bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of Peak width Skeletonized Mean Diffusivity in AD disease progression
Authors: Jarholm Jonas Alexander , Tecelao Sandra , Pålhaugen Lene , Kirsebom Bjørn‐Eivind , Bjornerud Atle , Fladby Tormod , Selnes Per
Published: January 2025

Background

Cerebral small vessel disease (CSVD) is common in Alzheimer’s disease (AD), but it is unclear how CSVD affects cognition and disease progression. Peak width of Skeletonized Mean Diffusivity (PSMD) is a Magnetic Resonance Imaging (MRI) marker of global white matter integrity, believed to reflect both total vascular burden and the cognitive impact of CSVD. We examined the relationship between PSMD and memory, processing speed and executive function, and to assess the predictive value of PSMD on clinical progression.

Method

265 cases and controls between 40‐80 years old were recruited from the Norwegian multi‐center study DDI (Dementia Disease Initiation), with 2‐5 follow ups (0.7‐8 years). Subjects were according to the Clinical Dementia Rating (CDR), with 0 as cognitively unimpaired (CU) if, 0,5 as mild cognitive impairment (MCI) if CDR, and ≥ 1 as dementia. Amyloid status was determined from Amyloid‐PET or from amyloid‐β42/40. PSMD was obtained from 6 MRI scanners and harmonized for scanner effects in R using ComBat, with age, sex, staging and amyloid status at baseline as covariates.

The relationship between PSMD and cognitive scores was assessed using a general linear model, with age, sex, education and an PSMD‐amyloid interaction variable as covariates. Subjects were classified into the following groups: A‐ low PSMD, A+ low PSMD, A‐ low PSMD, A+ high PSMD high, where PSMD high or low signifies above or below the group median. Survival analysis was performed in 195 subjects, using the “survival” package from R, with progression from CU to MCI/dementia or from MCI to dementia as the events of interest. Hazard ratios were assessed with the Cox proportional‐hazards model with age and A status/PSMD at baseline and sex as covariates.

Result

There was a significant relationship (p<0.01) between PSMD and TMT A and B, but not with CERAD recall. PSMD low A+ subjects had 5.5 times higher risk of cognitive decline (p<0.01) than PSMD low A‐, while PSMD high A+ had 14.3 times higher risk.

Conclusion

We found that high PSMD load increases the risk of AD disease progression, but is not significantly associated with delayed recall, the core cognitive biomarker of AD.
Role of the Gut Microbiome in Cognitive Health of Puerto Ricans: A Novel Perspective for Understanding Alzheimer’s Disease
Authors: Herrero‐Rivera Carlos Alberto , Morales Hiram , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Olivieri‐Henry Gerianne , Godoy‐Vitorino Filipa , Sepulveda Vanessa
Published: January 2025

Background

Alzheimer’s disease (AD) comprise over 70% of dementia cases in the United States (US), characterized by progressive neurodegenerative symptoms. In the US and Puerto Rico (PR), AD is the sixth and fourth leading cause of death, respectively. The Gut‐Brain Axis is a bidirectional communication mechanism between the central nervous system and microbes that reside in the gastrointestinal tract. Research shows that neuroactive metabolites influence neurological responses and inflammatory pathways. Even though a correlation between gut microbiome and some neuropsychological diseases (e.g., Parkinson’s) has been described, its association with AD is understudied. This study compared the gut microbiome of Puerto Ricans with AD to healthy controls to help elucidate the role of gut microbiota as a possible contributing factor for the high prevalence in this population.

Method

The study evaluated 100 participants: AD (n = 50) and controls (n = 50) with a medical history, physical exam, ApoE genotype, and cognition using the Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating Scale (CDR). Stool for genomic DNA extractions and microbiome characterization using 16S rRNA genes (V4 region) via Illumina MiSeq.

Result

Microbial Alpha Diversity showed no significant difference between AD and controls. Microbial Beta Diversity showed a significant difference between groups (P‐value = 0.034). Phyla‐level taxa tendencies in AD showed a higher relative abundance of Actinobacteria, Verrucomicrobia, and Euryarchaeota. Taxonomic profiling also showed reduced levels of neuroprotective genera Faecalibacterium and Bacteroides, and increased levels of pro‐inflammatory opportunistic Eggerthella. Regarding CDR testing of AD groups, there were significant differences in alpha diversity among normal CDR with mild and severe dementia. The microbial richness of controls declined with their cognitive status based on MoCA. One variant of ApoE4 was present in 92% of AD patients (46/50) and 94% in controls (47/50). Only one subject had E3E3 phenotype while 30.4% E3E4, 2.9% E4E4, and 5.9% E2E3.

Conclusion

This study, the first of its kind in PR, suggests that microbial diversity and richness are associated with cognitive status. Furthermore, it showed possible bacterial dysbiosis in AD patients compared to controls which paves the way for identifying microbial biomarkers and modulation‐based interventions.
Significant Relationship Between Worsening Sleep and Declining Brain Metabolism in APOE4+ Individuals
Authors: Hogue Anne E. , Silverman Daniel H.
Published: January 2025

Background

We recently reported that subjects who had worsening sleep over time had a clear worsening of both memory and brain metabolism compared to subjects whose sleep improved over time, and metabolic decline was particularly significant in the posterior cingulate cortex (PCC) (Alzheimer’s Dement. 2023; 19(Suppl. 24):e082867), an area of the brain that metabolically declines in the earliest stages of Alzheimer’s disease. Here we investigate the impact of worsening sleep on regional metabolic decline in Apolipoprotein E epsilon 4 positive (APOE4+) subjects compared to APOE4‐ subjects.

Method

A consecutive series of 2,005 cognitively normal and mildly impaired subjects from more than 50 North American sites participating in the first three phases of the Alzheimer’s Disease Neuroimaging Initiative were studied. Changes in cognition assessed through formal neuropsychological testing, and in regional cerebral metabolism assessed through brain PET using the radiotracer [F‐18]fluorodeoxyglucose were examined. Activities in 47 standardized volumes of interest (sVOI’s), as normalized to each subject’s pons activity, were longitudinally measured.

Result

In this consecutive series of subjects, 211 were found to have had a change in insomnia status during their participation: 83 who were documented to have insomnia at baseline that was subsequently alleviated (“improving sleep”), and 128 who were documented to have no insomnia at baseline but developed it during the study period (“worsening sleep”); of the 211, 62 (29%) underwent FDG‐PET scans during both baseline insomnia and subsequent insomnia‐free status, or both baseline normal sleep and subsequent insomnia status periods. Within this group, 27 subjects were APOE4+ and 35 were APOE‐, with 59% of the APOE4+ subjects belonging to the worsening sleep group, and 41% within the improving sleep group. In the worsening sleep group with APOE4+ status, there was metabolic decline in bilateral mesial temporal and right thalamic regions (p<0.0001), but not among those with APOE4‐ status (p>0.50).

Conclusion

Worsening sleep was associated with regionally specific cerebral metabolic decline, as described above, in APOE4+ but not APOE4‐ non‐demented subjects, suggesting that poor sleep status may pose especially heightened risk of decline for those bearing APOE4 alleles.
Operationalizing postmortem pathology‐MRI association studies in ADRD with MRI‐guided histology sampling: does closer proximity lead to stronger associations?
Authors: Athalye Chinmayee , Khandelwal Pulkit , Bahena Alejandra , Trotman Winifred , Ohm Daniel T , Emrani Sheina , Teunissen‐Bermeo Eric , Capp Noah , Lim Sydney A , Levorse Lisa M , Denning Amanda E , Ittyerah Ranjit , Schuck Theresa , Gabrielyan Marianna , Prabhakaran Karthik , Mizsei Gabor , Robinson John L. , Detre John A. , Lee Eddie B , Irwin David J , McMillan Corey T , Tisdall M. Dylan , Das Sandhitsu R. , Wolk David A , Yushkevich Paul A.
Published: January 2025

Background

Histopathological analysis of autopsied brains is the gold standard of diagnosis in neurodegenerative disorders. Co‐registered histology and MRI scans aid in understanding pathology and structural features. Previous studies focused on the medial temporal lobe (MTL) for atrophy patterns in phosphorylated tau (p‐tau) pathology and in whole hemisphere scans with contralateral semi‐quantitative p‐tau measures. Here, we extend this to study ipsilateral quantitative p‐tau and cortical thickness.

Method

We used 29 brain hemispheres from patients with Alzheimer’s Disease (AD) diagnosis. We identified 19 regions of interest (ROIs), spanning the cortex and MTL. The ROIs were manually marked on the T2‐weighted 7T hemisphere MRI (0.3mm3 isotropic). The MRI scans were used to build a 3D‐printed mold of the brain. This mold helped identify the slabs with ROIs for histological staining. We used LFB‐CV (Luxol fast blue cresyl violet) stain and AT‐8 antibody for p‐tau on each ROI slide, which were then registered to the whole hemisphere MRI scans in a semi‐automatic manner. We used a weakly‐supervised learning algorithm WildCat to get quantitative measures of p‐tau for each ROI in the histology. Regional cortical thickness at the ROI markers was measured as the diameter of the maximally inscribed sphere in the topologically‐corrected automated deep learning‐based segmentations. Separately, whole hemisphere‐based thickness measurements were derived using a surface‐based parcellation scheme.

Result

One‐sided Spearman rank test was performed to assess the correlation between p‐tau and cortical thickness measurements. For ipsilateral quantitative p‐tau, this test showed significant correlation in the posterior cingulate gyrus (r = ‐0.53, p‐value = 0.0072), anterior cingulate gyrus (r = ‐0.45, p‐value = 0.019), and the middle frontal gyrus (r = ‐0.41, p‐value = 0.025). We performed the same test with contralateral semi‐quantitative tau scores (Table 1). A generalized linear model showed significant correlations between whole hemisphere vertex‐wise thickness with regional measurements of neuronal tangles in the anterior cingulate (Figure 2).

Conclusion

Postmortem MRI‐guided ipsilateral quantitative p‐tau burden measures showed better correlation with cortical thickness, in absolute terms, than contralateral semi‐quantitative tau scores. Replication and understanding whether co‐localization or improved quantification are most responsible for this improvement will require larger brain donor cohorts.
Clinical Utility of U‐p53AZ as a prognostic biomarker for the prediction of progression rate, in individuals with early stages of Alzheimer’s Disease
Authors: Agus Shmuel , Piccirella Simona , Durrant Abe , Duncan Garrett B , Dickson Samuel P. , Hendrix Suzanne B. , Kinnon Paul
Published: January 2025

Background

Despite recent success in AD clinical trials, many obstacles still prevent effectively halting disease progression. Many suspect that treating subjects earlier in the disease process will be key to providing more effective treatment. Better early diagnostics will aid the design and execution of prevention and early AD studies. Furthermore, early identification of rapid progressors may be valuable in treatment development, since imbalance of rapid progressors can disrupt the proper identification of effective treatment. We present the performance of U‐p53AZ (AZ284) to identify slow progressors and rapid progressors.

Method

A total of 629 participants were randomly selected from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and the Alzheimer Disease Research Center (ADRC). 172 participants were classified as AD, 303 as cognitively normal, and 154 as MCI or other. U‐p53AZ measurements were taken at baseline and the prognostic value of U‐p53AZ was assessed through multiple analyses. Logistic regression models were fit to predict clinical diagnosis at time points up to 6 years and analyzed through receiver operating characteristic (ROC) analyses. Additionally, U‐p53AZ was used to predict “rapid progressors”. Rapid progressors were defined as patients that progressed in clinical diagnosis to AD within 2 years and as patients which progressed in clinical outcomes using a global statistical test (GST).

Result

U‐p53AZ shows strong predictive performance as a standalone metric throughout both cohorts with an overall AUC of 0.956 when predicting clinical diagnosis at 6 years. Adding demographic variables in the AIBL study raises the AUC over 0.98. For modeling rapid progressors to a clinical diagnosis, U‐p53AZ returns an AUC of 0.887 between both studies. Using a GST of clinical outcomes to define rapid progressors results in an AUC of 0.914. In each case, U‐p53AZ returned a higher AUC compared to PET imaging or CSF.

Conclusion

U‐p53AZ can be used to improve prognostic accuracy of progression to AD over both 2 and 6 years, which will improve screening for AD patients in the clinic and in clinical trials. This prognostic accuracy will help obtain early treatment in those subjects and save resources among those unlikely to develop AD.
Association of later‐life emergent affective dysregulation with neuroinflammatory biomarkers in dementia‐free older adults
Authors: Ghahremani Maryam , Ismail Zahinoor
Published: January 2025

Background

Neuroinflammation has emerged as a significant factor in the pathogenesis of dementia. Elevated levels of proinflammatory and anti‐inflammatory cytokines such as interleukin‐6 (IL6), interleukin‐10 (IL10), and tumor necrosis factor‐alpha (TNFα) have been observed in the cerebrospinal fluid and plasma of patients with Alzheimer’s disease, associating with cognitive decline and dementia. Here, we explored the cross‐sectional association between plasma inflammatory biomarkers and the affective dysregulation domain of Mild Behavioral Impairment (MBI), a validated neurobehavioral syndrome capturing later‐life emergent and persistent neuropsychiatric symptoms (NPS).

Method

Data from dementia‐free older adults were acquired from the Health and Aging Brain Study: Health Disparities (HABS‐HD). MBI‐affective dysregulation (MBI‐affect) was operationalized based on a diagnosis of depression and/or anxiety within 5 years of baseline. Comparator groups included participants with no previous diagnosis of depression or anxiety (No‐affect) and those with a diagnosis >5 years prior to baseline (Non‐MBI‐affect). Plasma concentrations of inflammatory biomarkers IL5, IL6, IL10, and TNFα were obtained using single molecule array (SiMOA) technology. Linear regressions modeled the cross‐sectional association between NPS group (predictor) and inflammatory biomarker level (outcome), adjusted for age, sex, education, race, and cognitive diagnosis (normal cognition or mild cognitive impairment (MCI)).

Result

The sample comprised 74 MBI‐affect (age = 62.4±7.5; 81.1% female; 23.0% MCI), 143 Non‐MBI‐affect (age = 64.3±7.1; 76.2% female; 21.0% MCI), and 396 No‐affect participants (age = 66.7±8.9; 51.8% female; 13.6% MCI). Those with MBI‐affect had significantly higher baseline levels of plasma IL6 (b = 3.10, 95%CI:1.01‐5.19, p = 0.004) and TNFα (b = 1.66, 95%CI:0.43‐2.89, p = 0.008) compared to No‐affect, after multivariable adjustment. Biomarker levels in Non‐MBI‐affect did not differ significantly from the No‐affect group. For IL5, while MBI‐affect participants did not significantly differ from No‐affect (b = 0.03, 95%CI:‐0.002‐0.07, p = 0.06), the magnitude and direction of the effect were similar to the other biomarkers (Table 1).

Conclusion

Compared to No‐affect, MBI affective dysregulation was associated with higher levels of inflammatory biomarkers IL6 and TNFα, while Non‐MBI‐affect showed no association. The link between MBI affective dysregulation and neuroinflammation further informs our understanding of the biological underpinnings of MBI. These findings add to the evidence base for MBI as a clinically relevant approach to identify high‐risk individuals for cognitive decline and incident dementia.
Maternal Care and Offspring Development Trajectories in Mice: Effects of Alzheimer’s Disease Genotype and Maternal Age
Authors: Prakapenka Alesia V , Parpala Sophia , Cary Mallica , Ramirez Edith , Kujawa Stacy , Hawkey Andrew
Published: January 2025

Background

Pregnancy and birth uniquely alter female physiology, biology, and behavior. Contrasting findings on pregnancy and AD risk association suggest that confounding variables (e.g., age at birth) mediate pregnancy’s role in AD risk. We aim to elucidate the impact of age at first birth on female behavioral and brain health at middle‐age in the triple‐transgenic AD mouse model. Since strain and genotype differences in maternal care and offspring development exist, maternal care and offspring development trajectories as a function of genotype and maternal age were assessed.

Methods

Wildtype (WT; C57BL/6J) and AD virgin females were paired with WT males for pregnancy and birth to occur at 2‐m‐o. Gestational weight gain and litter characteristics (i.e., pup number, sex ratio, body weight) were recorded. Maternal care measures included retrieval of four pups to nest following 5‐min separation on postnatal day 2 (PND2) and evaluation of maternal activities for two hours on PND3 and PND17. Offspring development was assessed by righting reflex (PND5‐8) and negative geotaxis (PND10‐13) tests.

Results

All mice were pregnant and gave birth, with two WT litters lost after birth. AD dams tended to have increased gestational weight gain compared to WT dams [p < 0.1]. Gestational weight gain was similar across genotypes after accounting for pup number and lost litters. All dams successfully retrieved pups on the retrieval task. Genotype by pup interaction [F(3, 36) = 2.814, p = 0.05] indicated that latency to retrieve increased with each subsequent pup in AD versus WT dams. Preliminary analyses suggest AD dams spent more time digging during the task compared to WT dams, which may modulate observed pup retrieval differences. Dam genotype impacted offspring development trajectories, whereby WT litters exhibited longer righting reflex latencies and shorter negative geotaxis latencies compared to AD litters.

Conclusions

Findings suggest that maternal care and offspring development trajectories differ as a function of AD genotype in 2‐m‐o dams. Ongoing study evaluates 5‐6‐m‐o and 8‐9‐m‐o maternal ages. Future work will assess age at first birth effects on maternal health outcomes (e.g., behavior, neuropathology) in these dams at middle‐age, correlating to observed maternal care and offspring development measures.
Tinnitus and hearing loss in people with dementia
Authors: Machado Mariane Gomes , Machado Thais Helena , Caramelli Paulo , de Resende Luciana Macedo
Published: January 2025

Background

Tinnitus has variable prevalence in the general population and is often associated with some degree of hearing loss. There are few studies on tinnitus in people with dementia. The objective of the study was to investigate the occurrence of tinnitus complaints in patients with dementia and evaluate possible relationships with hearing acuity.

Method

Observational study carried out with individuals treated at a cognitive neurology outpatient clinic. The inclusion criteria were patient being monitored for dementia, patient’s ability to answer the question “Do you feel tinnitus/noise in your ears or head?” and respond to audiometry. Descriptive analysis was performed. Research Ethics Committee 5626511.

Result

Overall 187 patients with mild to moderate dementia who answered the anamnesis questions. Among these patients, 70 (37.43%) reported tinnitus and had a mean age of 66.71 years, 33 (47.14%) women and 37 (52.85%) men. It was possible to perform audiometry on 62 patients, due to difficulties in carrying it out due to dementia. Of the 62 patients who complained of tinnitus and underwent audiometric evaluation, hearing loss was detected in 54 (87.10%).

Conclusion

In our study, 37.43% of patients with dementia complained of tinnitus. The prevalence of tinnitus complaints in the general population varies greatly, ranging between 4.4 and 15.1% in adults and 22.2% in older adults. Changes and severity of mental status and type of dementia may worsen the perception of tinnitus. The vast majority of tinnitus patients had some degree of hearing loss. The complaint of tinnitus is strongly associated with hearing loss in previous studies. Hearing rehabilitation may be a recommended treatment for patients with dementia, hearing loss and tinnitus. In addition to improving hearing acuity, rehabilitation can reduce the perception of tinnitus, as this symptom can lead to changes in mood and behavior that are difficult to manage. The perception of tinnitus in people with dementia may be greater compared to the general population. More studies need to be carried out to better characterize the tinnitus reported by people with dementia of different types and stages to better define management by professionals.
Cerebrovascular pathology and neurovascular coupling impairment in aged‐mouse model of Alzheimer’s disease
Authors: Promkan Moltira , Phikulthong Kamonchat , Kimseng Rungruedee , Pauss Kate , Lee Tiffany , Weekman Erica M. , Nelson Peter T , Wilcock Donna M. , Sompol Pradoldej
Published: January 2025

Background

Vascular pathology profoundly comorbid with AD pathology could worsen disease progression and reduce treatment efficacy. Knowledge of small vessels and cerebrovascular function in AD mouse models is limited. Investigating vascular related aspects for preclinical AD studies is essential for biomarker development and treatment trials. Therefore, we aim to characterize cerebrovascular amyloid angiopathy (CAA), vascular degeneration, and cerebrovascular function in an aged Tg2576 mouse model of AD.

Method

WT and Tg2576 (∼ 2 years of age) were housed in a reversed light cycle room. Cranial window surgery and cranial window installation were performed. After 3 weeks of recovery, the animals were acclimated to an intravital multiphoton imaging platform. To visualize beta‐amyloid in the brain, Methoxy‐X04 (10mg/kg) was injected the day before the imaging. Cerebrovasculature was visualized by intravascular retro‐orbital injection of rhodamine‐dextran (5% V/W in saline). This procedure was done while the animals were under anesthesia and securely head‐fixed prior to the imaging. Z‐stack imaging was performed, and vascular structure was analyzed by using FIJI or ImageJ. Neurovascular coupling was performed to investigate vascular function in awake mice. While imaging penetrating arteriole, air‐puff stimulation of contralateral whiskers was conducted and increased vascular diameter is used as an indicator of hyperemic neurovascular function.

Result

Investigation of cerebrovascular pathology including CAA, vascular straightness, and vascular blebbing are ongoing. During whisker stimulation, vascular diameter was relatively reduced in Tg2576 compared to WT control mice.

Conclusion

Aged Tg2576 exhibits comorbidity of amyloid plaques, cerebral amyloid angiopathy, small vessel pathology and cerebrovascular dysfunction similar to human brain. This aged Tg2576 could be used as a preclinical translational mixed vascular/AD model.
Screening for the Spectrum of Cognitive Impairment in Primary Care: Development of a Machine Learning Informed, Workflow‐Friendly Care Model
Authors: Williamson Jeff D. , Jaeger Byron C , Bateman James R. , Benayoun Marc D. , Boehm Amy , Cleveland Maryjo , Kirkendall Eric D , Mielke Michelle M. , Pajewski Nicholas M. , Rigdon Joseph D , Snyder Heather M , Weiss Matthew G. , Yelton Paul D , Craft Suzanne
Published: January 2025

Introduction

Over 9 million Americans are projected to have dementia by 2030, and adults with mild cognitive impairment (MCI), a potential pre‐cursor to dementia, will also rise. With recent and emerging clinical trial evidence for interventions to slow the progression of MCI to dementia, identification of persons in primary care with undiagnosed early‐stage cognitive impairment may provide opportunity for preventive intervention.

Methods

A Machine Learning (ML)‐based prediction model trained using data from the electronic health record was applied to patients without formal diagnoses of cognitive impairment who were currently seen in selected primary care practices. The ML model is a super learner ensemble of prediction models, combining predictions from boosted trees, oblique random forests, and Cox regression trained using patient records from 2017‐01‐01 to 2018‐12‐31. We externally validated the super learner’s discrimination, calibration, and fairness using records from 2019‐01‐01 to 2020‐12‐31 (no overlapping patients). Patients for whom the model triggered an alert were recommended by their primary care practitioner to undergo cognitive assessment, consisting of a 30‐minute remotely‐administered tablet‐based cognitive battery. Patients also underwent blood collection for AD biomarkers (ptau217, Ab42, neurofilament light, GFAP), and neuroimaging (MRI, amyloid PET).

Results

In the testing cohort, the super learner obtained a concordance statistic (95% confidence interval) of 0.822 (0.810, 0.835), higher than any of the individual ML models (Figure 1), and its predicted risk aligned with observed risk in calibration slope plots (Figure 2). Results of cognitive testing plus expert adjudication of the first 75 patients will be presented by proportion of patients adjudicated as not impaired versus MCI. We will also report categories of therapy such as behavioral (sleep, exercise, etc.), medical (hypertension control, alcohol cessation), or pharmacologic (anti‐amyloid therapy) that were recommended based on cognitive, imaging, biomarker, and medical findings. Also reported will be initial feedback on workflow and provider satisfaction with this screening and care model from primary care providers.

Conclusion

While predictive models of undiagnosed cognitive impairment are imperfect, they can facilitate scalable and feasible primary care screening models leading to effective care plan design for patients with early cognitive impairment and without adversely affecting workflow.
Effective Practices for Enrolling Underrepresented Groups in Early Alzheimer’s Disease Trials: Insights from the Aducanumab Program
Authors: Showell Shardae , Murphy Jennifer , Gillis Cai , Maserejian Nancy N , Mayuram Sangeetha , Wilson Jenna , Farrell Aimee , King Katie , DaCosta Savine , Wilson Kate , Lovelace Kerry , Vigario Andrew , Dawson Katherine , Dent Gersham
Published: January 2025

Background

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impairment of daily functioning. It disproportionately affects certain racial and ethnic groups, with African Americans and Hispanics being 2 and 1.5 times more likely to develop Alzheimer’s disease compared to white non‐Hispanic Americans, respectively. Despite higher disease prevalence in these groups, enrolling these patients in Alzheimer’s disease clinical trials has been challenging, and they have historically been underrepresented. For the aducanumab program, we developed strategies to boost enrollment of African American and Hispanic participants. Here, we share insights from employing these strategies to further advance the enrollment of underrepresented groups in Alzheimer’s disease clinical trials.

Method

To boost enrollment of African American and Hispanic participants, we developed a cross‐functional work stream, incorporating members from clinical development, epidemiology, clinical operations, patient engagement, clinical trial diversity, and clinical country site management to collaborate on diverse recruitment and enrollment strategies. We executed and measured the impact of these strategies through the screening, enrollment, and retention of participants from these groups.

Result

The creation of intentional recruitment practices and site‐led strategies increased screening and randomization of underrepresented populations. Successful strategies included brain awareness education programs and faith‐based initiatives to build a trusting relationship with communities, mobile research unit initiatives to combat access barriers, and tailored site‐led programs that engaged populations in specific geographic/demographic locations. In parallel, targeted site communications and study‐wide webinars provided rationale for the goals and strategies of the trials, explaining the critical scientific need to include biological data from diverse populations.

Conclusion

Employing a wide range of operational interventions, incentivizing strategies, outreach initiatives, and site educational events enhanced the recruitment and enrollment of underrepresented populations in an aducanumab clinical study. Clinical trials that are representative of the overall Alzheimer’s disease population may aid in producing results that better reflect real world outcomes.
Associations Between Alzheimer’s Disease and Stroke: Clinical Studies of NA‐831 for AD and NA‐911 for Stroke
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern
Published: January 2025

Background

NA‐831 is a candidate for the treatment of Alzheimer’s Disease (AD). NA‐911 is an analog of NA‐831, serving as an IGF‐1 and GLP‐1 agonists. Animal studies of NA‐911 are evaluated for the treatment of by hypoxic‐ischemic injury, hemorrhagic stroke, and chronic neurodegenerative disorders

Method

For NA‐831: A randomized clinical trial of NA‐831 was performed in 112 participants with mild and moderate AD, half received the drugs and half received placebo. The patients with MCI received 10 mg of NA‐831 or placebo orally per day. The patients with mild and moderate AD received 30 mg of NA‐831 or placebo orally per day. Subjects with MCI to meet the NIA‐AA core clinical criteria, CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline. MMSE score ≥22. Subjects with mild & moderate AD to meet the NIA‐AA core clinical criteria. MMSE: 17‐21.

For NA‐911: We conducted animal studies of NA‐911 on adult male Sprague‐Dawley rats using the middle coronary artery occlusion (MCAO) method. This method is designed to mimic neurological and behavioral signs and symptoms of stroke in humans. Details of the animal study method will be described.

Results

NA‐831 showed a significant improvement for patients with mild and moderate AD with the ADAS‐Cog‐13 score change of an average of 4.1 as compared to the placebo after 24 weeks of treatment (p = 0.001; ITT). CIBIC‐Plus showed 78% patients improved (p = 0.01; ITT). mNA‐831 was well‐tolerated at 30 mg/day.

In the animal study of NA‐911, the area of infarct in animals treated with vehicle was 43.4±7.4 mm2 (n = 13, Treatment with NA‐911 (3 mg/kg/h) significantly reduced the area of the infarct to 17.3 ±5.4 mm2 when compared to its vehicle treated group (n = 15, * P<0.05). It has been shown that progenitor cells residing in the SVZ are potentially able to replace the loss of nervous tissue after stroke.

Conclusion

An association of Alzheimer’s disease and stroke has been suggested with clinical studies of NA‐831 and NA‐911. However, whether this association is causal requires further evaluation.
Concordance between visual interpretation of [18F]flortaucipir pet images and the Universal centaur scale
Authors: Moscoso Alexis , van Essen Martijn , Mainta Isminni , Camacho Valle , Rodríguez‐Fonseca Omar , Silva‐Rodríguez Jesús , Perissinotti Andrés , Franzmeier Nicolai , Grothe Michel J. , Frisoni Giovanni B , Garibotto Valentina , Schöll Michael
Published: January 2025

Background

Positron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this clinically approved definition of tau PET positivity and a recently proposed universal scale—CenTauR—for the standardized quantification of abnormal tau aggregates.

Method

We included 1849 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (A4 study, ADNI, OASIS‐3, and HABS) with available [18F]flortaucipir PET (mean age: 72.2 y, 55% females). Three trained readers scored each [18F]flortaucipir PET scan as positive/negative using an FDA‐approved visual interpretation method. Visual reads were compared to [18F]flortaucipir PET quantification using the Universal CenTauRz scale. Specifically, we analysed concordance by 1) performing a receiver operating characteristic (ROC) curve analysis of continuous CenTauRz (CTRz) values discriminating between positive/negative visual reads; and 2) computing sensitivity and specificity when using a previously proposed cut‐point of 2 CTRz.

Result

Concordance between visual interpretation and continuous CTRz measures was limited (AUC = 0.82 for CU and AUC = 0.87 for CI, Figure 1). When using a previously proposed cut‐point of 2 CTRz, this quantitative approach yielded a sensitivity of 49% [95% CI, 42% to 57%] and a specificity of 95% [93% to 96%] in CU individuals and a sensitivity of 73% [95% CI, 66% to 79%] and a specificity of 94% [95% CI, 90% to 96%] in CI individuals. Visual‐positive, CenTauRz‐negative individuals were more frequently Aβ‐positive than visual‐negative, CenTauRz‐positive individuals (87% vs 48%, p<0.001).

Conclusion

Visual interpretation of [18F]flortaucipir PET images and quantification using the universal CenTauRz scale exhibited limited agreement, particularly among CU individuals. Tau‐PET positivity based on visual interpretation aligns better with the presence of Aβ‐pathology. Visual interpretation seems to be more sensitive to early tau aggregation compared to universal CenTauRz quantification. Future analyses will compare clinical outcomes associated to each definition of tau‐PET positivity.
Psychometric properties of the Memory Alteration Test (M@T) using a confirmatory factor analysis and a Rasch model
Authors: Carbajal Alicia Boluarte , Boluarte Arantxa Sánchez , Santisteban Brian Florentino , López Angel Zegarra , Boluarte Sofía Sanchez
Published: January 2025

Background

Background. According to the World Health Organization, dementia is one of the leading causes of disability in the elderly, imposing a significant burden on global public health. It is estimated that dementia affects over 55 million people worldwide, with 60% of them living in low‐ and middle‐income countries. Early detection of cognitive impairment is crucial for timely intervention and management. In this context, neuropsychological assessment tools play a vital role in identifying individuals at risk. The Memory Alteration Test (M@T) has emerged as a promising tool due to its high sensitivity for early detection of dementia and MCI. To build on this, our study aimed to analyze the psychometric properties of the M@T, in order to ensure its validity and reliability in clinical settings.

Method

The study was conducted among 352 participants over 60 years of age, recruited from Municipal Elderly Care Centers in four socioeconomically distinct districts of Lima, Peru. The M@T captures five domains of memory: encoding, temporal orientation, semantic memory, free recall and cued recall. For this, we proposed a unidimensional model and a multidimensional model with 5 factors, using a confirmatory factor analysis and a Rasch modeling.

Result

The majority of participants were women (82.9%), with a notable proportion reporting a clinical history of hypertension (33.2%). The internal structure analysis and Rasch modeling exhibited a unidimensional structure with good fit and adequate reliability (GY = .897, ord = .934). On the other hand, the 5‐factor multidimensional model showed a poor fit with unreliable scores (GY = .174‐.785, ord = .576‐.898). Likewise, the Rasch analysis demonstrated that the test measures a general memory ability reliably (Rp = .813), while the multidimensional model showed that the scores in each domain were not consistent (Rp = .358‐.707).

Conclusion

The findings suggest that the M@T operates as a unidimensional factor, emphasizing the importance of considering the total score rather than individual dimensions. This underscores the need for caution when interpreting results, particularly when employing multidimensional models, which may not accurately capture the underlying structure of the test. Ultimately, a unidimensional approach offers a more parsimonious and reliable means of assessing cognitive function using the M@T.
Cerebello‐Basal Ganglia Functional Connectivity Differences in Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Gonzales Ivan Herrejon , Jackson T. Bryan , Hicks Tracey , Bernard Jessica A
Published: January 2025

Background

Extensive research on the cerebral cortex and the hippocampus has improved our understanding of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Historically, however, the cerebellum’s role in these stages of cognitive decline has been traditionally neglected due to its associations with motor function. Recent research has demonstrated cerebellar structural and connectivity differences in MCI and AD. Further investigating is however needed. In cognitively normal (CN) older adults cerebello‐basal ganglia (CB‐BG) functional connectivity is lower compared to younger adults. However, it remains an open question how these networks differ across different stages of cognitive decline and whether they are associated with cognitive and/or task performance.

Method

Here, we investigated CB‐BG resting state networks associated with motor and cognitive cortical circuits across CN, MCI, and AD populations. The Alzheimer’s Disease Neuroimaging Initiative (ADNI‐3) was used to obtain the data of 478 participants who completed a motor and cognitive battery. All participants also underwent resting state functional magnetic resonance imaging (fcMRI). Analysis was completed using the CONN toolbox.

Result

We found a higher FC between Crus I with globus pallidus pars externa and lower FC between lobule VIIIb and dorsal caudal putamen in AD compared to CN individuals. However, no significant results were found when comparing AD to MCI or MCI to CN, suggesting that this stage of cognitive decline does not affect cerebello‐basal ganglia networks

Conclusion

Further understanding of network dysfunction that includes the cerebellum can help inform future clinical work and elucidate the mechanisms of MCI and AD.
Exploratory CSF proteomics biomarker outcomes of the the phase 2 clinical trial shine to assess the effects of CT1812 in Alzheimer’s patients
Authors: Caro Valentina Di , Lizama Britney N , Cho Eunah , Duong Duc M , Pandey Kiran , Blennow Kaj , Zetterberg Henrik , Levey Allan I. , Teunissen Charlotte , Caggiano Anthony O , Seyfried Nicholas T , Hamby Mary E.
Published: January 2025

Background

SHINE (NCT03507790, COG0201) is a Phase 2 randomized, double‐blind, placebo‐controlled 6‐month trial, conducted to study the effect of the sigma‐2 receptor (S2R) modulator CT1812 in patients with Alzheimer’s disease (AD). An unbiased assessment of CSF proteomes from the patients that completed the SHINE trial was performed to identify pharmacodynamic (PD) biomarkers of target/pathway engagement and disease modification for CT1812.

Method

Tandem‐mass tag mass spectrometry (TMT‐MS) CSF proteomics was performed on baseline and end of study samples from an analysis of SHINE Part A and B to test the effects of two doses (100 mg, 300 mg; given orally, once daily) of CT1812 compared to placebo in mild to moderate AD patients. Change from baseline was calculated for each participant (N = 47), and differential abundance analysis (CT1812 vs placebo) was performed to assess treatment effects followed by Brain network mapping, Gene Ontology, and pathway analyses using STRING and Metacore (p≤0.1, p≤0.05). Pearson correlation analyses across levels of proteomic proteins and AD core biomarkers were also performed.

Result

In the interim analysis of the first 24 patients (SHINE‐A), differential expression analyses identified proteins altered (p≤0.1 and p≤0.05) in CT1812 vs placebo CSF, and hierarchical clustering demonstrated stratification of patients by treatment. Comparisons to reference standards showed proteins disrupted in or genetically linked to AD that were impacted by CT1812. Proteins dysregulated in AD were found to be normalized with CT1812 treatment (i.e., CLU) and biomarkers of pathway engagement were identified (i.e., APP, NPC1). Brain network mapping and pathway analysis identified statistically significant biological processes altered by CT1812, including those related to synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Analyses of SHINE‐A and ‐B combined (N = 47) will be presented at this meeting.

Conclusion

CSF biomarker findings of the completed SHINE trial extend beyond that previously identified in the interim Part A analysis and shed light on potential biological proteins and/or pathways affected by CT1812. Pharmacodynamic biomarkers of CT1812 pathway engagement and disease modification were identified. Future investigation is warranted to determine if findings replicate in independent cohorts of AD patients.
Delivering Multidomain Lifestyle Intervention Via Telehealth: Findings from a Brain Health Program in the United States
Authors: Rao Anitha , Anderson Leyla , Wilkes Travis , Verdooner Steven R
Published: January 2025

Background

Multidomain lifestyle interventions have been shown to improve cognition and functional status in adults at elevated risk of developing dementia. The delivery of lifestyle interventions has primarily occurred during face‐to‐face clinical encounters. Unfortunately, this limits patients who live in rural and underserved areas, as well as patients who have mobility issues and transportation difficulties.

Method

A lifestyle curriculum was developed and delivered using telehealth. The study enrolled patients who met the criteria of a Mini‐Mental State Examination score >18 and could participate in the study through telehealth. Referrals primarily came from neurology and primary care clinics. An electronic medical record system was utilized to document progress and improvement. All participants shared their wearable technology data. A BrainHealth Educator (BHE) delivered personalized digital content to participants, focusing on exercise, nutrition, and sleep. The content was tailored to each participant’s risk factors, APoE genotype, and communication preferences.

Result

The study included 30 participants, with 23 females and 7 males ranging in age from 40 to over 70 years old. The enrollment and completion rates for exercise programs was 83%, for sleep programs was 83%, for nutrition programs was 58%, with an updated module currently being tested. The average duration of BHE telehealth visits was 30 minutes. There was high acceptance and satisfaction with communicating APOE test results via telehealth. 75% of participants actively used the app and 25% used the phone. 50% of patients logged in once per week. The study covered 9 geographic divisions across the US, achieving engagement across diverse practices, clinicians, and socioeconomic backgrounds, including neurologists, primary care physicians, and geriatricians. 75% of patients provided wearable data, with continuous wearable data submissions. The attrition rate was <10%.

Conclusion

This study successfully demonstrates that lifestyle intervention delivered via telehealth by a BHE resulted in high patient engagement and satisfaction at nationwide scale. As cognitive health assessment and management rapidly develops, there is a need for lifestyle intervention programs that are structured to support patients at all stages and eliminate health disparities.
Improving the Chance of Success for Alzheimer’s Clinical Trials by Identifying and Mitigating the Risk of Fraudulent Practices
Authors: Hendrix Suzanne B. , O'Keefe Patrick P , Zhang Jeffery , Hendrix Kent , Wang Lixia , Dickson Samuel P.
Published: January 2025

Background

Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer’s disease (AD) clinical trials. Successful trials are reliable despite possible victimization by these practices because these sites introduce a negative bias. Ease of simulating Alzheimer’s diagnosis documentation (based on clinical or blood markers) and clinical outcome data, coupled with inadequate oversight by Contract Research Organizations (CROs), facilitates deceptive practices.

Fraudulent practices at sites and with patients (“professional patients”) often go hand‐in‐hand and flourished during COVID. These must be aggressively addressed in the post‐COVID environment. Requiring and scrutinizing PET scans increases the chance of detecting fraud. Alarmingly, sites most prone to deceitful practices include predominantly underrepresented populations, thwarting inclusion efforts.

Method

We reviewed completed and ongoing studies to estimate the percentage of potentially fraudulent sites. We developed medical audit methods to identify issues invisible in regulatory audits. Traditional data management and statistical analysis methods fail to identify these issues. We use expected enrollment and true effect size to estimate potential bias and added variability introduced by these sites. We propose methods for detecting fraud based on clinical and operational data.

Result

In studies not requiring PET scans, approximately 10% of sites may be fraudulent, corresponding to a higher proportion of enrolled subjects (∼20‐30%). These sites can reduce observed effect size by 40% (estimated bias) at best and can completely cancel out a true treatment effect at worst. We estimate variability increases by 35‐100%, reducing our ability to observe significance. Algorithms to identify fraudulent sites will be gladly shared confidentially, but not broadly, to prevent sites from circumventing our algorithms.

Conclusion

AD clinical trials affected by even a minority of fraudulent sites may have underestimated treatment effects. We developed a toolbox for combating these issues. It includes best practices for enhanced CRO oversight, incorporation of medical expertise in audits, and identification of problems based on targeted, blinded statistical algorithms. We freely share it with qualified researchers. Awareness of and taking an aggressive stance as a community against these fraudulent practices can safeguard AD research integrity, protect and benefit vulnerable populations, and accelerate development of effective therapeutics.