bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal imaging in polarized light of two different protein deposit types found in the retina in different neurodegeneration diseases (NDDs)
Authors: Campbell Melanie CW , Gallop Hannah , Mason Erik L , Emptage Laura , Redekop Rachel , Kitor Monika , Hsiung Ging‐Yuek Robin , MacKenzie Ian R , Hirsch‐Reinshagen Veronica
Published: January 2025

Background

Amyloid and alpha synuclein proteins are brain biomarkers of different neurodegenerative diseases, many years before symptoms. We have shown that imaging dye‐free with polarized light makes retinal amyloid deposits visible as a biomarker, in the brain, of amyloid and Alzheimer's disease (AD) severity. Here, we extend to presumed retinal alpha synuclein deposits in those with brain pathology consistent with alpha synuclein. We have previously shown, using machine learning, that polarized light interactions of pure amyloid beta deposits and pure alpha synuclein deposits, grown on glass, differ.

Methods

Eyes and brains were donated by 10 individuals with brain pathology consistent with amyloid and moderate to high likelihood of AD, and from two individuals with pathology in which brain alpha synuclein is expected ‐ one with dementia with Lewy bodies (DLB) and one with multiple system atrophy (MSA). Retinas were fixed and flat‐mounted, then imaged in differing polarized light states. 274, 47 and 12 deposits were imaged in retinas of those with AD, DLB and MSA respectively. Interactions with polarized light were calculated for each protein deposit imaged.

Results

Presumed amyloid beta and alpha synuclein deposits were visible in polarized light in retinas with brain pathologies consistent with AD, or DLB and MSA respectively (Figure 1). After correction for repeated measures, the means of many polarized light interactions were significantly different for the two presumed deposit types (Table 1). The distributions of the strengths of polarized light interactions and deposit areas (Figure 2) overlapped across deposit types. However, a combination of polarized light interactions separated the presumed retinal deposits of amyloid from those of alpha synuclein in two machine learning algorithms: random forest with an accuracy of >85% and a convolutional neural network (CNN) with an accuracy of > 90%. Linear retardance, which helped to separate the two types of retinal deposits in CNN was previously used to separate deposits of the two pure proteins.

Conclusions

Multiple interactions with polarized light differ between deposits of different retinal proteins. Dye‐free polarized light imaging of the retina shows promise in differentiating these deposits as biomarkers of different neurodegenerative diseases in the brain.
TDP‐43 association with Subiculum and CA1 Hippocampal Subfield Atrophy in Primary Age‐Related Tauopathy
Authors: Youssef Hossam , Gatto Rodolfo G. , Pham Nha Trang Thu , Petersen Ronald C. , Machulda Mary M. , Reichard Ross R. , Dickson Dennis W. , Jack Clifford R. , Whitwell Jennifer L. , Josephs Keith A.
Published: January 2025

Background

The TAR DNA‐binding protein of 43 kDa (TDP‐43) is linked to hippocampal volume loss and faster rates of hippocampal atrophy in Alzheimer's disease and primary age‐related tauopathy (PART). Hence, TDP‐43 is becoming an important player in age‐related neurodegeneration. To advance our understanding of TDP‐43 effect on hippocampus, we conducted an imaging‐pathological study to determine which specific hippocampal subfields are affected by TDP‐43 in cases of PART.

Method

One‐hundred fifteen autopsied cases from Mayo Clinic Alzheimer Disease Center, Study of Aging and Neurodegenerative Research Group were analyzed. All had completed antemortem brain MRIs, underwent neuropathological examination per NIA and Alzheimer’s Association (NIA‐AA) criteria and had additional assessment for TDP‐43 deposition. Only cases meeting criteria for PART (Thal phases 0‐2 and Braak NFT stages I‐IV) were included. Hippocampal subfield segmentation was performed using FreeSurfer‐7. Brain volumes were normalized to total intracranial volume (TIV) when comparing TDP‐43 groups. Statistical analyses including logistic regression analyses were utilized to explore associations between TDP‐43 status and hippocampal subfield volumes.

Result

Forty‐nine of the 115 cases (43%) with PART were female. Thirty‐seven (32%) cases were TDP‐positive. Mean age at last MRI was 84 years. There were no differences in pathological characteristics between both groups except for presence of hippocampal sclerosis which was more frequent in the TDP(+) group (P <0.001). Whole hippocampal volume was significantly smaller in the TDP(+) group (176 ±31 vs. 188 ±27, p=0.049). After stratification of hippocampus into head, body, and tail, TDP‐positive cases had smaller volumes of hippocampal body (p=0.031) and tail (p=0.021) but did not reach significance for hippocampal head (p=0.129). When regions were subdivided into hippocampal subfields, TDP(+) cases showed smaller volumes of molecular layer of the hippocampal body (p=0.046), CA1 body (p=0.031), subiculum body (p=0.023), and presubiculum body (p=0.046) compared to TDP(‐) cases. Logistic regression analysis adjusting for TIV confirmed these associations.

Conclusion

This study underscores the association between TDP‐43 and the hippocampus and provides further evidence that TDP‐43 targets multiple regions and subfields of the hippocampus in patients with PART. Intriguingly, regions targeted are those where TDP‐43 deposition is microscopically observed, suggesting a direct “hit” by TDP‐43 deposition.
Network‐based Plasma Proteomics Reveals Molecular Overlap Between Physical Activity and Dementia Risk
Authors: Saloner Rowan , Paolillo Emily W. , Cadwallader Claire J. , VandeBunte Anna M. , Chen Coty , Wyss‐Coray Tony , Kramer Joel H. , Casaletto Kaitlin B.
Published: January 2025

Background

Physical activity (PA) is associated with lower dementia risk; however, underlying molecular pathways are poorly understood. We leveraged large‐scale plasma proteomics to identify biological signatures of objectively‐monitored PA in cognitively unimpaired (CU) older adults and cross‐validated signatures in independent exercise intervention and Alzheimer’s disease (AD) cohorts.

Method

Discovery cohort included 65 CU adults (meanage = 76.6; 60% female; 34% PET Ab+) from the UCSF Memory and Aging Center with plasma assayed on SomaScan v4.1 (7,288 proteins). 30‐days of observational FitbitTM monitoring quantified PA (average daily steps). Generalized linear models (GLMs) examined individual protein correlates of PA, adjusting for age and sex. Weighted gene network analysis assembled proteins into unbiased modules of protein co‐expression, which were annotated for gene ontology and cell‐type enrichment. Modules were tested for overrepresentation of PA‐related proteins using Fisher’s exact tests with false discovery rate (FDR) correction. To validate PA pathways, modules were cross‐referenced with published plasma exercise intervention data (Robbins et al., 2023) of proteins that changed following a 20‐week endurance training intervention. To establish clinical relevance, PA‐related proteins from discovery analyses were compared between CU (N=189) and AD patients (N=55) from an independent cohort with plasma SomaScan (Stanford ADRC).

Result

Discovery: PA related to 568 proteins in GLMs. Of 32 protein modules identified from network analyses, six showed overrepresentation of PA‐related proteins. Module 12 (M12) positively associated with PA and harbored the largest proportion of PA‐related proteins. M12 was enriched for extracellular matrix (ECM) and nervous system development pathways with endothelial, neuronal, and oligodendrocyte cell type markers. Validation: M12 was significantly enriched for ECM‐related proteins that increased in the exercise intervention. Four proteins from M12 were significantly decreased in AD plasma compared to CU after FDR correction, including highly‐connected ‘hub’ proteins anthrax toxin receptor cell adhesion molecules 1 and 2 (ANTXR1, ANTXR2) and matrix remodeling associated 8 (MXRA8).

Conclusion

Large‐scale analysis of the plasma proteome highlights ECM and neurodevelopmental pathways that increase with PA and decrease in AD. Cross‐validation with independent cohorts identified a biological link between PA and dementia risk. PA‐related ‘hub’ proteins, such as ANTXR1, ANTXR2, and MXRA8, may represent key molecular targets for dementia prevention.
Subclinical Vascular Disorders in Relation to Cognitive Decline and Impairment: The Multi‐Ethnic Study of Atherosclerosis
Authors: Tanley Jordan E. , Jaeger Byron C , Chen Haiying , Rudolph Marc D. , Sachs Bonnie C. , Li Clara , Rascovsky Katya , Luchsinger Jose A. , Hayden Kathleen M. , Ding Jingzhong , Liu Yongmei , Bertoni Alain G. , Heckbert Susan R. , Post Wendy , Szklo Moyses , Lockhart Samuel N. , Hughes Timothy M.
Published: January 2025

Background

Vascular disorders are proposed as modifiable risk factors for dementia; yet, physiologic mechanisms connecting vascular disorders to cognitive impairment remain unknown. We examined subclinical cardiovascular measures to determine which predict global cognitive decline and domain specific cognitive impairment and point to potential pathways linking subclinical vascular disease and dementia.

Methods

MESA includes a diverse cohort of 6,814 participants free from clinical cardiovascular disease with follow‐up over 6 clinical examinations and annual follow‐up calls. At baseline in 2000‐2002, 24 subclinical vascular measures were collected (e.g., blood pressure, carotid distensibility, artery elasticity index, heart rate, coronary calcification, carotid intima media thickness) that prior work generalized into four uncorrelated factor composites representing: atherosclerosis, arteriosclerosis, blood pressure, and cardiac function (Table 1). During Exam 5, participants began cognitive testing with the Cognitive Abilities Screening Instrument (CASI), which was repeated 10 years later (2010‐2012 to 2019‐2021) and modeled using linear mixed effects models. At Exam 6 (2019‐2021), the Uniform Data Set v3 battery was administered. Scores were normed, grouped into domains (e.g., Memory, Processing Speed, Executive Function) and modeled using generalized linear models. Cognitive impairment was adjudicated as mild cognitive impairment (MCI) or probable dementia and modeled using logistic regression. Results are reported as beta estimates or odds ratios and 95% confidence intervals (95%CI) including adjustment for baseline CAIDE dementia risk score (Figure 1), race/ethnicity, and language.

Results

Baseline arteriosclerosis and atherosclerosis were independently associated with greater cognitive decline 10 years later (Figure 1a), lower domain specific cognitive performance (Figure 1b) and higher odds of cognitive impairment 20 years later (Table 2) after multi‐variable adjustment. One standard deviation increase in baseline arteriosclerosis was associated with modestly increased odds of MCI and almost two fold increased odds of probable dementia. Baseline cardiac function and blood pressure were not significantly associated with cognitive decline or impairment beyond CAIDE. Cognitive decline results were generally consistent across racial and ethnic groups (Figure 1c, p‐interaction>0.10).

Conclusions

These findings suggest that arteriosclerosis and atherosclerosis are more consistently associated with cognitive impairment and global cognitive decline than cardiac function and blood pressure in a diverse population with 20 years of follow‐up.
Do patients with early‐stage cognitive impairment have an increased risk to have a reduction in walking speed? A cross‐sectional study
Authors: Lopes Pedro de Castro , Leopoldino Amanda Aparecida Oliveira , Machado João Carlos Barbosa , Barbosa Maira Tonidandel , Garcia Luana Rodrigues , Aguiar Bianca Pessoa , de Souza Júlia Caroline Barbosa , Ferreira João Pedro Neres Antunes
Published: January 2025

Background

Gait speed is an important measure in the evaluation of elderly patients. The gait speed reduction is associated with high‐impact outcomes such as: loss of functionality, frailty and increased mortality. Several clinical conditions lead to a reduction in gait speed. In patients with advanced dementia, it could be associated with disability. However, the relationship between cognition and motor function is not well known, especially in the early stages of dementia and further studies are needed. It is also important to understand whether patients with mild cognitive impairment have increased risk of a worse gait speed.

Method

This is a cross‐sectional study in which 87 community‐dwelling elderly people were included and evaluated in relation to the presence of cognitive impairment and gait speed. Patients with severe cognitive impairment, assessed by a score less than 6 in the CS‐10 (Point Cognitive Screening) were excluded. Individuals with a score between 6 and 7 on the CS‐10 were considered to have mild or moderate cognitive impairment and participants with a score greater than 7 on this test were considered to have no cognitive impairment. In order to evaluate gait speed, individuals were stimulated to walk for 4 meters, and those with a walking speed lower than 0.82 m/s were considered to have it reduced. With the aim of estimate the association between the characteristics, Pearson’s chi‐square test was used. If the p‐value was lower than the significance level of 0.05, it is possible to conclude the association between the lower walking speed and a worse score in CS‐10.

Result

Statistical analysis showed an association between the reduction in gait speed and CS‐10 score (p‐value 0.041). Patients who had lower score on the cognitive assessment are likely to have a lower gait speed. The mean CS‐10 score for patients with gait impairment is 7.91, while for patients without gait impairment is 8.95 points. The Kruskal‐Wallis test indicates that there is a significant difference in the results (p‐value 0.016).

Conclusion

Individuals with mild cognitive impairment have an increased risk of developing reduced gait speed.
Older Adults’ Views about Blood Biomarker Testing for Alzheimer’s Disease: Update from the U.S. National Poll on Healthy Aging
Authors: Cox Chelsea G , Roberts J. Scott
Published: January 2025

Background

Blood‐based biomarker testing (BBT) for Alzheimer’s disease (AD) to detect amyloid‐beta and tau is becoming part of dementia care, with likely future clinical use in asymptomatic populations. Little is known about older adults’ awareness of BBT or their perceptions of its potential benefits, risks, and limitations.

Method

We analyzed data from the March 2023 fielding of the University of Michigan National Poll on Healthy Aging, a nationally representative web and telephone survey of community‐dwelling older U.S. adults. Poll respondents ages 65‐80 were provided a brief definition of BBT for AD and asked about their 1) awareness of BBT, 2) perceptions of its risks and benefits, and 3) anticipated responses if they tested positive. Multivariable logistic regression analyses examined self‐reported sociodemographic (i.e., age, sex, race and ethnicity, education, income, employment, martial status) and clinical characteristics (i.e., physical health, mental health, subjective memory, family history of dementia) associated with BBT awareness and anticipated negative responses to a positive AD blood biomarker result.

Result

Of 1,298 U.S. adults surveyed, 19% said they were at least somewhat familiar with BBT for AD. Older adults with more education and better mental health had higher odds of BBT awareness (p<0.05). Overall, older adults were more likely to endorse possible benefits versus risks of testing. For example, 76% said BBT could be useful to inform medical care or advance planning, while 32% endorsed concern about the privacy of their results. More than half of older adults were somewhat or very likely to say that a positive BBT result would prompt potential negative reactions, including beliefs that they would develop AD (72%), have significant distress (61%), or be viewed differently by others (54%). Being female, non‐Hispanic White (compared to Hispanic), and having a family history of dementia were associated with higher odds of anticipating negative outcomes of BBT (p<0.05).

Conclusion

Most older U.S. adults are not aware of BBT for AD but view it as potentially beneficial for informing clinical care. Many older adults anticipate potential social and psychological challenges of receiving a positive BBT result, with these test perceptions differing significantly by gender and race/ethnicity.
Retinal AD Biomarkers in Cognitively Unimpaired Older Adults
Authors: Price Ashley N. , Snyder Peter J. , Strenger Jennifer , Thompson Louisa I. , Stradtman Megan , Sinoff Stuart , Alber Jessica
Published: January 2025

Background

The retina is a novel biomarker target for examining AD pathology, specifically beta‐amyloid (Aβ). Though relationship between retinal Aβ and standard preclinical AD biomarkers (cerebral Aβ PET) remains understudied, retinal inclusion bodies (IB, strongly hypothesized to contain fibrillar Aβ), predict cerebral Aβ load in the anterior cingulate cortex (ACC). This study explored the value of retinal IB as a preclinical AD biomarker, comparing number and surface area (SA) of IB with cerebral Aβ PET.

Method

36 older adults aged 55‐80 were identified as cognitively unimpaired based on Clinical Dementia Rating Scale (CDR) of 0 and a score ≥24 on the Montreal Cognitive Assessment (MoCA). PET status (20 Aβ+, 16 Aβ‐) was available through prior studies. Retinal IB data was captured on Heidelberg SPECTRALIS using blue light fundus autofluorescence. Number and surface area of IB were computed manually by two qualified raters. Inter‐rater reliability was measured with Cohen’s Kappa. Binomial logistic regression and ROC assessed the accuracy, sensitivity, and specificity of retinal IB in predicting Aβ PET status (positive vs. negative).

Result

Inter‐rater reliability was high (Cohens kappa =0.9). Mann Whitney U Tests showed no significant group differences in the number (U=156.5, p=.906) and SA of IB (U=156.5, p=.962) between the Aβ+ and Aβ‐ PET groups. Binomial logistic regression including predictors (APOE status, age, MoCA score, and SA of IB), showed that SA of IB accurately predicted PET status 61.1% of the time, (sensitivity 75%, specificity 43.8%, AUC =.408). The analysis was repeated with the number of IB, showing that PET status was correctly predicted 63.9% of the time (sensitivity 85%, specificity 37.5%, AUC=.448).

Conclusion

Retinal IB, strongly hypothesized to contain fibrillar Aβ, were not strongly predictive of Aβ PET status in this sample. Given the sample characteristics, the results align with what we hypothesized. Further longitudinal analysis with larger sample sizes and PET centiloid readings in regions of early cerebral Aβ accumulation could help determine the value of retinal imaging as a risk biomarker in preclinical AD.
Lessons Learned: Social and Ethical Issues Related to Clinical Implementation of Blood‐Based Biomarkers for Alzheimer’s Disease
Authors: Ketchum Fred B.
Published: January 2025

Background

Integrating blood biomarker testing for Alzheimer’s Disease (AD) into clinical practice has the potential to transform AD care by enabling broadly accessible and accurate diagnosis, more precise prognostication, and timely initiation of disease‐modifying therapy. While there are several scientific challenges to implementing blood biomarkers (e.g. validity in different populations or the impact of comorbidities), the range of ethical and social issues that must be addressed to ensure that blood biomarker testing is appropriately implemented has received less attention.

Methods

Incorporating current data through a critical literature review focused on ethical and social aspects of AD biomarker and specifically blood biomarker testing, disclosure, and implementation, we extracted arguments, grouped them according to bioethical principles, and developed a framework to categorize ethical and social issues around blood biomarkers across clinical settings.

Results

Issues identified were related to the four basic principles of bioethics: respect for autonomy, beneficence, non‐maleficence, and justice; and were informed by social norms including standards of professional practice and definitions of health and disease. The main ethical and social issues were related to: clinical and personal utility of testing; prognostic uncertainty of results; the expansion of disease categories; preferences among patients, caregivers, and families regarding testing and disclosure; facilitating positive psychological outcomes; enabling positive health‐related behavior changes; potential for stigma, privacy, and discrimination; decision‐making and communication in diverse clinical settings and patient populations; effective use of diagnostic and treatment resources; and ensuring equitable access to testing and care.

Conclusion

Implementing blood biomarkers in clinical practice in an ethically and socially responsible manner will require 1) maximizing benefits while minimizing risks; 2) informing and empowering individuals to make decisions about their brain health; and 3) ensuring testing is available equitably. Ethical and social issues may be different before versus after testing, and while some issues are similar to those encountered in AD diagnosis more generally, others are specific to blood biomarkers. Key areas in which data are needed include approaches to minimizing negative psychosocial outcomes, determining clear distinctions between disease and at risk‐states, and promoting effective communication, education, and equitable access.
Deep Learning Algorithms for Alzheimer’s Disease Detection based on Diffusion MRI: Tests in Indian and North American Cohorts
Authors: Chattopadhyay Tamoghna , Joshy Neha Ann , Ozarkar Saket S. , Buwa Ketaki S. , Feng Yixue , Laltoo Emily , Thomopoulos Sophia I , Villalon‐Reina Julio E , Joshi Himanshu , Venkatasubramanian Ganesan , John John P , Thompson Paul M.
Published: January 2025

Background

Deep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimer’s disease or infer dementia severity from T1‐weighted brain MRI. Here we tested the added value of incorporating information from 3D diffusion‐weighted MRI ‐ a technique sensitive to microstructural differences ‐ alongside traditional 3D T1‐weighted images. We evaluated our classifier’s performance on cohorts from India and North America. We also tested if classification accuracy improved after applying 3D CycleGAN approach to harmonize the imaging datasets prior to training the CNN models. Our experiments reveal that, in the majority of cases, classification performance sees improvement following harmonization, particularly when utilizing dMRI as input.

Method

We analyzed data from 1,195 participants (age: 74.36 ±7.74 years; 600 F/595 M; 633 CN/421 MCI/141 dementia), who had both structural T1w and dMRI, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The second dataset came from an Indian population assessed at NIMHANS in Bangalore, India – a population not typically well represented in neuroimaging studies. It had 301 participants (age: 67.23 ±7.86 years; 169 F/132 M) with a distribution of (123 CN/88 MCI/90 dementia). We used the T1ws and dMRI‐derived maps of microstructural parameters ‐ FA, MD, RD and AxD as inputs to our model. Initially, a 3D CycleGAN (Figure 1) was used to harmonize the two datasets. Then, both a 3D CNN architecture (Figure 2a) and a Y‐shaped 3D CNN architecture (Figure 2b) were used for the classification task. The latter can take dual modalities as input simultaneously. Performance was assessed using Balanced Accuracy and F1 Score.

Result

Table 1 shows the performance of the models. The best performances are seen for the Y‐shaped model, and when harmonization is used before training.

Conclusion

In general, performance improved after harmonizing the datasets using the unsupervised 3D CycleGAN architecture. Training the model on the merged dataset incorporating diverse cohorts made the classifier more robust. When smaller datasets are available for training, AD classification was more accurate when based on DWI‐derived maps, compared to T1w images. A concatenated model incorporating multiple image modalities outperformed a model using only T1w MRIs as input.
Model‐Based Assessment of Lecanemab Maintenance Dosing Regimen Shows Continued Suppression of Amyloid Plaque, Disease Progression
Authors: Willis Brian A. , Bhagunde Pratik , Bell Robert , Penner Natasha , Charil Arnaud , Reyderman Larisa
Published: January 2025

Background

Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. In two clinical studies (phase 2, NCT01767311 and phase 3 ClarityAD, NCT03887455) in early Alzheimer’s disease, lecanemab substantially reduced amyloid PET and significantly slowed clinical decline on multiple measures of cognition and function, including CDR‐SB at 18 months. Models describing the change in amyloid PET and CDR‐SB in response to lecanemab treatment were used to explore the impact of changing from the initial dosage regimen (10 mg/kg every 2 weeks [Q2W]) to a less intensive maintenance dosing regimen (10 mg/kg every 4 weeks [Q4W]) on clinical efficacy, and to explore the optimal duration of the initial dosing regimen.

Methods

Models describing the relationship between serum lecanemab exposure, amyloid PET, and CDR‐SB have been previously described. Individual post hoc model estimates for pharmacokinetics, PET, and CDR parameters were obtained from Clarity AD subjects who received lecanemab and were used to simulate change in amyloid PET and CDR‐SB over 4 years. Simulations were conducted to evaluate the effect of lecanemab after continuous Q2W treatment or transitioning to a less intensive dosing regimen (10 mg/kg Q4W) at 18 or 24 months. Simulations were also evaluated for the subgroups of subjects with baseline amyloid PET <60 CL and ≥60 CL.

Results

After 18 months of lecanemab treatment, the mean amyloid PET level was ≤25 CL in both the high and low baseline PET groups. Continued lecanemab treatment with Q2W and Q4W resulted in a similar additional reduction of amyloid PET over 4 years of treatment. The difference in amyloid reduction between continuous Q2W treatment and Q4W treatment initiated at 18 months was 2.5 CL and 5.1 CL in the low and high baseline PET groups respectively. No significant difference in CDR‐SB was projected between the two groups, regardless of when the subjects transitioned.

Conclusions

Subjects receiving lecanemab 10 mg/kg Q2W may transition to a less intensive (Q4W) maintenance regimen after 18 months. The maintenance regimen has no clinically meaningful impact on amyloid or disease progression relative to the Q2W regimen.
Differences in Dementia Diagnosis Rates in Primary Care in Traditional Medicare and Medicare Advantage
Authors: Haye Sidra , Jacobson Mireille , Zissimopoulos Julie M
Published: January 2025

Background

Approximately half of Medicare beneficiaries enroll in Medicare Advantage (MA) plans. Unlike Traditional Medicare (TM), MA plans coordinate patient care through physician networks and care practices, often relying on Primary Care Providers (PCPs). PCPs also play an important role in diagnosing dementia; the majority of persons living with dementia are diagnosed by PCPs. Studies document that dementia diagnosis rates are lower in MA than TM. There is a gap in knowledge about how barriers to and incentives for diagnosing dementia among physicians in MA and TM impact rates of diagnosis. To examine whether incident dementia diagnosis rates vary for beneficiaries in TM and MA seen by the same Primary Care Provider (PCP).

Methods

We use propensity score matching and linear regression models, with and without PCP fixed effects, to analyze differences in incident dementia diagnoses in 2017 in MA relative to TM. The analysis includes 100% of Medicare claims for TM and MA beneficiaries who were 65 and over and who were continuously enrolled in Part D and in either TM or MA from 2016 to 2018 or died in 2018. Each beneficiary is assigned to the PCP with whom they have the maximum number of evaluation and management visits in a year.

Results

Among 15,633,290 beneficiaries with assigned PCPs, the dementia diagnosis rate was 3.12% in TM and 2.78% in MA. Adjusting for patient characteristics, we find that the probability of incident dementia diagnosis was 0.27 percentage points lower for MA patients compared to TM. Adjusting for patient characteristics and PCP, we find that the probability of incident dementia diagnosis was 0.12 percentage points lower (around 4% lower relative to TM mean) for MA patients compared to TM patients assigned to the same PCP.

Conclusion

We find that even for a matched sample of TM and MA patients with the same PCP, dementiadiagnosis rates are lower in MA relative to TM. Differences in care practices as indicated by access to dementia specialists and incentives for coding dementia diagnosis may contribute to some of the differences in diagnosis rates.
Pharmacological and functional characterization of the first small molecule TREM2 agonist, VG‐3927, for the treatment of Alzheimer’s disease
Authors: Mirescu Christian , Dejanovic Borislav , Larson Kelley C. , Kiragasi Beril , Gergits Frederick W. , Figley Matthew D. , Renoux Abigail J. , Huang Liyue , Pandya Bhaumik A. , Houze Jonathan B. , Thackaberry Evan A. , Gray David L.
Published: January 2025

Background

TREM2 is a lipid‐sensing receptor expressed by microglial sub‐populations within neuropathological microenvironments, whose downstream signaling promotes microglial survival, plasticity, and migration. Multiple loss‐of‐function variants strongly implicate TREM2 as a key regulator of Alzheimer’s disease (AD) risk. Accordingly, TREM2 antibodies are currently in development to evaluate the therapeutic potential of TREM2 agonism in neurodegenerative diseases. Small molecule TREM2 agonist could represent a significant advancement for patients by providing potential key advantages in route of administration, superior brain penetration, and alternative mechanisms of action versus monoclonal antibodies. Herein, we share recent in vitro and in vivo preclinical data identifying VG‐3927, the first and only small molecule TREM2 agonist in clinical development as a potential disease‐modifying therapeutic.

Methods

The agonist pharmacology of VG‐3927 was determined across an array of human cellular systems. Human iPSC‐derived microglia, astrocytes and neurons tri‐cultures were utilized to measure changes in microglia function and impact on neurodegeneration biomarkers in response to pharmacological and genetic modulation. Additionally, a humanized TREM2 amyloidosis mouse model (hTREM2‐5xFAD) was employed to determine the impact of VG‐3927 on AD‐associated neuropathological endpoints.

Results

Pharmacologic data suggest VG‐3927 is a highly potent, selective and brain penetrant TREM2 agonist with a favorable functional profile. In human tri‐cultures, VG‐3927 promoted anti‐inflammatory microglia activation and suppressed a broad spectrum of neurodegeneration‐associated biomarkers. Mutagenesis mapping studies demonstrated that the activity of VG‐3927 is on‐target, and results in functional effects via the coordinated clustering of TREM2. Following only 6 weeks of oral dosing in humanized TREM2 plaque‐bearing mice, VG‐3927 also reduced pathological forms of Aβ, insoluble ApoE levels, and peri‐plaque dystrophic neurites. Additional PKPD studies in non‐human primates further confirmed the brain penetrance and pharmacological activity in CNS.

Conclusions

VG‐3927 represents the first potent, selective small molecule TREM2 agonist able to favorably tune human microglia activation and impart a broadly neuroprotective profile across preclinical model systems. Initial PKPD studies have confirmed brain penetrance and pharmacological activity in CNS; an ongoing clinical study aims to further interrogate the potential of VG‐3927 as an AD modifying therapeutic with transformative potential as an orally bioavailable treatment.
Dietary exposure to chemical contaminants and risk of dementia in older persons
Authors: Lefèvre‐Arbogast Sophie , Duquesne Pauline , Helmer Catherine , Sirot Véronique , Samieri Cécilia
Published: January 2025

Background

Diet is a primary source of exposure to chemicals in the general population. Dietary contaminants originate from food production (e.g.pesticides) or from environmental contamination by industrial (polychlorinated biphenyls [PCB]) or naturally‐occurring substances (metals). Many are present at non‐negligible levels in human biofluids, and some were found in the human brain. Since many chemicals are lipophilic, the dietary composition, especially the fat content, likely modifies their toxicokinetics. We aimed to explore the link between dietary exposure to multiple chemicals and dementia risk in older persons, considering effect modification by dietary fat content.

Method

We included 1,288 non‐demented participants from the French Three‐City cohort who completed a food survey (2001‐2002) and were followed for incident dementia. Dietary exposure to 167 chemicals (covering 9 families) was assessed by combining individual food intakes with food chemical content measured in the French second Total Diet Study. We assessed the relation of each individual chemical with dementia risk using Cox proportional hazard models adjusted for age, sex, education, ApoE‐ε4 and Mediterranean diet adherence and exploring effect modification by high‐fat diet content (defined as >35% of energy from fat). We subsequently considered all chemicals simultaneously and performed chemical variable selection using elastic‐net regularization.

Result

Participants were 76 years‐old on average at baseline; 62% were women; 30% reported a high‐fat diet. Over a median follow‐up of 10 years, 314 individuals developed dementia. No chemical was associated with dementia risk in the whole population. However, having a diet with higher fat content was a strong effect modifier for 82 chemicals (FDR‐corrected p<0.05 for interaction tests). Higher intakes of these chemicals were significantly associated to higher dementia risk among high‐fat diet consumers only. The strongest hazard ratios (HR>1.40 for one SD‐increase in intake) were observed for contaminants provided by seafood and meat, including the brominated flame retardant hexabromocyclododecane‐alpha (HBCDD‐α), perfluorooctane sulfonate (PFOS) and PCB‐77. Among high‐fat diet consumers, the elastic‐net identified 33 chemicals associated with dementia risk, with PFOS and nitrites ranking as primary chemicals.

Conclusion

In our study, dietary exposure to specific chemicals, was associated with higher dementia risk among older persons consuming >35% of energy from fat in their diet.
CD33 competitive inhibitor peptide IMAD‐001 modulates innate immunity in Alzheimer’s disease
Authors: Green Jennifer L , Dressman Dallin , Rashid Mamun , Hobson Ryan , Elyaman Wassim , Bradshaw Elizabeth M
Published: January 2025

Background

Genetic studies indicate a causal role for microglia, the innate immune cells of the central nervous system (CNS), in Alzheimer’s disease (AD). Despite the progress made in identifying genetic risk factors, such as CD33, and underlying molecular changes, there are currently limited treatment options for AD. Based on the immune‐inhibitory function of CD33, we hypothesize that inhibition of CD33 activation may reverse microglial suppression and restore their ability to resolve inflammatory processes and mitigate pathogenic amyloid plaques, which may be neuroprotective. Here, we investigate the effects of a competitive inhibitor peptide of CD33 binding, IMAD‐001, on downstream immune response in AD.

Method

Primary human monocyte‐derived microglia‐like cells (MDMi) and monocytes were treated with IMAD‐001 and we determined its effect on microglial function and immune signaling by measuring gene expression changes in markers of microglial activation by qPCR and amyloid beta (Aβ) uptake by flow cytometry. To measure the in vivo effects, we treated 12‐month‐old 5xFAD mice with weekly subcutaneous injections of 5mg/kg IMAD‐001 or vehicle control for 28 days and examined Aβ clearance by immunohistochemistry and CNS immune cell phenotypes by single‐cell (sc)RNA‐seq.

Result

IMAD‐001 treatment increased Aβ uptake in primary monocytes. In in vivo experiments, we see clearance of Aβ in the brains of the 5xFAD mice with weekly administration. Using scRNA‐seq of CD45+ cells, we identified the expected populations in the brains of the animals and found that peptide treated mice had an increase in classical dendritic cells and a slight decrease in disease‐associated microglia (DAM) and homeostatic microglia. Microglia cells regulated their phenotype in response to the peptide as well with notable downregulation of CD274/PD‐L1, an immunosuppressive molecule in which disruption of its interaction with PD‐1 was found to clear Aβ and improve cognitive performance. Interestingly, peptide treatment resulted in downregulation of IFITM3 and upregulation of CD74, suggesting CD33 inhibition influences microglia to inhibit Aβ production.

Conclusion

IMAD‐001 inhibition of CD33 resolved Aβ induced suppressed microglial immune signaling and increased microglial phagocytosis and response to their environment in vitro and in vivo, without inducing inappropriate activation, suggesting its potential for therapeutic use in AD.
Impact of State‐Level Equity Indices on Psychosocial Outcomes Among Sexual and Gender Minority Caregivers of People with Alzheimer’s Disease and Related Dementias
Authors: Anderson Joel G , Kittle Krystal R. , Winberry Joseph , Hancock Kari A. , Westcott Jordan , Mukherjee Namrata , Flatt Jason D.
Published: January 2025

Background

Our previous work has found that sexual and gender minority (SGM) or LGBTQIA+ caregivers of people living with Alzheimer’s disease and related dementias (ADRD) experience higher levels of stigma, depressive symptoms, and stress than non‐SGM caregivers and that these outcomes are associated with experiences of microaggressions related to their SGM identities. Guided by the Health Equity Promotion Model, we sought to explore the impact of the environmental context on psychosocial outcomes among SGM caregivers of people living with ADRD.

Methods

Data from a cross‐sectional online survey using a non‐probabilistic sample of SGM caregivers of people with ADRD recruited via social media (n = 284) were combined with publicly available data reporting composite equity climate index scores across five domains: legal/non‐discrimination protections, youth/family support, political/religious attitudes, health access/safety, and work environment/employment. The bimodal distribution of states by total equity climate score was used to create a low/high‐score variable for comparisons in global health status, lifetime and day‐to‐day discrimination, lifetime victimization, microaggression, perceived stress, family quality of life, caregiver stigma, and depressive symptoms.

Results

SGM caregivers of people with ADRD in states with lower equity climate scores reported significantly more experiences of microaggressions (p = 0.036), lower levels of perceived stress (p = 0.050) and family quality of life (p = 0.037), and higher levels of caregiver stigma (p<0.001) and depressive symptoms (p<0.001) compared with SGM caregivers living in states with higher equity climate scores. Gay caregivers living in states with lower equity climate scores reported levels of caregiver stigma 18% higher than those living in states with higher equity scores (p = 0.004). There were no significant differences in global health status, lifetime and day‐to‐day discrimination, and lifetime victimization by equity climate scores.

Conclusion

The environmental context of SGM lived experiences influences psychosocial outcomes related to ADRD caregiving. These differences may be driven by the unique minority stressors experienced by SGM caregivers of people with ADRD, which are known to influence the overall physical and mental health of the SGM population. Further research is warranted to understand the impact of these environmental influences on SGM caregivers of people with ADRD to develop supports and policy approaches to promote well‐being.
Do patients in early‐stage cognitive impairment have an increased risk of developing sarcopenia? A cross‐sectional study
Authors: Lopes Pedro de Castro , Leopoldino Amanda Aparecida Oliveira , Machado João Carlos Barbosa , Barbosa Maira Tonidandel , Garcia Luana Rodrigues , Aguiar Bianca Pessoa , de Souza Júlia Caroline Barbosa , Ferreira João Pedro Neres Antunes
Published: January 2025

Background

Sarcopenia is a prevalent condition defined by a loss of muscle mass associated with reduction in muscle power and physical performance. It is associated with several adverse outcomes such as risk of falls and fractures, hospitalization and higher mortality. It can be triggered by several clinical conditions and dementia is one of them. Many studies point the relationship between cognition and sarcopenia, especially in advanced cases of dementia. However, more studies are necessary to understand whether patients with mild cognitive impairment have also increased risk for developing sarcopenia.

Method

This is a cross‐sectional study in which 87 community‐dwelling elderly people were included and evaluated in relation to the presence of cognitive impairment and sarcopenia. Patients with severe cognitive impairment, assessed by a score less than 6 in the CS‐10 (Point Cognitive Screening) were excluded. Individuals with a score between 6 and 7 on the CS‐10 were considered to have mild or moderate cognitive impairment and participants with a score greater than 7 on this test were considered to have no cognitive impairment. In order to evaluate the presence of sarcopenia it was applied the SARC‐F CC questionnaire. Those with a score greater than or equal to 11 were considered sarcopenic and a score between 0 and 10 without sarcopenia. With the aim of estimate the association between the characteristics, Pearson’s chi‐square test was calculated. If the p‐value was lower than the significance level of 0.05, it is possible to conclude the correlation between the development of sarcopenia and a worse score in CS‐10.

Result

In the sample studied, 29.1% were classified with an increased risk for sarcopenia. The mean CS‐10 score was 8.2 with a standard deviation of 1.7 points. Patients with higher SARC‐F CC scores had a lower mean score on the CS‐10, but these results did not show a statistically significant difference (p‐value 0.232).

Conclusion

Despite of a tendency for patients with mild cognitive impairment to have a higher risk for developing sarcopenia, it is not possible to affirm this relationship from this study, since no statistically significant association was identified.
Neighborhood Deprivation, Subjective and Objective Cognitive Impairment
Authors: Sun Britney , Yeh Fangyu , Zheng Pauline , Curtis Laura M , Yoshino‐Benavente Julia , Luu Han Q , Cecil Patrick , Agyare Prophecy , Zuleta Rodolfo , Wolf Michael S , Kim Minjee
Published: January 2025

Background

Social determinants of health have been associated with disparities in health outcomes, including cognitive impairment and Alzheimer’s disease. While individual‐level disparities have been characterized, more research is needed into structural social determinants of health (SSDoH) and their association with cognitive outcomes, especially for those in midlife. This study aimed to investigate the association between SSDoH and subjective and objective measures of cognitive impairment.

Methods

English‐speaking adults ages 35‐64 were recruited from an academic general internal medicine practice and federally qualified health network in the Chicagoland area. SSDoH was evaluated using the Area Deprivation Index (ADI), a validated factor‐based index of neighborhood socioeconomic context using participant census block, then divided into terciles with the highest tercile indicating highest neighborhood deprivation. Subjective cognitive concern was measured by a single question assessing concern about cognitive or memory issues as part of the Everyday Cognition Cog scales. Objective cognition was measured using the Montreal Cognitive Assessment (MoCA) with MoCA < 23 (out of 30) indicating cognitive impairment. We used univariate and multivariable logistic regression models to characterize the relationship between SSDoH and cognitive impairment, including a priori covariates of age, sex, education, and number of chronic conditions.

Results

A total of 596 participants (age 52±8; 64% female; 42% non‐Hispanic Black, 34% non‐Hispanic White, 16% Hispanic; 62% college graduate) were included in the analysis. Younger age, female sex, non‐Hispanic Black race, and lower education and income were associated with higher ADI (Table 1). One‐third of participants (34%) reported subjective cognitive concern, whereas objective cognitive impairment was found in 22.6%. Compared to the lowest ADI tercile (i.e. least deprived), the highest ADI tercile (i.e. most deprived) was significantly associated with objective cognitive impairment (aOR, 3.0; 95% CI, 1.5‐5.9; p = 0.001) but not subjective cognitive concerns (aOR, 1.2; 95% CI, 0.7‐2.0; p = 0.46), after adjusting for a priori covariates (Table 2).

Conclusions

Neighborhood deprivation is associated with Future research should investigate the possible mechanisms of this association to identify optimal interventions at the neighborhood level.