah F , Glymour M. Maria
Published: January 2025

Background

The All of Us (AoU) Research Program, an ongoing large‐scale research initiative enrolling diverse groups across the U.S offers a valuable opportunity for dementia research. It is vital to assess if AoU findings are applicable to the general population. We compared dementia incidence and risk factor associations in AoU to those in a population‐based cohort, the Health and Retirement Study (HRS).

Method

AoU participants aged ≥ 60 without a dementia diagnosis at baseline (N = 130,551, mean age = 69.6) were included. We identified all‐cause dementia cases by ICD codes from linked EHRs. We included HRS participants aged ≥ 70 from 2000 to 2016 who had no dementia status before baseline (N = 14,016, mean age = 73.4). Dementia status was determined at each wave using a validated algorithm (Expert Model). We calculated age‐specific dementia incidence rates overall and by sex and race/ethnicity. We used Cox models to evaluate associations of education, obesity (body mass index ≥ 30), smoking history (ever vs not), and type 2 diabetes (T2D) with incident dementia, adjusting for age, sex, and race/ethnicity.

Result

1,403 dementia cases accrued during a mean of 2.6 years follow‐up in AoU compared to 4,814 dementia cases during a median of 7.1 years follow‐up in HRS (Table 1). Age‐specific dementia incidence rates over 70 years were lower in AoU compared with HRS, with more pronounced differences at older ages (Figure 1). Risk factor associations showed larger relative effect sizes in AoU, except for education, which showed similar associations (Figure 2). For example, the hazard ratio for T2D and dementia in AoU (HR = 2.89, 95%CI = 2.59‐3.23) was larger than in HRS (HR = 1.69, 95%CI = 1.57‐1.82, Figure 2).

Conclusion

Dementia incidence rates were much lower in AoU than HRS, consistent with prior work showing a healthy volunteer bias for study enrollment. This may also represent underdiagnosis of dementia in the EHR or overdiagnosis in HRS. Associations between risk factors and dementia were similar or stronger in AoU compared to the HRS. Future studies should approach the generalization of AoU study findings to the US adult population with caution.
Does the message matter: A strategy to improve retention in recruitment registries
Authors: Lee Yongjun , Grill Joshua D , Gillen Daniel L , Witbracht Megan G. , Hoang Dan , Delehoy Brandon
Published: January 2025

Background

To be successful, recruitment registries must retain participants until they can be recruited to studies. Yet, strategies and tactics to improve retention in online recruitment registries remain understudied. This study seeks to quantify the preferences of registry participants’ when it comes to video message content aimed at increasing registry renewal.

Method

Active participants of the UC Irvine Consent‐2‐Contact (C2C) Registry were invited to participate in a discrete choice experiment to test whether four short video messages about the reasons to renew, delivered alone or in combination, would elicit a clear preference. The messages highlighted reasons that individuals might choose to renew their enrollment in the registry: 1) some recruiting studies offer financial compensation, 2) to advance research toward improved outcomes in health and disease, 3) to be matched to a study relevant to one’s own health, and 4) promotion of novel research within the registry using data collected at renewal. From 15 possible combinations, participants viewed 7 random pairs of videos. After viewing each pair, participants were asked to select the video that would most compel them and others to renew their participation in the registry. Each participant was asked to complete a final survey including 8 Likert scale items assessing participant attitudes toward renewal. The study employed a Bradley‐Terry model to identify the combination deemed favored by the participants. To estimate topic‐specific preferences, interaction between the topics across all combinations, along with covariate adjustments for participant demographics were modeled via an extension of the Bradley‐Terry model in combination with the study’s fractional factorial design.

Result

Statistical power to identify the most preferred topic along with topic‐specific orderings were carried out via simulation. Data collection is underway. Presented results will include efficacy of individual messages as well as optimal message combinations and concordance with survey results.

Conclusion

This study introduces a novel design where the effect of video messages from a fractional factorial combination of four incentives can be estimated through a paired rank analysis model. Results will inform a future randomized factorial design trial of retention interventions.
GEAR 2.0 ‐ Care Transitions
Authors: Shah Manish N
Published: January 2025

Older adults use the emergency department (ED) as an important source of acute illness care, making over 20 million visits annually. Persons living with dementia are twice as likely to use the ED and 1.5 times more likely to have an avoidable visit. When in the ED, they may not be able to give the clinicians a complete and accurate medical history, including information regarding their dementia. Further, they struggle with the environment and conditions. These challenges, along with other risks, put patients living with dementia at greater likelihood for poor outcomes.

Approximately 50 percent of patients with impaired cognition are discharged to their homes after receiving ED care, but approximately 40 percent of those discharged home will experience an adverse event (ED revisits, other hospitalizations, or death) in the 30 days following discharge—a rate significantly higher than for those without impaired cognition.

This session will review the interventions delivered to patients with impaired cognition to improve ED discharge transitions and the measures of quality ED discharge transitions that are important to ED patients with impaired cognition and their care partners.
ED‐to‐community care transitions for persons living with dementia
Authors: Gettel Cameron
Published: January 2025

Objectives

Little data exists to date regarding effective interventions to improve emergency department (ED)‐to‐community care transitions for persons living with cognitive impairment (PLWCI) and their care partners. We sought to develop, refine, and pilot test the innovative pairing of artificial intelligence (AI)‐enabled digital advisors and an occupational therapist‐led care coach intervention to improve ED‐to‐community care transitions for PLWCI and their care partners.

Methods

We used a mixed methods, multi‐phased approach to develop the intervention, with PLWCI and care partners sampled from the LiveWell Dementia Specialists network. In the first phase, we conducted semi‐structured focus groups and two researchers coded the professionally transcribed data using a combined deductive and inductive approach. In the second phase, we performed a 2‐day design thinking workshop using a user‐centered design approach, involving PLWCI, care partners, health care professionals, community‐based partner organizations, technologists, and AI experts. In the final phase, we pilot tested the paired intervention among PLWCI and care partners experiencing ED‐to‐community care transitions, assessing: 1) intervention outcomes and 2) patient‐ and care partner‐centered outcomes.

Results

In the first phase, we performed two focus groups, involving a total of 16 participants, with PLWCI and care partners expressing: 1) concerns that their unique needs related to cognition were not addressed in the ED setting, 2) frustration with the ED discharge process and their perceived ability to follow‐up in the outpatient setting and obtain desired resources, and 3) openness to the incorporation of AI to facilitate successful ED‐to‐community care transitions. In the second phase, 23 individuals participated in the design thinking workshop. We characterized perceived barriers and facilitators for intervention adoption during open forum discussions and identified 10 Lessons Learned for future investigators to consider in intervention development. In the third phase, 16 participants have completed all surveys up to 30‐day follow‐up with evidence of improvements in the 4‐item Zarit Caregiver Burden scale (13.9 to 12.2) and the Fortinsky Caregiver Self‐Efficacy Scale (52.9 to 64.8).

Conclusion

PLWCI and care partners were integrally engaged in the co‐creation of a two‐component novel intervention to improve ED‐to‐community care transitions.
Intergenerational educational attainment and risk for incident dementia: The Atherosclerosis Risk in Communities [ARIC] Neurocognitive Study
Authors: Gupta Soumya , Morrill Valerie , Groechel Renée C. , Kucharska‐Newton Anna M. , Mosley Thomas H. , Lutsey Pamela L. , Meza Erika , Gottesman Rebecca F.
Published: January 2025

Background

Individuals with higher educational attainment have a lower risk for dementia, but it is less clear how educational attainment of an individual’s parents may influence dementia risk, particularly in diverse populations. The study goal was to investigate the association between intergenerational educational attainment for two adjacent generations (individuals and their parents) and the risk of incident dementia, in a community‐based study.

Method

Participants from the Atherosclerosis Risk in Communities (ARIC) study, a prospective community‐based cohort, were asked their own educational level (at study baseline; 1987‐1989; ages 44‐66 years) and that of each of their parents several years later. Dementia status was ascertained from baseline through 2020 using expert committee diagnoses from comprehensive neuropsychological assessments, informant interviews, telephonic assessments, hospitalization codes, and death certificates. Participants without dementia at baseline, and with non‐missing covariates and educational history were included. Educational level was classified (for participants and the higher‐educated parent) as less than high school (HS). We defined “overachievement” as a participant having higher educational attainment than their parent. Cox‐proportional hazard models were used to evaluate the association between intergenerational educational attainment and incident dementia risk.

Result

Among 10,626 participants (21.8% Black; 56.0% female) the overall dementia incidence rate was 7.9 [95% CI, 7.6‐8.3] per 1000 person‐years, with differences by educational category (Figure 1; log‐rank p<0.0001). High parental education level (>HS: HR, 0.88; 95% CI, 0.80‐0.99) and individual education level (>HS: HR, 0.62; 95% CI, 0.55‐0.70) were each significantly and independently associated with a lower risk of dementia (Table 1). Additionally, among participants whose parents had HS (HR, 0.65; 95% CI, 0.56‐0.75)), as compared to matching parental education, was significantly associated with lower dementia risk (Table 2).

Conclusion

Individuals with parents of higher educational attainment exhibit a reduced risk of dementia, and higher individual educational level is associated with reduced dementia risk, independent of parental education. Moreover, surpassing parental educational attainment, rather than matching it, is associated with a reduced risk of dementia.
Harmony of Mind and Motion: Exploring the Interplay between Physical Activity and Mild Behavioral Impairment in Dementia‐Free Older Adults
Authors: Mudalige Dinithi M , Guan Dylan X. , Smith Eric E. , Ismail Zahinoor
Published: January 2025

Background

While dementia typically presents in later life, early‐to‐mid‐life factors like physical inactivity contribute to dementia risk. Mild Behavioral Impairment (MBI), marked by emergent and persistent behavioral changes in older adults, also contributes to dementia risk. However, there is limited research on the impact of physical activity in those with MBI. In a community‐dwelling sample of dementia‐free older adults, we determined the association between the total weekly frequency of engaging in physical activity and MBI severity and whether this association depended on the total duration of physical activity.

Methods

Data were obtained from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behavior, Function, and Caregiving in Aging (CAN‐PROTECT) study. Measures included the MBI Checklist (MBI‐C) and physical activity questions from the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. Four physical activity domains were established (physical labor, cardiovascular activities, mind‐body exercises, and strength training). Multivariable negative binomial regression models modeled associations between MBI and weekly frequency of engaging in total and domain‐specific physical activity. All models were adjusted for age, sex, years of education, marital status, ethnocultural origin, and occupation type. Duration engaging in physical activity was explored as a covariate and a moderator.

Results

For every 1 standard deviation (SD) increase in the total physical activity frequency was associated with a 18.3% (95%CI: ‐31.3—6.6, p = 0.002) lower MBI‐C total score. This association was moderated by total duration engaging in physical activity (expB = 1.0, 95%CI: 1.0‐1.0, p = 0.008), where the strength of the association weakened as the duration of physical activity increased. Additionally, every 1 SD increase in cardiovascular activity frequency and mind‐body activity frequency were associated with 18.1% (95%CI:‐30.9—6.5, p = 0.003) and 15.7% (95%CI:‐28.9—3.7, p = 0.006) lower MBI‐C total scores.

Conclusions

More frequent weekly physical activity and cardiovascular and mind‐body exercise were associated with lower MBI severity. As the duration of physical activity increased, the impact of the frequency of physical activity on MBI severity decreased, and vice versa. Since lower MBI scores are associated with a lower risk for dementia, these results might inform dementia risk reduction, even in those with few cognitive symptoms.
Specific plasma proteins and metabolites convey the effects of lifestyle interventions that improve cognition and function in Alzheimer’s disease
Authors: Roach Jared C. , Funk Cory C , Glusman Gwênlyn , Merrill David A. , Hodes John F. , Rapozo Molly K. , Edens Lance , Vaidyaraman Ananya , Shankle William R , Hood Leroy , Bramen Jennifer E. ,   the COCOA Consortium
Published: January 2025

Background

The Coaching for Cognition in Alzheimer’s (COCOA) Trial was a prospective RCT testing a remotely coached multimodal lifestyle intervention for participants early on the Alzheimer’s disease spectrum. Intervention focused on diet, exercise, cognitive training, sleep, stress, and social engagement. Enrollment criteria targeted individuals with cognitive decline who were able to engage remotely with a professional coach. COCOA demonstrated cognitive and functional benefits. Dense omics data were collected on 53 individuals (≥ 58 years).

Methods

We sought to identify blood analytes that mediated the effects of specific elements of the multimodal intervention on specific outcomes. Outcomes were assessed with the MCI Screen (MCIS) and the Functional Assessment Staging Tool (FAST). We combined these and other measures with proteomics and metabolomics data. We analyzed the resulting dataset of over 300,000 distinct molecular data points—reflecting over 1400 measures— assayed over a period of two years. We used MEGENA to hierarchically multiscale cluster analytes based on correlated responses and identified individual metabolites and functional clusters associated with each intervention and outcome. We analyzed individual time courses of key analyte mediators to illustrate personalized effects of interventions and individualized functional and cognitive outcomes.

Results

Distinct sets of correlated serum analytes (“communities”) convey effects to functional (FAST) outcome and to cognitive (MCIS) outcome. Distinct communities respond to different modalities of intervention. Participants followed different aspects of the multimodal recommendations to different extents, and the analytes in their blood also responded idiosyncratically; analyte trajectories in different individuals show distinct dynamics. We made personalized predictions of future inflections in outcome based on observed changes in key serum mediators. We validated results with data from the Precision Recommendations for Environmental Variables, Exercise, Nutrition and Training Interventions to Optimize Neurocognition (PREVENTION) Trial.

Conclusions

Lifestyle interventions have profound effects on blood metabolites (Figure 1). These in turn convey subtler specific effects to cognition and broad‐based effects to function. Pathways that ameliorate the impact of AD via lifestyle interventions in some individuals include nitrogen subsystems, kidney function, and mitochondrial metabolism. These highlight the importance of clinical attention to overall health spanning multiple organ systems in individuals across the Alzheimer’s disease spectrum.
Lecanemab Slows Tau PET Accumulation
Authors: Charil Arnaud , Cao Youfang , Willis Brian A. , Hersch Steven , Irizarry Michael C. , Reyderman Larisa
Published: January 2025

Background

Lecanemab is an approved anti‐amyloid monoclonal antibody that binds with highest affinity to soluble Aβ protofibrils, which are more toxic than monomers or insoluble fibrils/plaque. In clinical studies, biweekly lecanemab treatment demonstrated a slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer’s disease (AD). Herein, we describe the impact of lecanemab treatment on tau PET.

Method

Changes over time in tau PET SUVR ([18F]MK6240) were compared between placebo and lecanemab‐treated groups. Associations between baseline and change from baseline (CFB) in tau PET SUVR across brain regions were investigated. A quantitative systems pharmacology (QSP) model was developed to describe the dynamics of medial temporal (MTL) tau PET based on AD pathophysiology with three interlinked modules: Aβ pathway, tau pathway, and cognitive function. MTL tau PET data from the lecanemab Clarity AD study and other biomarkers from Clarity AD and lecanemab Study 201, and Alzheimer’s Disease Neuroimaging Initiative (ADNI), were used to inform and validate the model. QSP model‐based simulations were conducted to investigate the effect of lecanemab treatment on tau pathology.

Result

Higher baseline tau levels were associated with higher tau accumulation across brain regions with disease progression. Lecanemab treatment significantly slowed accumulation of tau in temporal regions relative to placebo and disrupted association between baseline tau and CFB in tau across brain regions. QSP simulations predicted MTL tau PET accumulates 0.064 SUVR/year in placebo, and 0.092 SUVR/year in high baseline tau group (tau PET SUVR>1.5). QSP simulations predicted that lecanemab treatment halted tau PET accumulation in MTL region over 18 months of treatment and maintained suppression with continued biweekly lecanemab regardless of baseline tau levels.

Conclusion

Lecanemab treatment demonstrated an impact on tau accumulation across brain regions. QSP model adequately described MTL tau PET for placebo and lecanemab across 30 months of Clarity AD data. QSP simulations suggest that lecanemab halts tau PET accumulation by clearing major tau pathology drivers of amyloid protofibril and plaque, slowing down long‐term cognitive decline. Taken together, tau PET data and QSP modeling support additional benefits of continued lecanemab treatment.
Long‐Term Effects of Lecanemab on Biomarkers of Neurodegeneration in Plasma
Authors: Teunissen Charlotte , Willis Brian A. , Bhagunde Pratik , Bell Robert , Penner Natasha , Sachdev Pallavi , Reyderman Larisa
Published: January 2025

Background

Lecanemab, a novel humanized immunoglobulin G1 monoclonal antibody targeting both neurotoxic Aβ protofibrils and Aβ plaques, has demonstrated the ability to substantially reduce markers of amyloid and significantly slow clinical decline on multiple measures of cognition and function in early AD in phase 2 (Study 201) and phase 3 (Clarity AD) studies. In these clinical studies, several plasma biomarkers assessments (Aβ42/40 ratio, p‐tau181, GFAP, and p‐tau217) showed improvements comparing lecanemab with placebo. Herein, we utilized modelling and simulations to evaluate the long‐term effects of lecanemab on biomarkers of neurodegeneration in plasma.

Method

Models describing the relationship between serum lecanemab exposure and change in plasma biomarkers were developed using data pooled from lecanemab phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population pharmacokinetic model and correlated with plasma biomarker concentrations using indirect response models. Simulations were conducted to evaluate the effect of lecanemab (10 mg/kg IV every 2 weeks) after 4 years of continuous treatment, discontinuation after 18 months of treatment, or transitioning to less frequent dosing at 18, 24, or 30 months.

Result

Data were available for up to 48 months continuous lecanemab treatment (Clarity AD) or 18 months continuous treatment, followed by a pause in dosing (average 24 months, range 5‐59 months) followed by a resumption of dosing (Study 201). All models were well parameterized and adequately described the data. Simulations demonstrated that biomarkers reverted towards pre‐treatment baseline after cessation of lecanemab treatment, with an average half‐life of approximately 1‐1.5 years. Transitioning to less frequent monthly dosing was sufficient to stabilize plasma biomarker concentrations at levels consistent with lecanemab efficacy.

Conclusion

Models describing the change in plasma biomarker levels over time in response to lecanemab treatment have been developed. Simulations conducted with these models demonstrate that continued treatment with lecanemab is required to sustain the benefit of lecanemab on amyloid and neurodegenerative pathology, but that less intensive dosing regimens are sufficient to maintain the changes in plasma biomarker levels consistent with lecanemab efficacy.
Association between number of teeth and cognitive decline: a systematic review and meta‐analysis of more than 4 million people
Authors: Chambergo‐Michilot Diego , Montesinos Rosa , Custodio Belen , Rivera Eva Arias , Butler Christopher , Custodio Nilton
Published: January 2025

Background

Dementia has sparked interest in identifying modifiable risk factors. It has been proposed that the number of teeth could play a crucial role in cognitive decline, suggesting possible mechanisms such as nutritional influence, inflammation, and neuronal feedback.

Methods

We performed a systematic literature search in January 2024 in PubMed, Scopus and Embase to search observational studies that reported the association between number of teeth and dementia or cognitive decline. We pooled the reported or calculated odds ratios in forest plots.

Results

We included nine studies in our systematic review. The total sample size was 4022654 patients. There was one study with more than 4 million people. Three studies reported the independent variable (number of present teeth) as a continuous variable, and six studies reported it as a categorical variable. Three studies reported the reference category as ≥ 20 present teeth, and the remaining three studies reported the reference category as ≥ 22 present teeth. The most common tool to define cognitive decline was the Mini‐Mental State Examination. We did not find a significant association between number of teeth as a continuous variable and dementia or cognitive decline (OR: 1.00, 95% CI: 0.70‐1.44) (Figure 1). Regarding the 3 studies with reference category ≥ 22 present teeth, having 11‐21 present teeth was not significantly associated with dementia or cognitive decline (OR: 2.61; 95% CI: 0.61‐11.06) (Figure 2), in contrast to people with 0‐10 present teeth where it was significantly associated with dementia or cognitive decline (OR: 14.58; 95% CI: 3.52‐60.40) (Figure 3). Additionally, the other 3 studies with reference category ≥ 20 present teeth, having 10‐19 present teeth was not significantly associated with dementia or cognitive decline (OR: 1.93; 95% CI: 0.87‐4.27) (Figure 4), however, having 1‐9 present teeth was significantly associated with dementia or cognitive decline (OR: 1.34; 95% CI: 1.32‐1.36) (Figure 5).

Conclusion

A low number of teeth is associated with cognitive decline. Patients with cognitive decline should have a periodontal disease screening.
Characterizing Exposure to Traffic‐Related Air Pollution in a Diverse Alzheimer’s Disease Research Center Cohort
Authors: Decarli Charles , Farias Sarah Tomaszewski , Tobias Michele , Harvey Danielle J. , Carney Randy , Wexler Anthony , Bein Keith , Kleeman Mike , Lein Pamela , Meyer Oanh L.
Published: January 2025

Background

Most studies on the associations between traffic related air pollution (TRAP), cognition, and dementia focus on particulate matter (PM) 2.5, are cross‐sectional and based on non‐Hispanic White (NHW) individuals. Less is known about how exposure to ultrafine PM (UFPM) affects cognition in racially/ethnically diverse cohorts. The UC Davis Alzheimer’s Disease Research Center (UCD ADRC) recently launched a study on TRAP that will assess the impact of UFPM on cognition, brain imaging and neuropathology. This abstract describes the broad geographic location, varying TRAP exposure, and demographic diversity of the cohort.

Method

A total of 985 adults, average age of 81.3 ± 8.2 years, 62.6% female and consisting of 44% NHW, 24% Hispanic/Latino, 26.4% Black/African American, and approximately 4% other races/ethnicities had physical addresses geocoded to identify geographic coordinates; 29% of participants were cognitively normal, 18% had questionable cognitive impairment, 23% had mild cognitive impairment, and 30% had dementia. Detailed neuropsychological assessments and MRI were conducted annually along with collection of blood samples and data regarding social cultural variables. Median exposure of nearly 30 different TRAP measures including PM ranging in size from 0.1 to 10 µm measured over the years 2000‐2019 were calculated. Individual exposures were determined over an average of 4.4 ± 4.7 years of participant follow‐up.

Result

Participants lived in 28 counties throughout northern California with major clusters in the East Bay, Vallejo, Fairfield, Vacaville, Sacramento, and Central Valley south of Sacramento. We found highly significant differences in ethnoracial distribution according to county designation (Figure 1; p < 0.001; Fisher’s exact) and in both state and national Area Deprivation Index scores (ADI; Figure 2; p <0.0001, one‐way ANOVA). ADI varied significantly with ethnoracial background with Hispanic/Latino participants having the highest ADI at 29 ± 1. MANOVA analysis found significant (p <0.0001) geographic differences in 0.1 µm sized particles (e.g. Figure 3 for sodium and elemental carbon).

Conclusion

Preliminary analysis indicates significant differences in location, ethnoracial background, ADI, and TRAP exposure amongst UCD ADRC participants. This heterogeneity will allow comprehensive evaluation of the clinical impact of TRAP exposure on cognition among diverse individuals.
Effect of incident stroke on the risk of dementia over 10 years of follow‐up in a cohort of Asian American and White older adults in Northern California
Authors: Rojas‐Saunero L. Paloma , Zhou Yixuan , Hayes‐Larson Eleanor , Wu Yingyan , Nianogo Roch A , Whitmer Rachel A. , Gilsanz Paola , Elser Holly C , Mayeda Elizabeth Rose
Published: January 2025

Background

Acute stroke may increase dementia risk. Previous work has not accounted for time‐varying covariates that could increase risk of stroke and dementia over time, and there has been very limited evidence on the effect in Asian Americans. We aimed to estimate the effect of incident stroke on dementia risk over 10 years of follow‐up among Asian American and White older adults in Northern California considering time‐varying covariates.

Methods

We included Chinese (n = 6034), Filipino (n = 4649), Japanese (n = 3099), and White (n = 133208) members of Kaiser Permanente who participated in the Research Program on Genes, Environment, and Health and the California Men’s Health Study surveys (2002‐2009), with linked electronic health records (EHR) data until 2020. Inclusion criteria included age 60‐89 years old and no history of stroke or dementia at the time of survey (baseline). Incident stroke (ischemic and hemorrhagic) and incident dementia diagnosis were defined based on ICD codes from EHR. To ensure comparability between those with and without incident stroke at all time points before incident stroke, we fit annual inverse probability treatment weights (IPTW) to adjust for confounding, including baseline sociodemographic covariates and time‐varying (annual) cardiovascular covariates. We also fit censoring weights (IPCW) so that those who remained alive over follow‐up are representative of those who died. We estimated the risk ratio (RR) and risk difference (RD) for incident stroke and subsequent dementia from weighted Kaplan‐Meier survival estimators at 10 years of follow‐up for each racial/ethnic group. Sensitivity analyses examined ischemic stroke as the outcome.

Results

The cause‐specific cumulative incidence of stroke at 10 years of follow‐up ranged between 10.9% (95%CI: 10.0%, 11.8%) for Chinese and 14.1% (95%CI: 12.7%, 15.5%) for Japanese participants. After adjusting for confounding and censoring, the RR for the effect of incident stroke on subsequent dementia was 5.6 (95%CI: 4.2, 7.3) for Chinese, 3.8 (95%CI: 2.7, 5.1) for Filipino, 4.9 (95%CI: 3.0‐6.6) for Japanese participants, and 3.3 (95%CI: 3.1‐3.5) for White participants. Confidence intervals between groups mostly overlapped (Figure). Restricting analysis to ischemic stroke only yielded similar results.

Conclusion

The effect of stroke on risk of dementia is large among Asian American and White older adults.
Neuro‐Dynamic Quantitative Systems Pharmacology (Qsp) Model Supports Continued Lecanemab Treatment With Maintenance Dosing For Alzheimer’s Disease
Authors: Cao Youfang , Willis Brian A. , Sachdev Pallavi , Penner Natasha , Wildsmith Kristin R , Charil Arnaud , Horie Kanta , Koyama Akihiko , Reyderman Larisa
Published: January 2025

A 10 mg/kg every 2 week (Q2W) dose of the humanized IgG1 monoclonal antibody lecanemab was approved after demonstrating significant clinical benefit in slowing cognitive decline in early Alzheimer’s disease (AD) in two clinical studies (the phase 2 Study 201 and phase 3 Clarity AD). A less frequent every 4 weeks lecanemab 10 mg/kg maintenance dosing (Q4W) has been proposed after a sufficient initial Q2W treatment. To further understand long‐term benefit of continued Q4W lecanemab treatment, a quantitative systems pharmacology (QSP) model was developed which mechanistically describes AD pathophysiology using multivariate data from clinical studies. The population QSP model incorporated 3 interlinked modules describing Aβ pathway, tau pathology and cognitive decline, where Aβ triggers tau pathology and tau pathology leads to cognitive decline due to neuronal damage and degeneration. The model was developed using nonlinear mixed‐effect modeling and was successfully validated using a multivariate dataset (N = 4057) consisting of amyloid PET, CDR‐SB, ADAS‐Cog14, plasma Aβ42/40 ratio and ptau181, and tau PET data from the lecanemab trials, as well as amyloid PET, ADAS‐Cog and CDR‐SB data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Simulations were conducted to investigate long‐term lecanemab benefits with Q4W dosing following the initial lecanemab Q2W treatment. QSP simulations showed additional benefits gained across clinical outcomes, amyloid plaque and protofibrils, Tau PET, and plasma biomarkers with continued lecanemab treatment beyond 18 months. Specifically, maintenance lecanemab continued to reduce brain amyloid plaques and protofibrils in subjects who did not reach amyloid negativity following the initial 18‐month Q2W lecanemab. Simulations showed plasma ptau‐181 continued to decline and plasma Ab42/40 ratio continued to increase with Q4W maintenance dosing. Furthermore, simulations showed continued suppression of tau PET, and additional reductions in cognitive decline (CDR‐SB, ADAS‐Cog14) with Q4W maintenance dosing. Sustained protofibril clearance was indicated as a key driver for long‐term (>18 months) lecanemab effect on halting tau pathology and slowing cognitive decline, particularly after plaques are cleared following initial lecanemab Q2W treatment. QSP simulations demonstrated the importance of continuing lecanemab treatment after plaque removal and support Q4W maintenance dosing following initial treatment.
Associations between Social Determinants of Health and Alzheimer’s Disease and Related Dementia among American Indian and Alaska Native and White Medicare Beneficiaries
Authors: Yang Manxi , Abdulsalam Ruqoyat , Adjei‐Boateng Richard , Li Lingling , Manson Spero , O'Connell Joan , Jiang Luohua
Published: January 2025

Background

Alzheimer’s disease and related dementias (ADRD) present a growing challenge in the US and has emerged as a significant health concern in American Indian and Alaska Native (AI/AN) communities. ADRD prevalence and risk factors among AI/AN adults remain poorly understood and plagued by inconsistent findings. This study addressed this knowledge gap by examining the associations of social determinants of health (SDOH) with ADRD between AI/AN and non‐Hispanic White (White) populations.

Method

AI/AN and a 5% random sample of White adults aged 68 and above enrolled in fee‐for‐service (FFS) Medicare in 2019 were included in this study. We used the 2019 Medicare Beneficiary Summary File to obtain data on beneficiaries’ demographics, chronic conditions, and health coverage. We obtained county‐level data from the 2019 Area Health Resource File and the National Center for Health Statistics. Medicaid eligibility and Part D enrollment were used as proxies for individual‐level SDOH. County‐level measures were defined by the percentage of households with incomes below the federal poverty level, the percentage of adults without a high school degree, and county rurality. Separately for AI/AN and White populations, we calculated crude and age‐adjusted prevalence of ADRD and used logistic regressions to examine associations between ADRD and SDOH, controlling for demographics and chronic conditions.

Result

Among 111,635 AI/AN and 1,015,809 White Medicare beneficiaries included, the ADRD prevalence was 15.6% (age‐adjusted) and 13.4% respectively (OR = 1.24, 95% CI:1.22, 1.27) (Table 2). After multivariate adjustment, the odds ratio of AI/AN for ADRD was not statistically significant (OR = 1.006, 95% CI: 0.980, 1.033). As shown in the Figure, Medicaid eligibility was associated with a substantially higher odds of ADRD among both AI/AN (OR = 2.38, 95% CI: 2.26, 2.50) and White individuals (OR = 3.23, 95% CI: 3.17, 3.29). Part D enrollment was associated with higher odds of ADRD among AI/AN individuals only while county‐level income and education were associated with higher odds of ADRD among White individuals only. Additionally, rurality was associated with lower odds of ADRD in both populations.

Conclusion

SDOH are potentially modifiable factors, therefore, a deeper understanding of their effects on ADRD can inform future interventions aimed at reducing ADRD prevalence and disparities.