bluuebunny/crossref_metadata_2025 huggingface dataset:
Driving Difficulty is an Important Mediator of the Impact of Visual Field Loss on Cognitive Impairment among Older Latinos
Authors: Zheng Alan C , McKean‐Cowdin Roberta , Torres Mina , Varma Rohit , Jiang Xuejuan
Published: January 2025

Background

Recent studies have identified visual impairment as a potentially modifiable dementia risk factor. However, the underlying mechanism linking visual impairment and cognitive decline is still not fully understood. Additionally, there has been a dearth of research focusing on Latinos.

Method

Data were obtained from the Los Angeles Latino Eye Study (LALES), a population‐based longitudinal study of Mexican Americans aged 40 and above. The study performed comprehensive eye examination. Self‐reported vision‐related functioning was assessed using the National Eye Institute Visual Function Questionnaire (NEI‐VFQ‐25). Vision data were collected from the baseline visit, while the cognition data were obtained from the 8‐year follow up visit using the Cognitive Abilities Screening Instrument‐Short (CASI‐S) form. Multivariable linear regression models were used to assess the association with cognition. We explored the mediation effect of vision‐related health domains, such as driving difficulty, dependency, social function, and mental health. All analyses were conducted in R program.

Result

A total of 3904 participants had valid vision and cognition data available for analyses. Visual acuity was not associated with CASI‐S score (P = 0.27) after adjusting for age, education level, and sex. However, greater visual field loss at baseline had a dose‐dependent association with lower CASI‐S score (P trend<0.001). Compared with individuals without visual field loss (mean deviation of ≥‐2 decibels [dB]), those with mild (‐6 dB ≤ to ←2dB), moderate (‐12dB ≤ to ←6dB), and severe (←12dB) loss demonstrated CASI‐S scores 0.45, 0.87, and 1.85 lower, respectively (Ps<0.001). With regards to individual vision disorders, such as cataracts, age‐related maculopathy, and diabetic retinopathy, no significant associations with CASI‐S scores were observed after adjusting for visual field loss, except for open‐angle glaucoma (β = ‐0.69, P = 0.022). Of the 10 vision‐related functioning indicators tested, driving difficulty had the largest mediatory effect. Notably, vision‐related driving difficulty was found to mediate 15.8% of the relationship between visual field loss and CASI‐S score, and social functioning accounted for 5.4%.

Conclusion

In a cohort of community‐dwelling older Latinos, we found that visual field loss is associated with cognitive impairment. Vision‐related driving difficulty was identified as a more important mediator than social functioning, dependency, and mental health.
Association of retirement with MRI markers of vascular injury and neurodegeneration in a diverse cohort: Findings from KHANDLE and STAR
Authors: Chen Nancy X , Lor Yi , DeCarli Charles S. , Barnes Lisa L. , Gilsanz Paola , George Kristen M. , Maillard Pauline , Mayeda Elizabeth Rose , Glymour M. Maria , Whitmer Rachel A.
Published: January 2025

Background

Prior research suggests that early retirement is associated with cognitive decline, but mechanisms are unknown. We investigated whether retirement is associated with MRI biomarkers of neurodegeneration and vascular injury in two diverse cohorts of adults ages 65+.

Methods

The Kaiser Healthy Aging and Diverse Life Experiences and the Study of Healthy Aging in African Americans are harmonized longitudinal cohorts of racially/ethnically diverse adults who are long‐term Kaiser Permanente Northern California members. We included adults 65+ years and categorized baseline retirement status (retired vs not retired). Regional brain volumes and white matter (WM) integrity were measured using 3T MRI among a random subset of the harmonized cohorts. Hippocampal volume (cm3), lateral ventricle volume (cm3), third ventricle volume (cm3), and log‐WM hyperintensities (log‐WMH) (cm3) were normalized on intracranial volume and age at scan. We also examined free water fraction (FW) and fractional anisotropy (FA) normalized at age at scan. Linear regression models estimated associations of retirement status with regional brain volumes and WM integrity. All models adjusted for gender, race/ethnicity, and education. Sensitivity analyses examined retirement categorized as 1) retired before age 65, 2) retired at age 65+, and 3) not retired.

Results

Participants’ (N = 363) mean age at scan was 77.5 (SD = 6.3), 56% were women, 50% had < college education, 24% identified as non‐Latino White, 91% were retired, of whom 82% retired before age 65 (Table 1). Retirement was not associated with MRI, whereas timing of retirement was. Adults who retired at 65+ had smaller hippocampal volume (b = ‐0.17, 95%CI ‐0.35,0.00), compared to those who retired before 65 (Table 2). Adults who retired at 65+ also had larger ventricular volumes (lateral ventricle: b = 5.06, 95%CI 0.93,9.19; third ventricle: b = 0.16, 95%CI 0.05,0.27) and higher FW (b = 0.005, 95%CI 0.000,0.01) than those who retired before 65 (Table 2).

Conclusion

Retiring at 65+ appeared detrimental to late‐life brain health in this diverse cohort of older adults, contrary to the cognitive decline literature. Future studies should explore factors contributing to the impact of later retirement on late‐life brain health.
Relationship between perivascular spaces and white matter hyperintensities in Alzheimer’s disease
Authors: Tang Serena , Tosun Duygu
Published: January 2025

Background

There is increasing evidence that cerebrovascular and glymphatic‐related deficits may precede and influence AD pathology. In this study, we investigated the relationship between enlarged perivascular spaces (EPVS) as a measure of glymphatic clearance integrity and white matter hyperintensities (WMH) as a measure of cerebrovascular integrity.

Method

Participants from ADNI‐3 (N = 1026) who were diagnosed as cognitively unimpaired (CU) (n = 567), mild cognitively impaired (MCI) (n = 345), or AD dementia (n = 114) were included (Figure 2). Up to five visits (approximately one visit per year) were recorded for each participant. EPVS were segmented and quantified on 3T T1‐weighted images using a novel fully‐automated algorithm, while WMH were segmented on FLAIR images using the Lesion Segmentation Toolbox (Figure 1). Pairwise comparisons between EPVS and WMH metrics were tested using Mann‐Whitney U‐tests. A GLM was used to model the relationship between EPVS and WMH in each diagnostic group. LMMs were used to determine whether changes in WMH influenced EPVS changes between the groups. Age and sex were included as potential confounding factors, and data were transformed as needed.

Result

In the cross‐sectional analysis, the AD group had more EPVS count, volume, and WMH volume than the CU and MCI groups (Figure 2). A significant association was found between EPVS metrics and WMH volume (R‐squared = 0.4; p<0.001; Figure 3). MCI compared to CU presented a stronger association between EPVS count and WMH volume (p = 0.02). In the longitudinal analysis, EPVS count and volume significantly increased with time, however, no differences were found between groups (Figure 2). Changes in EPVS count were associated with changes in WMH volume, however, this association did not significantly differ between groups (Figure 2).

Conclusion

We found that the association between measures of EPVS and WMH varies with different clinical stages of AD. This suggests that cerebrovascular and glymphatic‐related deficits may interact and exacerbate in all clinical stages with varying degrees and timing. Untangling the relationship between these pathophysiological changes and their influence on AD progression will further our understanding of the etiology of AD and highlight potential modifiable risk factors.
Association of Blood‐based DNA Methylation Markers with Cognition in Alzheimer’s Disease
Authors: Ng Kok Pin , Wang Ling , Dorajoo Rajkumar , Loh Marie , Ng Adeline Su Lyn , Hameed Shahul , Ting Simon Kang Seng , Kandiah Nagaendran , Liu Jianjun
Published: January 2025

Background

DNA methylation is an epigenetic change characterized by the addition of methyl groups to DNA, typically in the cytosine‐ phosphate‐guanine (CpG) nucleotide base pairings. Given that DNA methylation alterations are shown to be associated with Alzheimer’s Disease (AD) pathology in autopsied brains, blood‐based DNA methylation changes are increasingly being studied as a potential peripheral biomarker for AD. However, the role of blood‐based DNA methylation changes as a marker of cognitive impairment in AD remains unclear. In this study, we aim to identify the blood‐based DNA methylation signatures that are associated with worse cognitive performance and brain atrophy in AD individuals.

Methods

277 AD patients of Chinese ethnicity were recruited from a tertiary memory clinic (National Neuroscience Institute, Singapore). All participants underwent the Montreal Cognitive Assessment (MoCA) test and blood collection. CpG probe methylation was measured using the Illumina Infinium MethylationEPIC BeadChip. A subset of participants (n = 218, 78.7%) underwent MRI brain scan and medial temporal lobe atrophy (MTA) score was measured visually. Regression analysis evaluated the associations of each methylation marker with MoCA and MTA scores, corrected for age, gender and years of education.

Results

We identified two methylation markers (cg11103255 and cg10845701) to be associated with MoCA scores. Hypermethymation at the cg11103255 site was associated with lower MoCA scores (p = 2.86e‐07) while hypomethylation at the cg10845701 site was associated with lower MoCA scores (p = 8.18e‐07). Furthermore, hypomethylation at the cg10845701 site was associated with higher MTA scores. cg11103255 is mapped to the Microtubule Crosslinking Factor 1 (MTCL1) gene, a protein coding gene that enables microtubule binding activity. cg10845701 is mapped to the Solute Carrier Family 44 Member 5 (SLC44A5) gene, a protein coding gene that enables transmembrane transporter activity. While the role of MTCL1 gene on AD is not known, SLC44A5 was previously reported to be associated with brain atrophy in an AD GWAS.

Conclusion

Our findings demonstrate the potential role of blood‐based DNA methylation markers as measures of worse cognitive performance among AD. Further longitudinal studies in an independent cohort are needed to validate these findings.
Biological characterization and clinical application of tRF in cognitive impairment associated with white matter injury after chronic hypoperfusion
Authors: Fang Min
Published: January 2025

Background

Recent studies have revealed that tRNA‐derived fragments(tRFs)are closely associated with the immunoinflammatory process of brain injury after stroke.

Method

Firstly, 3 patients with WMI and the same number of healthy volunteers' peripheral blood in the control group were collected. EVS in the subjects' peripheral plasma was isolated and purified, and tRFs high‐throughput sequencing was performed. Subsequently, we verified significant differential expression of tRFs in sera from different oxygen glucose deprivation (OGD) cell lines and WMI patients. Next, possible tRF‐bound proteins were detected by RNA pull down combined with LC‐MS/MS targeted quantitative mass spectrometry. Finally, we collected serum samples from patients with WMI, including 20 each of cognitively normal and WMI‐associated cognitive impairment patients, analysed the relationship between significantly different tRFs and clinical indicators, and analysed the diagnostic efficacy of tRFs for WML‐associated cognitive impairment by ROC curves.

Result

1. The expression level of 3'Val‐TAC tRF was significantly higher in the serum of patients with WMI compared with controls; 2. 3'Val‐TAC tRF was not only significantly up‐regulated in OGD neuronal cells, but also was significantly highly expressed in the sera of patients with WMI; 3. 3'Val‐TAC tRF originated from mitochondrial tRNA, which belongs to tRF‐3b. A total of 86 proteins bound to the 3'Val‐TAC tRF compared to the negative control. Given the 87% peptide coverage of USP30 in the mass spectrometry results, it is highly suggestive that 3'Val‐TAC tRF is able to bind to USP30;4. The expression level of 3'Val‐TAC tRF was negatively correlated with the MoCA score (r = 0.376, P = 0.017). ROC curve analysis showed that 3'Val‐TAC tRF expression level had a high diagnostic value for WMI‐related cognitive impairment (AUC 0.835, P<0.001).

Conclusion

3'Val‐TAC tRF should be a small RNA that is highly expressed in WMI patients and induces WMI‐related cognitive impairment.
Investigation of amyloid‐beta 42 levels in human nasal discharge fluid from healthy and Alzheimer’s discovers diagnostic values
Authors: Jung Da Hae , Son Gowoon , Wang Shengmin , Lim Hyun Kook , Moon Cheil
Published: January 2025

Background

Alzheimer’s disease (AD) therapy requires timely and accurate diagnosis for prompt drug intervention, emphasizing the need for a more accessible biomarker screening test. Previous studies identified higher expression of oligomeric Aβ in AD patients, however, the quantitative measurements of nasal Aβ42 levels of the full AD continuum remain unknown.

Method

We collected nasal discharge samples from 161 subjects who underwent neuropsychological battery tests and amyloid‐PET and nasal Aβ42 levels were measured via enzyme‐linked immunosorbent assay (ELISA).

Result

Our results revealed that the second‐highest quartile (Q3) group of nasal Aβ42 had the majority of patients with AD diagnosis, and those in the Q3 group exhibited the most impaired cognitive function with a strong significance. Nasal Aβ42 levels were also associated with brain amyloid PET results and increased risk of developing AD.

Conclusion

Our findings suggest that nasal Aβ42 is a promising biomarker for AD diagnosis and risk assessment.
Ffar4 regulates inflammatory oxylipin balance in the brain
Authors: Murphy Katherine A , Harsch Brian A , Shearer Gregory C , O'Connell Timothy D
Published: January 2025

Background

Oxylipins are oxygenated fatty acid (FA) metabolites that are important mediators of inflammation. Neuroinflammation is a hallmark of Alzheimer’s disease (AD), and brains of AD patients contain more pro‐inflammatory and less anti‐inflammatory oxylipins compared to healthy controls. Free fatty acid receptor 4 (Ffar4) is a G‐protein coupled receptor for medium and long‐chain FAs, including, but not limited to, omega‐3‐polyunsaturated FAs. Ffar4 is expressed in a variety of tissues, including neurons, astrocytes, and microglia. Ffar4 signaling produces anti‐inflammatory and pro‐resolving oxylipins that can attenuate inflammation, reduce oxidative stress, and prevent apoptosis. This suggests that targeting Ffar4 signaling will preserve a more anti‐inflammatory/pro‐resolving oxylipin profile and potentially improve outcomes.

Method

We accessed a biorepository that contains de‐identified electronic health records linked to patient genetic data for associations with Ffar4 polymorphisms and health reports. APPSAA knock‐in (KI) mice (Jackson, strain #034711) were used to model AD. Brain regions from wild‐type (WT), APPSAA KI, Ffar4 knockout (KO), and APPSAA KI/Ffar4KO mice underwent LC/MS/MS analysis to detect oxylipins. RAW264.7 cells were treated with the Ffar4 agonist, TUG‐891, and subjected to LC/MS/MS to detect oxylipins.

Result

In humans, we discovered that the Ffar4 inactivating polymorphism, R270H, was associated with an increased risk of AD and memory loss. We observed pronounced alterations in the oxylipin content of brain tissues, with a reduction in anti‐inflammatory oxylipins in Ffar4KO brains compared to WT. APPSAA KI mice had an increase in pro‐inflammatory oxylipins that was exacerbated by loss of Ffar4. Ffar4 activation with a synthetic agonist in a macrophage cell line resulted in increased production of anti‐inflammatory oxylipins, while decreasing pro‐inflammatory oxylipins. These data indicate that Ffar4 mediates oxylipin production and Ffar4 activation promotes the production of anti‐inflammatory and pro‐resolving oxylipins.

Conclusion

The anti‐inflammatory properties of Ffar4 make it an intriguing target for diseases that result from chronic inflammation, such as AD. Our data show that Ffar4 can modulate the inflammatory tissue environment by controlling oxylipin synthesis. Given that Ffar4 attenuates inflammation, activating Ffar4 could mitigate AD‐related neuroinflammation. By targeting Ffar4 it might be possible to redirect the immune response, alter oxylipin profiles, and improved prognosis.
Sabirnetug (ACU193) Lowers CSF Levels of Synaptic Biomarkers in INTERCEPT‐AD Phase 1 Study in Early AD
Authors: Cline Erika N , Johnson Elizabeth , Sundell Karen , Antwi‐Berko Daniel , Koel‐Simmerlink Marleen JA , Teunissen Charlotte , Siemers Eric , Zhang Hao , Hyland Maddelyn , Sethuraman Gopalan , Vanderstichele Hugo , Kaplow June , Dean Robert A , Jerecic Jasna
Published: January 2025

Background

Sabirnetug (ACU193) is a humanized IgG2 antibody targeting soluble, synaptotoxic amyloid β oligomers (AβOs). AβOs accumulate in Alzheimer’s disease (AD) and induce pre‐ and post‐synaptic changes, resulting in dendritic spine loss, neuronal degeneration, and release of synaptic proteins into the CSF. Recently, we reported that three administrations of sabirnetug in an early AD population (INTERCEPT‐AD Phase 1 study, NCT04931459) significantly lowered CSF levels of the post‐synaptic protein neurogranin as well as pTau181. Here, we present data on additional CSF synaptic biomarkers and AD plasma biomarkers measured in INTERCEPT‐AD.

Method

INTERCEPT‐AD was a randomized, placebo‐controlled study with two parts: single ascending dose (SAD) randomized in a 6:2 ratio to sabirnetug (2, 10, 25, 60 mg/kg) or placebo and multiple ascending dose (MAD) randomized 8:2 to sabirnetug (three administrations at 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) or placebo. Biomarkers were measured blinded in CSF and EDTA‐plasma, before and after drug administration, by Amsterdam UMC.

Result

CSF levels of vesicle‐associated membrane protein 2 (VAMP2), a protein involved in pre‐ and post‐synaptic vesicle trafficking, were significantly normalized (lowered) in sabirnetug treated participants relative to placebo in all three MAD cohorts. Levels of the pre‐synaptic protein neuronal pentraxin 2 (NPTX2), which acts on post‐synaptic excitatory synapses, regulates complement activity, and lowers with cognitive decline, trended lower with sabirnetug than placebo. Plasma levels of GFAP, pTau181, and pTau217 trended towards normalization (lowering) of AD‐dependent changes in the 60 mg/kg Q4W cohort.

Conclusion

In INTERCEPT‐AD, three administrations of sabirnetug lowered CSF levels of both pre‐ and post‐synaptic proteins, consistent with sabirnetug’s proposed mechanism of action to inhibit AβO synaptic binding. VAMP2 appeared most sensitive to sabirnetug in this study, lowering significantly in all three MAD cohorts; other markers previously reported to have a statistically significant response to sabirnetug ‐ neurogranin and pTau181 ‐ did so at the highest dose. No statistically significant changes in plasma biomarkers were observed in this short study. Long‐term changes in biomarker levels and their relationship to clinical efficacy will be evaluated in the 18‐month ALTITUDE‐AD phase 2 study of sabirnetug beginning in the first half of 2024.
Tau‐related cortical thinning is concentrated in sulcal depths
Authors: Maboudian Samira A. , Parker Benjamin J. , Weiner Kevin S. , Jagust William J.
Published: January 2025

Background

Prior studies suggest sulci are more vulnerable to age‐ and Alzheimer’s disease (AD)‐related atrophy than gyri, but the pattern of regional vulnerability to tau pathology is incompletely understood. We performed this study to determine whether tau‐related atrophy preferentially affects sulci and specifically the early‐developing, deepest portions of sulci, which have been shown to be connectivity hubs.

Methods

We used MRI, amyloid and tau PET scans from 809 Alzheimer’s Disease Neuroimaging Initiative participants: 92 with AD, 249 with MCI, 468 cognitively normal. Correlation between vertex‐wise cortical thickness and whole‐brain tau was performed using FreeSurfer’s GLM pipeline. Following cluster‐wise multiple comparisons correction, an ROI of significant clusters was generated (“clusters;” Fig. 1). Overlap between the clusters and whole‐brain sulcal or gyral ROIs was calculated using the dice coefficient. We then generated labels of the deepest 5% of points in the sulcal ROI or the remaining 95%, as well as the deepest 5% of points of the superior temporal sulcus (STS) and collateral sulcus (COS, chosen as a control), and calculated their overlap with the clusters. For all comparisons we used mixed‐effects ANOVAs to examine the effects of ROI (sulcal/gyral, deeper/shallower points, STS/COS) and hemisphere (left/right) on the amount of overlap with the clusters.

Results

Clusters of significant negative tau‐thickness correlation overlap significantly (p<.0001) more with sulci than gyri (Fig. 2B). This overlap is also significantly (p<.0001) greater in the deepest sulcal points compared to the rest of the sulci (Fig. 2C). This effect was greater in the STS than COS (Fig. 3). There is a right hemisphere (RH) bias in this overlap, which is stronger for the STS.

Conclusions

We find that tau‐related thinning occurs mostly in sulci, and particularly in sulcal depths. This overlap is particularly striking within the STS, a brain region particularly vulnerable to AD pathology and deeper in the RH. These results show greater specificity for sulcal vulnerability in aging and AD, particularly in the deepest parts of sulci. This anatomical specificity may underlie the profound effects of tau deposition on cognition.
Behavioral deficits in an Alzheimer’s Disease mouse model containing both APOE4 and Tau
Authors: Booth Aaron , Neff Samuel , de Lillo Vincenzo , Campitell John , Marediya Amrah , Gray Samantha , Flinn Jane
Published: January 2025

Background

Alzheimer’s Disease (AD) is a neurological disease characterized by two major biological components; amyloid beta (abeta) and hyperphosphorylated tau. Research suggests that the hyperphosphorylated tau aggregation seen in late‐onset AD is characterized by two independent pathways, one caused by abeta buildup, and the other potentially caused by Apolipoprotein 4 (APOE4). However, research examining the relationship between hyperphosphorylated tau and APOE4 in the absence of abeta has been both inconsistent and lacks behavioral results. Likewise, research suggests that zinc exacerbates the effects of both tau and abeta in AD mouse models, however, there is limited research in how zinc interacts with APOE4.

Method

We analyzed 8 groups of mice; 4 genotypes (WT, APOE4, Tau, APOE4xTau), 2 treatment groups (lixit water, zinc water), none of which contained abeta. Behavioral tests were run at 3 and 6 months of age to examine activities of daily living (Nesting & Burrowing), anxiety & motor ability (Open Field), and spatial memory (Morris Water Maze).

Result

Initial results at 3 months indicate that Tau and APOE4xTau mice demonstrated impaired activities of daily living (Nesting; (p<.001), Burrowing (p<.001)), higher risk taking (p<.001), and impaired spatial memory (p<.001) compared to WT or APOE4 mice. APOE4 mice demonstrated improved spatial memory compared to WT; p<.001, and APOE4xTau mice demonstrated improved spatial memory compared to Tau; p<.001. However, APOE4 and APOE4xTau mice did not show differences in activities of daily living, nor anxiety compared to WT and Tau mice respectively. Additionally, Zinc did not significantly influence behavior at 3 months. Results will be re‐analyzed at 6 months of age, and brains will be analyzed for proteins of interest.

Conclusion

Our initial findings provide evidence that APOE4 enhances certain behaviors at 3 months of age. This is consistent with previous research that APOE4 may show beneficial effects at a young age in both humans and mouse models. Subsequent analysis at 6 months will determine whether these beneficial effects continue at an older age.
Project FRONTIER: a Cohort to Study Aging in Rural West Texas
Authors: Decourt Boris , Singer Jonathan , Molinar‐Lopez Veronica , Yin XiangLing , Neugebauer Volker
Published: January 2025

Background

In the past decades, the NIH has identified a large knowledge gap in the study of health and disease in diverse and underserved inhabitants. The most recent estimates (2020) indicate that rural dwellers represent 15‐20% of the total US population, but these individuals experience worse health status than urban counterparts. A major challenge to the study of health disparities in rural areas is the dearth of structured rural cohorts that can be used for scientific research purposes.

Method

Project FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) was initiated in 2006 as an epidemiological study to explore the natural course of chronic disease development and its impact on longitudinal cognitive, physical, social and interpersonal functioning in a multi‐ethnic adult sample from rural communities of West Texas.

Result

Currently, project FRONTIER is collecting data from Cochran, Bailey, Parmer, Hockley and Lubbock counties, with expansion to additional counties soon [update: Lamesa/Dawson county]. In recent years, the cohort has been utilized more for cognitive and Alzheimer’s disease research than other conditions, though we collected limited data and biospecimens. Thus, there is a huge opportunity to better characterize this cohort at the genetic and metabolic levels to gain large amounts of information on the aging processes in rural dwellers. The demographics of this cohort are: 1374 unique individuals, 66% female, 56% Hispanics, mean age of 58.9±12.2 years, 21% with a high school degree, and 23% with some college education. Although challenging, we are attempting longitudinal collections on this cohort. However, as our group is recruiting more experts on rural cohort research, we are currently implementing more rigorous protocols to collect accurate data and high quality biospecimens more frequently from this cohort.

Conclusion

Our Project FRONTIER cohort provides very informative data on dementia risk factors in rural dwellers. As we make progress, we intend to share these materials with the scientific community for the deep genotyping and phenotyping of our study participants.
Self‐reported sleep health characteristics may capture attention, memory, and global cognitive performance in older African‐Americans
Authors: Romain Stanley , White Payton G. , Fausto Bernadette A. , Gluck Mark A.
Published: January 2025

Background

Older African Americans bear a disproportionate burden of both sleep problems and cognitive dysfunction. Alarmingly, poorer sleep health may put an individual at higher risk of cognitive dysfunction. However, the relationship between sleep and cognition in older African Americans continues to be understudied. This study aimed to examine the relationship between subjective sleep health characteristics and cognitive function among older African Americans.

Method

62 older African American participants (mean age = 72.19; SD = 6.651; mean education = 14.28; SD = 6.651; 51 female; 11 male) from the Pathways to Healthy Aging in African Americans study completed a demographic questionnaire as well as cognitive assessments of attention, episodic memory, executive function, language, and global cognition. The following sleep health characteristics were derived from the Pittsburgh Sleep Quality Index: Subjective sleep quality; sleep latency; sleep duration; sleep disturbances; use of sleeping medications; daytime dysfunction; and global index score. Hierarchical linear regression analyses were employed to investigate the relationship between sleep health characteristics and cognitive function while controlling for age, sex, education, waist‐to‐hip ratio, and depressive symptomology.

Result

The relationship between subjective sleep quality and episodic memory (B = ‐1.715; p < 0.001); sleep disturbances and global cognition (B = ‐1.581; p = 0.020); sleep latency and global cognition (B = ‐1.033; p = .011); and sleep efficiency and attention (B = 0.249; p = 0.038) were significant before and after controlling for covariates. Overall, poorer sleep health across multiple characteristics was associated with worse cognitive function.

Conclusion

Self‐reported sleep disturbances and longer sleep latency appear to be tapping into poorer global cognition, whereas poorer subjective sleep quality and sleep efficiency are tapping into worse episodic memory and attention, respectively. These findings highlight the importance of assessing self‐reported sleep health in populations at higher risk for both sleep disorders and cognitive dysfunction.
Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans
Authors: Liu Hesong , Bas Brouwers , He Yang , Liu Hailan , Yin Na , Yang yongjie , Yu Meng , Wang Chunmei , Xu Yong
Published: January 2025

Background

A decline in memory is a hallmark of Alzheimer’s disease (AD). Experiments in rodents and post‐mortem studies in humans with AD suggest that serotonin (5‐HT) plays a role in memory, but the molecular and neural mechanisms mediating its effects are unknown.

Method

100,000 individuals in UK Biobank were studied for the role of serotonin 2C receptor (5‐HT2CR) in the regulation of memory. We examined both wild‐type (WT) and transgenic mice (F327L) expressing a human loss‐of‐function serotonin 2C receptor (HTR2C). Memory function was assessed using Radial Arm Water Maze test. Additionally, we conducted neural tracing by injecting retrograde viruses expressing GFP into the vCA1 of WT mice. We disrupted serotonin synthesis in vCA1‐projecting neurons using AAV‐Cre virus in Tph2‐CreER mice and deleted 5‐HT2CRs on vCA1 neurons in Htr2cflox/Y
mice. Furthermore, we evaluated the integrity of 5‐HT to vCA1 circuit using Tph2‐CreER/Rosa26‐LSL‐tdTOMATO/ AppNL‐G‐F
mice. Lastly, we explored the effects of lorcaserin, a selective 5‐HT2CR agonist, in AppNL‐G‐F
mice.

Result

Our findings revealed that a rare loss‐of‐function mutation in HTR2C significantly impaired short‐term memory in both humans and F327L mice. Neural tracing experiments demonstrated that midbrain serotonin neurons project to the vCA1 hippocampal region. Disruption of serotonin synthesis in vCA1‐projecting neurons and deletion of 5‐HT2CRs on vCA1 neurons led to memory impairment. Notably, the 5‐HT to vCA1 circuit was disrupted in AppNL‐G‐F
mice. However, lorcaserin corrected memory loss in a mouse model of amyloid pathology.

Conclusion

The 5‐HT to vCA1 circuit regulates working memory. By utilizing 5‐HT2CR agonists, we can potentially bypass the damages in this circuit and enhance memory function in AppNL‐G‐F
mice.
Digital marketing for increasing participant diversity in ADNI4 – early insights from initial rollout
Authors: Conti Catherine C. , Amaza Hannatu , Miller Melanie J. , Thao Mai Seng , Flenniken Derek , Kwang Winnie , Ashford Miriam T. , Fockler Juliet , Truran‐Sacrey Diana , Strong Joseph , Sorce Jennefer , Alaniz Roxanne , Weiner Michael W. , Okonkwo Ozioma C , Mindt Monica Rivera , Nosheny Rachel L.
Published: January 2025

Background

The Alzheimer’s Disease Neuroimaging Initiative (ADNI4), whose goal is to validate biomarkers for AD clinical trials, aims to increase participation of individuals from historically underrepresented populations (URPs) so results are more generalizable. ADNI uses digital marketing to recruit and enroll older adults into a digital cohort, for screening into in‐clinic ADNI. Challenges and insights from initial marketing efforts, including enrollment rates, local demographics, and effectiveness at enrolling URPs are presented.

Methods

We employed a culturally‐informed marketing approach developed in partnership with ADNI’s Community Scientific Partnership Board and marketing firm, including digital campaigns (Meta ads, websites, and emails) designed using themes aimed to resonate with Black and Latinx communities (solo, family, community; Fig. 1). Varying ads run simultaneously to compare effectiveness. Ads direct to study websites, registration pages, and consent to join a digital cohort. Ads run in geographies based on clinical site readiness to enroll participants.

Result

Most initial sites to utilize digital marketing (Universities of Kansas, Kentucky, and Mayo Clinic) were in areas of lower ethnocultural diversity compared to other ADNI sites (Table 1). Three months into recruitment, we shifted to optimizing ads in an area with higher ethnocultural diversity (UKentucky) to maximize data on highest enrolling ads (Tables 1&2). Additional digital recruitment began for sites in areas with higher ethnocultural diversity (UCSF, Wake Forest; Table 1). We subsequently saw a 317% increase in enrollment of Black older adults, with no significant improvement for other URPs (Fig. 1c). Following campaign launches (Butler, Georgetown) further supported our campaigns’ ability to enroll Black adults (Table 2). Initial results suggest “solo” and “community” themed ads yield highest enrollments in Black population campaigns. (Fig. 1b). Despite running in areas with large Latinx populations (UCLA), ADNI4’s Latinx campaigns were generally not obtaining enrollment rates comparable to our Black population campaigns (Tables 1&2).

Conclusion

Our early successes in recruitment of older Black adults (43% of digital cohort enrollments) strongly demonstrates the feasibility of culturally‐informed, site‐specific digital marketing to specific URPs for AD clinical studies. More work is needed to increase inclusion of Latinx adults (7% of enrollments) and other URPs in ADNI4’s digital cohort.
Amyloid‐ß oligomer Aß*56 is associated with Alzheimer’s dementia independently of amyloid pathology
Authors: Liu Peng , Lapcinski Ian , Ashe Karen
Published: January 2025

Background

A current hypothesis of the etiology of Alzheimer’s disease (AD) suggests that soluble amyloid‐ß (Aß) oligomers (Aßo) play a more significant role than amyloid plaques. Among the numerous Aßo discovered in the brain, Aß*56 has been shown to be associated with aging and cognitive dysfunction in mice, dogs, and humans, and impair memory in rodents. Evidence from our recent study indicates that Aß*56 produced from Tg2576 mice modeling AD is a ∼56‐kDa, SDS‐stable, A11 (anti‐amyloid oligomer antibody)‐reactive, water‐soluble oligomer that impairs memory in healthy wild‐type mice; and that there exist at least two Aß*56 variants—Aß(40)*56 and Aß(42)*56—that contain canonical Aß(1‐40) and Aß(1‐42), respectively, in AD mouse models. In addition, Aß*56 appears prior to the formation of amyloid plaques in Tg2576 mice, suggesting that the biogenesis of Aß*56 is independent on plaques. Here, we extend the characterization of this non‐plaque‐dependent oligomer to human AD cases and investigate the relationship between Aß*56 and cognitive dysfunction in AD dementia.

Method

We analyzed AD‐affected, inferior temporal gyrus (ITG) postmortem specimens from de‐identified elderly individuals enrolled in the Religious Orders Study/Memory and Aging Project. This cohort consisted of cognitively normal (CN) individuals, individuals with mild cognitive impairment (MCI), and individuals with AD dementia (N = 19‐23 per group) that were age‐matched, sex‐balanced, and contained comparable amyloid plaque loads in the ITG. Using immunoprecipitation/western blotting coupled with densitometry‐based semi‐quantitative analysis, we measured levels of Aß(40)*56 and Aß(42)*56. We then compared levels of Aß*56 variants between different clinical diagnoses and correlated them to cognitive assessments.

Result

We showed that both levels of Aß(40)*56 and Aß(42)*56 are elevated in individuals with AD dementia compared to CN individuals and individuals with MCI. In addition, we showed that levels of Aß*56 variants are correlated to mini‐mental state examination scores and severity of impairment in global cognitive function, episodic memory, and semantic memory, but not working memory.

Conclusion

Our data suggest an association between Aß*56 to AD dementia in elderly human brains that is independent of amyloid pathology. Such findings support the use of Aß*56 as a molecular marker for AD diagnosis.
Clinical validation of the Eli Lilly SPX P‐tau217 blood‐based immunoassay as a laboratory‐developed test (LDT)
Authors: Hodsdon Michael , Abel Adam , Chambers Antonio , Lu Ming , Morris Amanda , Pontecorvo Michael , Reiske Heinz , Collins Emily C. , Mintun Mark , Schade Andrew E. , Beck Rose C.
Published: January 2025

Background

Blood‐based biomarkers have significant potential to aid in the diagnosis of Alzheimer’s disease (AD), providing a more accessible option than cerebrospinal fluid testing or positron emission tomography (PET). This study evaluated performance of a plasma P‐tau217 immunoassay for identifying AD pathology as detected by amyloid or tau PET.

Method

Plasma samples from screened participants from the donanemab Phase 3 trial (NCT04437511) were analyzed using a chemiluminescent immunoassay for plasma P‐tau217 on the Quanterix SP‐X platform. A Receiver Operating Characteristic (ROC) curve explored the relationship between plasma P‐tau217 values and positive amyloid PET (Aβ+), defined as 24.1 Centiloid (CL). A two‐threshold approach was used to propose P‐tau217 cut‐points that result in sensitivity and specificity each ≥90%; <20% of cases falling between the two cut‐off values (classified as indeterminate). Similar evaluation was performed for P‐tau217 against tau PET in a subset of participants.

Result

Plasma samples from 2071 participants (mean age 73.1 [SD = 6.4 years], Mini Mental State Examination mean 24.8 [SD = 2.5], 53.3% female, 50.7% APOE ε4 carriers, 65% Aβ+) were examined. The area under the curve (AUC) for the ROC of plasma P‐tau217 identifying Aβ+ participants was 0.915 (Figure 1). Stratification of P‐tau217 concentrations into three levels using two P‐tau217 cut‐points resulted in an upper‐level group with 95% positive predictive value (PPV) for Aβ+ and a low‐ level group with 84% negative predictive value (NPV) for Aβ‐, with a false positive rate of 7.5% and a false negative rate of 7.3% (Table 1). The remaining indeterminate group represented 18% of participant samples, of which 60% were Aβ+. Within this cohort, 359 participants had available tau PET results. Preliminary analysis revealed 93% ROC AUC for P‐tau217 against tau PET visual read (Figure 2).

Conclusion

The presented plasma P‐tau217 assay has high concordance with amyloid PET for identification of amyloid pathology, indicating its potential utility in the diagnostic workup of AD. Preliminary analysis demonstrated a relationship between plasma P‐tau217 and tau PET; however, additional work is needed to establish the assay’s diagnostic performance for tau pathology.
The power of cognitive rehabilitation in Alzheimer’s disease ‐A Systematic review and meta analysis
Authors: Ahmad Logien Abuelgasim , Khalifa Mostafa A. , Hashad Mohammed Alaa
Published: January 2025

Background

Alzheimer’s disease (AD) is a challenging condition that forbids individuals of their memories and abilities to carry out their daily functioning. In the research for solutions, cognitive rehabilitation (CR) has emerged as a promising intervention to help individuals with Alzheimer’s disease improve their daily activities. Despite its potential benefits, the effectiveness of clinical trials (CT) remains a mystery, inconclusive further investigation. In this study, we aim to unravel the potential of CR in enhancing the lives of individuals with AD, with a focus on evaluating whether CR leads to meaningful enhancements in daily functioning as assessed by validated measures.

Method

Our research is based on the PRISMA guidelines, and to identify relevant studies, a comprehensive search was conducted across multiple databases, including PubMed, Cochrane Library, Scopus, and Web of Science Keywords were used for searching, from inception to 2024. The research was limited to randomized controlled trials examining the effects of cognitive rehabilitation, including a total of 14 clinical trial articles, excluding studies focusing on cognitive stimulation, cognitive training, or cognitive intervention. Non‐English language articles and populations with diagnoses of other conditions are also excluded.

Result

Our systematic reviews yielded a total of 1919 studies. After removing 287 duplicate records, we screened the title and abstract of 1877 papers, excluding 1835. Then, we proceeded to review the full text of 42 articles. 14 of them met the inclusion criteria. A pilot study of four papers is underway, and its results are expected to add to the existing evidence on the effectiveness of cognitive rehabilitation in AD. The meta‐analysis results for other domains of cognitive functions were not statistically complete yet. Further research is warranted to confirm these findings.

Conclusion

Cognitive rehabilitation demonstrated significant positive effects on quality of life and occupational performance in patients with Alzheimer’s disease. Further, research is needed to investigate the efficiency of the intervention in specific domains to enhance understanding of Alzheimer’s disease management.
Exploring the impact of a co‐created dementia awareness session on dementia knowledge and attitudes in culturally diverse carers: a cross‐sectional analysis
Authors: Manimaran Manjari , Caballero Gabriela E , Shatnawi Eman , Tsouros Emy , Tran Mai , Jasim Nibras , Nguyen An , Cope Emily , Chan Sonia , Siette Joyce , Dadich Ann , DiGiacomo Michelle , Steiner‐Lim Genevieve Z , Karamacoska Diana
Published: January 2025

Background

Many carers of people living with dementia display misperceptions and negative attitudes about dementia due to limited education. This stigma can impact care and the accessibility of appropriate support services. Culturally diverse people living with dementia and their carers remain underserviced and lack culturally inclusive resources despite having specialised dementia needs. Our study aimed to explore the impact of a co‐created dementia awareness‐raising session on the dementia knowledge and attitudes of culturally and linguistically diverse carers.

Method

A quasi‐experimental cross‐sectional study was conducted in South‐Western Sydney, Australia, targeting English, Arabic, Vietnamese, Cantonese, Mandarin, and Greek‐speaking carers. A survey comprising 10 items from the dementia knowledge assessment scale (DKAS) and 15 items from the dementia attitudes scale (DAS) was administered to carers who attended a two‐hour awareness‐raising session co‐created with community stakeholders (intervention group) and online to carers who self‐reported having no previous dementia education (comparison group). The surveys and information sessions were translated and conducted in‐language by bilingual educators. Mann‐Whitney U tests were used to compare the mean rank differences between the two groups on each scale item.

Results

For 8 of 10 DKAS items that assessed knowledge of the risk factors, presentation, and management of dementia, the intervention group (n = 42) had a higher proportion of correct answers relative to the comparison group (n = 74) (all p ≤.041). For 3 of 15 DAS items, regarding self‐perceived knowledge and awareness of local services, the intervention group (n = 188) displayed more positive attitudes relative to the comparison group (n = 427) (all p <.001).

Conclusion

Our co‐created multilingual dementia education initiative was effective in supporting dementia knowledge and awareness of local services among carers. However, the single session was likely insufficient to modify attitudes towards people living with dementia. The observational design used limits our understanding of baseline levels of knowledge and attitudes and thus the impact of this initiative. Future pre/post‐test experimental research should examine the improvement of dementia knowledge and attitudes with longer‐term carer‐specific education.
Transcriptomic similarities in the brain of Alzheimer’s disease and COVID‐19 patients
Authors: de Mello Guilherme Bastos , Carello‐Collar Giovanna , de Souza Débora Guerini , de Bastiani Marco Antônio , Zimmer Eduardo R.
Published: January 2025

Background

Neurological symptoms, such as the lack of concentration, memory impairment and cognitive dysfunction are among the main complaints of COVID‐19 patients and seem to overlap with some of the Alzheimer’s disease (AD) symptoms. However, whether COVID‐19 and AD share a molecular signature is yet unclear. Thus, we aimed to explore transcriptomic similarities in the brains of COVID‐19 and AD individuals.

Method

We obtained frontal cortex transcriptomics datasets of COVID‐19 and AD from the Gene Expression Omnibus. Demographic characteristics of included individuals are reported in Table 1. Differentially expressed genes (DEGs) of COVID‐19 or AD versus controls were identified using the R statistical environment (FDR‐adjusted p‐value <0.05). Functional enrichment analyses (FEA) were accomplished to identify similar signatures considering the overlapped DEGs found between these two conditions.

Result

We identified 6,533 DEGs in COVID‐19 brains and 5,592 in AD brains. We found a striking overlap of 2,789 DEGs between these pathologies (Figure 1). Considering the DEGs in common, cluster observation suggests that COVID‐19 and AD share similar enriched processes, such as “central nervous system differentiation and development”, “signal release from synapse and neurotransmitter secretion” and “cognition, behavior, learning and memory” (Table 2).

Conclusion

Our results highlight core molecular programs shared by COVID‐19 and AD in the frontal cortex. These similarities may contribute to understanding the pathogenesis and the clinical course of COVID‐19 neurologic manifestations. These findings highlight the need for a careful evaluation of COVID‐19 survivors still presenting with neurological symptoms, which could be at high risk of developing AD.