bluuebunny/crossref_metadata_2025 huggingface dataset:
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes
Authors: Tsai Li‐Huei , Akay Leyla A , Blanchard Joel , Von Maydell Djuna K , Kellis Manolis , Bennett David A. A , Davila Jose
Published: December 2023

Background

APOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD), yet the cellular and molecular mechanisms by which APOE4 contributes to AD risk remain largely unknown

Method

We performed single‐nuclear RNAsequencing from the prefrontal cortex (Brodmann’s Area 10) of thirty‐two individuals, 12 APOE3/3 and 12 APOE3/4 carriers each, and one subgroup with 8 APOE4/4 carriers, and validated hypotheses using mouse models and patient‐derived iPSC lines.

Result

Differential expression and pathway analysis revealed that APOE4 is strongly associated with dysregulation of cholesterol homeostasis across multiple cell types, with oligodendrocytes being the most impacted. Strikingly, in human and mouse brains, APOE4 oligodendrocytes contained aberrant intracellular accumulations of cholesterol, whereas in non‐carriers, cholesterol preferentially localized to the oligodendrocyte cell membrane along myelinated neuronal tracts. Mass‐spectrometry‐based lipidomic analysis further revealed that APOE4 oligodendrocytes and APOE4 human post‐mortem brain tissue had elevated levels of cholesteryl esters, associated with intracellular storage of cholesterol as lipid droplets. Cholesterol transport and bioavailability are rate‐limiting steps in axonal myelination. Consistent with this, we discovered both APOE4 human and mouse brains were hypomyelinated relative to non‐carriers. We found that a small molecule known to facilitate cholesterol transport reduced cholesterol accumulation in APOE4 oligodendrocytes, increased axonal myelination, and improved memory in APOE4 mice.

Conclusion

These results provide a transcriptional atlas of cell‐type specific APOE4 effects in the human brain. Our results demonstrate that cholesterol homeostasis in oligodendrocytes is highly dysregulated in APOE4 oligodendrocytes and identify hypomyelination as a key APOE4‐associated phenotype. Collectively, these data establish a functional link between APOE4, cholesterol homeostasis, and myelination that presents new therapeutic opportunities for Alzheimer’s disease.
Association between metabolic syndrome and incident dementia: a prospective population‐based cohort study of UK Biobank participants
Authors: Qureshi Danial , Allen Naomi , Kuzma Elzbieta , Littlejohns Thomas J
Published: December 2023

Background

Globally, the prevalence of metabolic syndrome (MetS) is on the rise. Several studies indicate a potential relationship between MetS and dementia risk, however, findings remain inconclusive. We sought to investigate the association between MetS and risk of incident dementia, and further examine variations by follow‐up length, number of MetS components, and genetic risk for dementia.

Methods

Participants were selected from the UK Biobank, a prospective population‐based cohort study of half a million individuals aged 40‐69 years recruited between 2006‐2010. MetS at baseline was defined as the presence of at least three of the following five components, as per the 2009 Harmonized Criteria: elevated waist‐circumference, triglycerides, blood‐pressure and fasting‐glucose levels, and reduced HDL‐cholesterol. Incident dementia cases were identified through hospital inpatient and death registry records. Cox proportional‐hazards models were used to investigate the association between MetS and incident dementia. Models were adjusted for age, sex, ethnicity, Townsend‐deprivation index, education, household income, smoking status, alcohol intake, physical activity, and Apolipoprotein‐E (APOE)‐ε4 carrier status.

Results

We identified 176,249 dementia‐free participants aged ≥60 years at baseline, among which 73,510 (41.7%) had MetS. Over 15 years of follow‐up (median: 12.3), 5,255 participants developed dementia. MetS was associated with a 14% increased risk of developing dementia (Fully Adjusted Hazard‐Ratio [HR]: 1.14, 95% Confidence‐Interval [CI]: 1.08, 1.21), compared to no MetS. Associations were evident only among those with ≥5 years of follow‐up (e.g., ≥10 years of follow‐up, HR: 1.18, 95%CI: 1.09, 1.28). Only the presence of four (HR: 1.23, 95%CI: 1.06, 1.42) or five (HR: 1.57, 95%CI: 1.34, 1.83) MetS components was significantly associated with an increased risk of dementia, compared to zero components. There was a statistically significant interaction (p <0.001) between MetS and APOE‐ε4. MetS was associated with dementia risk in APOE‐ε4 non‐carriers (HR: 1.28, 95%CI: 1.18, 1.39) but not in APOE‐ε4 carriers (HR: 1.04, 95%CI: 0.96, 1.12).

Conclusion

MetS was associated with an increased risk of incident dementia. This risk varied according to follow‐up length, number of MetS components present, and genetic risk for dementia. Early identification and management of MetS may help prevent or delay dementia onset.
CD147 associates cerebrovascular lesion with Aβ pathology in Alzheimer’s disease
Authors: Gao Feng , Zhan Yaxi , Wang Qiong , Dai Linbin , Shen Yong ,   China Aging and Neurodegenerative Initiative (CANDI) Consortium
Published: December 2023

Background

Cerebrovascular abnormality is recognized as a major contributor to Alzheimer’s disease (AD). However, how cerebrovascular damage accelerates Aβ production/deposition remains poorly defined. CD147, a transmembrane molecule mainly expressed in cerebral small vessels, modulates γ secretase function and Aβ production in vitro. The present study was to study whether CD147 associated cerebrovascular damage with the Aβ pathology in autopsied human brains with AD, and whether CD147 in the CSF was related with CSF Aβ AD patients from China Aging and Neurodegenerative Initiative (CANDI) cohort.

Method

Amounts of soluble CD147, membrane CD147 / Claudin‐5 / CD31 and insoluble Aβ43 /42 /40 from autopsied human brain tissue samples were assessed by ELISA, Luminex and MSD, respectively. In CANDI cohort, CSF Aβ40 and 42, CSF CD147, CSF Aβ43, and CSFAβ38 were measure with Simoa, Luminex, ELISA, and MSD, respectively. Linear regression models were used to evaluate the associations between CSF CD147 with cognitive decline (MMSE and cortical thickness), GFAP, NFL, Aβ burden (18F‐Flobetapir), and Aβ isoforms (Aβ43/42/40/38).

Result

In autopsied human AD brains, the lower soluble/membrane CD147 ratio was significantly associated with worse BBB integrity (lower Claudin‐5/CD31 ratio) and with higher levels of insoluble Aβ43 and Aβ42. In the CANDI cohort, lower CSF CD147 in AD patients was also significantly associated with higher level of Aβ burden. Interestingly, CSF CD147 show a stronger association with shorter Aβ isoforms (Aβ38 ≈ Aβ40 > Aβ42 > Aβ43). Decreasing CSF CD147 was significantly linked to worse cognitive function (MMSE and cortical thickness) and with higher levels of CSF GFAP and NFL. White matter hyperintensity was negatively significantly associated with CSF CD147.

Conclusion

Cerebrovascular damage may impair the release of CD147 from vessels, thereby further exacerbate Aβ pathology via shifting the production of Aβ from longer to shorter isoforms. The findings suggest that soluble CD147 links cerebrovascular damage and Aβ pathology and cerebrovascular CD147 could be a potential therapeutic target for AD.
Associations of self‐reported psychological stress with memory and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged adults
Authors: Franks Katherine H. , Bransby Lisa , Buckley Rachel F. , Yassi Nawaf , Chong Trevor T.‐J. , Lim Yen Ying , Pase Matthew P.
Published: December 2023

Background

Self‐reported psychological stress is associated with an increased risk of cognitive decline and dementia. However, it remains unclear whether stress is related to key biomarkers of Alzheimer’s disease (AD). This cross‐sectional study examined the relationship of psychological stress with memory and cerebrospinal fluid (CSF) biomarkers of AD in middle‐aged adults without dementia.

Method

The Healthy Brain Project (HBP) is a prospective web‐based study of adults aged between 40 and 70 years. A total of 2208 participants (76% female) completed the Depression, Anxiety, and Stress Scale (DASS) and Paired Associates Learning subtest of the CANTAB unsupervised on the HBP web platform. Additionally, a sub‐group of participants (n = 67; 41% APOE e4 carriers) attended an in‐person assessment where CSF samples were obtained to measure levels of amyloid‐beta (Aβ42), total tau (t‐tau), phosphorylated tau 181 (p‐tau), and neurofilament light chain (NFL). Separate linear regression analyses investigated associations of the DASS‐Stress score with memory performance and AD biomarkers. All analyses were adjusted for age, sex, education, and race.

Result

In the web‐based cohort, higher levels of self‐reported psychological stress were significantly associated with poorer memory (unstandardised β = ‐0.014, standard error [SE] = 0.004, p <.001). However, there were no significant associations between psychological stress and CSF levels of Aβ42, t‐tau, p‐tau, and NFL (all p > .05), with small effect sizes (Cohen’s f2 ≤ 0.05).

Conclusion

Higher levels of self‐reported psychological stress were associated with poorer memory in a large middle‐aged cohort but were not associated with AD biomarkers in a subset of participants with available CSF. One potential explanation is that non‐AD pathologies may underlie the relationship between stress and poorer memory; for example, poor coping strategies (e.g., smoking, overeating, and physical activity) might increase the risk of vascular cognitive impairment. However, it is also likely that the small sample size of the in‐clinic cohort was insufficient to detect any subtle relationships between stress and AD pathologies. Further research is needed to determine the associations between stress and the development of the clinical and biological manifestations of AD.
Iterative refinement: Developing items to build an assessment of dementia caregivers’ caregiving style
Authors: Leggett Amanda N , Miner Jennifer A , Baker Elaina , Lee Hannah , Kallen Michael A , Tsuker Sophia , Carlozzi Noelle E
Published: December 2023

Background

Prior mixed‐methods research has classified 5 distinct dementia caregiving style profiles based on how caregivers vary across 5 domains: understanding of dementia, adaptability, orientation towards oneself vs. the care recipient, emotional expression, and behavioral management. Style profiles have been associated with important care outcomes, yet, for this construct to be useful, it must be measurable. Our study aims to develop the first comprehensive assessment of caregiver cognitive‐behavioral styles for clinical/service utility or self‐assessment.

Method

A preliminary item pool of 188 items was developed based on prior research. A literacy review of item content was conducted. Items then went through iterative refinement including: 1) expert review (2 content experts and 1 measurement development expert, with 63 items modified and 66 deleted); 2) cognitive interviews with 7 caregivers (caregivers reviewed each domain’s item set and provided interview feedback on the items, with 4 items modified and 18 deleted); and 3) translatability review for Spanish (review of wording that could impede translation to other languages, with 28 modified and 4 deleted).

Result

Our iterative item pool refinement process resulted in 99 items reflective of the 5 domains to be included in psychometric field testing: adaptability (32 items; e.g., I make adjustments to the way I provide care), behavioral management (20 items; e.g., I try to distract the person I care for when they are frustrated), emotional expression (25 items; e.g., I feel positive when it comes to handling caregiving difficulties), understanding (10 items; e.g., I recognize when I need to change how I communicate with the person I care for), and orientation to self or other (12 total; e.g., I do what is best for the person I care for, even at my own expense).

Conclusion

Our iterative item development process ensures that items developed for a future measure are person‐centered, clear, translatable, and relevant to empirical evidence. The developed items will be field tested among 200 caregivers. This measure is vital to the development of more effective and individualized treatment to enhance caregivers’ ability to support the PLwD, improve outcomes, and reduce the downstream burden of illness and healthcare costs.
Predicting the chance for being at‐risk of AD based on smartphone data obtained during an everyday wayfinding task in the real world
Authors: Marquardt Jonas , Mohan Priyanka , Spiliopoulou Myra , Glanz Wenzel , Butryn Michaela , Kuehn Esther , Schreiber Stefanie , Maass Anne , Diersch Nadine
Published: December 2023

Background

Patients with Alzheimer’s disease (AD) often show problems in spatial navigation. However, spatial navigation is rarely investigated in real world settings and in people at early disease stages. Capitalizing on recent advancements in digital technologies, we measured the performance of healthy younger (YA) and older adults (OA), as well as older adults with subjective cognitive decline (SCD) while they solved a smartphone‐based wayfinding task.

Method

Using the novel smartphone application “Explore”, we tracked GPS data and other behavioral indicators in 24 YAs, 25 OAs, and 23 SCDs, while they were asked to find points of interest on the medical campus in Magdeburg. In our analyses, we first quantified similarities between the GPS trajectories and identified wayfinding styles using k‐medoids clustering. Next, we extracted navigation profiles with aggregated performance measures as input features (e.g., wayfinding distance and number of help function calls) in a latent profile analysis. Mixed effect models were fitted to evaluate group differences for each performance measure separately. We then fed the performance measure that showed the largest groups differences into a multinomial logistic regression model to predict age and diagnostic group in unknown users via leave‐one‐out cross‐validation.

Result

The GPS data could be clustered into three wayfinding styles. However, the correspondence to our groups was rather low (Figure 1a). In contrast, navigation profiles obtained from the latent profile analysis showed a higher correspondence (Figure 1b). Particularly the number of brief stops during navigation differed between the groups, all p ≤ .006 (Figure 2), and predicted age group, p = .015, and diagnostic group above chance, p = .004 (Figure 3). The leave‐one‐out cross‐validation confirmed the successful prediction of group membership in unknown participants, accuracy = 0.57 (chance level 0.33).

Conclusion

Here, we show how information about the cognitive health status of an individual can be inferred from smartphone‐data, obtained during a brief episode of a frequently performed everyday behavior. In particular, the number of short stops during wayfinding could be used to distinguish between YA, OA, and SCDs. Hence, real‐world navigation data, obtained from mobile devices, might help to identify individuals at increased risk for developing AD.
A TREM2‐activating antibody with a blood–brain barrier transport vehicle enhances microglia function
Authors: Sanchez Pascal E.
Published: December 2023

Background

Loss‐of‐function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy.

Method

Here we describe a high‐affinity human TREM2‐activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis.

Result

Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti‐TREM2 antibody. In human induced pluripotent stem cell (iPSC)‐derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single‐cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism.

Conclusion

Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
Characterising the covariance pattern between lifestyle factors and structural brain measures: a multivariable study of two cohorts of older adults
Authors: Demnitz Naiara , Hulme Oliver J , Siebner Hartwig R , Kjaer Michael , Ebmeier Klaus P , Boraxbekk Carl‐Johan , Gillan Claire
Published: December 2023

Background

Modifiable risk factors have been shown to promote healthy brain ageing. However, most studies to date have focused on the relationship between a single risk factor and brain health. Given that risk factors do not occur in isolation, multivariable analyses may provide a more realistic model of the effects of modifiable lifestyle factors on brain ageing.

Method

Here, the relationship between 9 modifiable lifestyle factors and 7 indices of brain structure were examined using canonical correlation analyses to identify a covariance pattern between lifestyle factors associated with dementia risk and MRI‐derived measures of brain structure. Analyses were first conducted on a Danish cohort of older adults (n = 251) and then cross‐validated in an independent cohort of older adults from the United Kingdom (n = 668).

Results

In a 5‐fold cross‐validation analysis of the test dataset, a canonical correlation of 0.14 was observed between the lifestyle and brain variates. In the cross‐study validation, the lifestyle‐brain correlation was r = .10. In the Danish cohort, feelings of loneliness, BMI, depressive symptoms, and years of smoking were the primary contributors to the lifestyle variate (rs ≥ 0.3). In the British cohort, a different pattern of lifestyle factors was found to relate to brain structure the most (rs ≥ 0.3: physical activity, education, alcohol consumption, blood pressure and BMI).

Conclusion

In both cohorts, we found that a latent of lifestyle factors was positively associated with age‐related measures of brain structure and this relationship was validated across cohorts of older adults. However, the covariance pattern between lifestyle and brain outcomes differed between datasets. Taken together, these findings highlight how future lifestyle interventions should be tailored to suit their target populations.
Abnormality of the pulvinar in posterior cortical atrophy: A multimodal MRI study
Authors: Chu Min , Liu Li , Yang Caishui , Wu Liyong
Published: December 2023

Background

Although the pulvinar is known for its extensive connections with both ventral and dorsal visual streams, details of pulvinar functional connectivity in the setting of posterior cortical atrophy (PCA) remain unclearTo study pulvinar functional connectivity and relevant associations with higher visual dysfunction in PCA.

Method

A total of 29 patients with PCA and 30 normal controls were recruited. Each participant underwent comprehensive neuropsychological assessment and both structural and resting‐state functional MRI scanning. Voxel‐based morphometry (VBM) and seed‐based functional connectivity analyses were conducted to assess pulvinar gray matter volume as well as connectivity between the pulvinar and whole brain regions. A partial correlation analysis was performed to analyze neuropsychological test and pulvinar imaging data.

Result

Cognitive and visual functions including visuospatial processing, visual perception, episodic memory, and naming were impaired among PCA patients. Marked pulvinar atrophy was noted in PCA patients. Furthermore, functional connectivity between the pulvinar and precuneus was significantly decreased in PCA patients as compared to normal controls (FWE corrected; P<0.001). Left pulvinar gray matter volume was found to associate with object agnosia (r = 0.42, P<0.05) and right–left disorientation (r = 0.29, P<0.05) among PCA patients. The bilateral pulvinar region was found to associate with Boston Naming Test (left, r = 0.51, P = 0.015; right, r = 0.46, P = 0.03) and Activities of Daily Living (left, r = ‐0.46, P = 0.019; right, r = ‐0.53, P = 0.006) scores. Correlation analyses did not reveal significant findings concerning functional connectivity.

Conclusion

Our findings confirm pulvinar degeneration and its contributions in the setting of PCA.
Cognitive dynamics in healthy aging and mild cognitive impairment
Authors: Aschenbrenner Andrew J. , Jackson Joshua J.
Published: December 2023

Background

In observational and clinical intervention studies of Alzheimer disease (AD), cognition is typically assessed in an extended, “single‐shot” testing session to measure mean‐level changes in performance over time. However, this strategy ignores day‐to‐day fluctuations in cognition that may occur due to mood, stress or fatigue. It is possible that the overall magnitude of daily variability in cognition is a more sensitive endpoint than traditional metrics of cognitive change. Previous research has suggested that attention and personality traits are important predictors of AD, yet it is unknown how scores on these outcomes fluctuate over short intervals. The aim of this project was to evaluate the extent to which scores on attention, personality and mood and fatigue vary across 3 weeks of daily testing and whether cognitive variability increases in early‐stage AD.

Method

A total of 66 younger adults (YAs), 52 cognitively healthy older adults (OAs), and 37 individuals with cognitive impairment (CIs) completed 21 daily assessments of attention, personality, and mood. Cognitive impairment was determined as a rating of 0.5 on the Clinical Dementia Rating scale or a score of less than 11 on the mini Montreal Cognitive Assessment. Group differences in mean performance and variability were assessed using Bayesian mixed effects location scale models.

Result

Adherence was high with an average of 20.1, 19.7 and 19.2 daily sessions (out of 21 possible) completed for YAs, OAs and CIs, respectively. YAs reported overall lower mood compared to the OAs. No other mean comparisons were significant. In terms of daily variability, YAs had greater fluctuations in reported fatigue, conscientiousness and neuroticism compared to healthy OAs. Finally, both YAs and CIs had greater variability in attention relative to OAs. These differences persisted after accounting for global cognition.

Conclusion

Healthy aging (OAs compared to YAs) results in greater stability in personality ratings. In contrast, pathological aging (CIs compared to OAs) results in greater variability in attention scores with no detectable changes on mean performance. We argue that cognitive variability provides unique insight to cognitive changes that occur in healthy aging and early‐stage AD and should continue to be explored as primary outcomes.
Visit‐to‐visit blood pressure variability and medial temporal perfusion in APOE e4 homozygotes
Authors: Sible Isabel J , Nation Daniel A. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Blood pressure variability (BPV), independent of traditionally studied/targeted average blood pressure levels, is an emerging risk factor for cognitive impairment and Alzheimer’s dementia, possibly through links with cerebrovascular disease. Recent studies suggest vulnerability of the medial temporal lobes to tau accumulation and atrophy among individuals with elevated BPV, especially older APOE e4 carriers. Increased BPV has also been linked with lower cerebral blood flow (CBF) and perfusion decline in medial temporal regions, but it remains unclear how BPV and APOE e4 may interact to influence CBF. The aim of the current study was to determine whether the relationship between BPV and medial temporal lobe CBF varies by APOE e4 dose in older adults without dementia.

Method

105 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent 3‐4 blood pressure measurements between study baseline and 12‐months follow‐up and arterial spin labeling (ASL)‐MRI at 12‐months follow‐up or later (range: 0 – 84 months). Visit‐to‐visit BPV was calculated as variability independent of mean. CBF was determined for medial temporal regions (residualized by precentral [reference region] CBF), including hippocampus, parahippocampal gyrus, and entorhinal cortex. Venipuncture determined APOE e4 allele count (0 alleles: n = 71; 1 allele: n = 28; 2 alleles: n = 6). Multiple linear regression examined the interaction of BPV x APOE e4 dose on medial temporal CBF, controlling for age, sex, race/ethnicity, antihypertensive use, mean blood pressure, and cerebral metabolism (FDG‐PET).

Result

Elevated BPV was associated with lower CBF in entorhinal cortex (ß = ‐.96 [‐1.62, ‐.31]; p = .005) and parahippocampal gyrus (ß = ‐.63 [‐1.26, ‐.0002]; p = .049) in individuals with 2 APOE e4 alleles, whereas BPV was not significantly associated with CBF in these regions in individuals with 0 or 1 APOE e4 alleles (p’s > = .08). There was no significant interaction of BPV x APOE e4 dose on hippocampal CBF.

Conclusion

Higher BPV is associated with lower medial temporal CBF in APOE e4/e4 carriers, suggesting BPV may be an understudied vascular risk factor for those at greatest genetic risk for Alzheimer’s disease, with potential therapeutic implications.
In vivo tau is associated with retrospective change in memory and processing speed, but not reasoning, in cognitively unimpaired older adults.
Authors: Simon Sharon Sanz , Varangis Eleanna , Lee Seonjoo , Gu Yian , Gazes Yunglin , Habeck Christian , Stern Yaakov
Published: December 2023

Background

The relationship between tau accumulation and cognitive decline in cognitively unimpaired older adults is still unclear. The tau PET tracer 18F‐MK‐6240 has shown favorable imaging carachteristics to identify early tau accumulation in older adults.

Method

We evaluated the relationship between in vivo tau levels (18F‐MK‐6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, we created a set of regions of Interest (ROIs), selected a priori based on previous literature: 1) Total‐ROIs comprising all 16 areas selected; 2) Medial Temporal Lobe‐ROI, 3) Lateral Temporal Lobe‐ROI and Cingulate/Parietal lobel‐ROI.

Result

41 cognitively unimpaired older adults was included in the study, 82% classified as amyloid‐b negative. Higher tau burden in most meta‐ROIs was associated with steeper decline in memory and speed. There were no associations between tau and reasoning change.

Conclusion

Our finding reforces the notion that early tau accumulation in areas related tio Alzheimer’s disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample characterized with low amyloid‐b pathology. The novel contributin of this work is the relevante of tau accumulation beyond memory, particularly in processing speed decline.
Metabolites and 12‐Year Cognitive Measures Among a Cohort of Boston Area Puerto Ricans
Authors: Palacios Natalia
Published: December 2023

Background

Recent studies have identified plasma metabolites associated with cognitive decline and Alzheimer’s disease; however, little research on this topic has been conducted in Latinos, especially Puerto Ricans. This study aims to add to the growing body of metabolomics research in Latinos to better understand and improve the health of this population.

Method

We assessed the association between plasma metabolites and global cognition, as well as memory and executive function component scores, over 12 y of follow‐up in 736 participants of the Boston Puerto Rican Health Study (BPRHS). Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. We used covariable adjusted linear mixed models (LMM) with a metabolite*time interaction term to identify metabolites (of 621 measured) associated with ∼12y cognitive trajectory.

Result

We observed strong inverse associations between medium‐chain fatty acids, caproic acid, and the dicarboxylic acids, azelaic and sebacic acid, with global cognition and memory. Metabolites on the tyrosine and tryptophan pathways as well as several phospholipids, were associated with improvement in cognitive trajectory. We also observed an association between glucose and taurocholate, a primary bile acid, and worse executive function trajectory.

Conclusion

The metabolites identified in this study are generally consistent with prior literature and highlight a role for tryptophan, bile acid, branched chain amino acid, phospholipid and glucose metabolism in cognitive decline.
Anti‐MS4A4A Antibody Modulates Myeloid Cell Biology and TREM2 Signaling
Authors: Lightfoot Yaima Luzardo , Botte Alexandra , Trinh Ronnie The Pong , Ding Grant S. , McReynolds Morgan , Allen Jason K. , Gonzalez Michelle A , Shi Chunchua , Molldrem Jeffrey J. , Heffernan Timothy P. , Lofton Timothy E , Münch Alexandra , Marcora Edoardo , Goate Alison , Ray William J
Published: December 2023

Background

Genome‐wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) within the membrane‐spanning 4‐domains subfamily A (MS4A) gene locus are linked with protection from Alzheimer’s Disease (AD) risk, delayed age‐at‐onset, and reduced expression of MS4A4A and MS4A6A in myeloid cells. Recently, protective variants within the MS4A gene region have been associated with increased levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Despite these associations, the pathophysiological role(s) of MS4A family members in AD remain understudied. MS4A proteins have been reported to modulate immune cell activation by regulating calcium exchange and the signaling of other immunoreceptors. Therefore, targeting these cell membrane proteins with antibodies that mimic the aforementioned gene signatures may lead to a functional microglial state that is protective in AD.

Method

MS4A4A was overexpressed in HEK293 and HEK293/TREM2+DAP12 cells to measure impact of MS4A4A on calcium flux and TREM2 signaling, respectively. An antibody targeting human MS4A4A was developed and used to treat primary human macrophages in vitro. Cellular localization of MS4A4A and MS4A6A were determined in human macrophages. Surface expression of MS4A4A, MS4A6A and TREM2, as well as sTREM2, were measured in macrophages after antibody treatment. Phosphorylation of spleen tyrosine kinase (pSYK) in anti‐MS4A4A pre‐treated macrophages was measured upon triggering of TREM2 signaling with an activating antibody.

Result

MS4A4A overexpression in HEK293 cells resulted in an increase in basal calcium influx, but impaired calcium mobilization after depletion of stores. Significant inhibition of TREM2 signaling (pSYK) was observed in HEK293/TREM2+DAP12 cells overexpressing MS4A4A. This effect was partially rescued with a commercial MS4A4A antibody. Similarly, treatment of primary human macrophages with a proprietary anti‐MS4A4A antibody increased pSYK levels after TREM2 activation. Anti‐MS4A4A treatment reduced surface levels of both MS4A4A and MS4A6A, while increasing surface TREM2 and sTREM2. Antibody treatment also led to lipid raft remodeling and cluster formation in macrophages.

Conclusion

Our findings indicate that, like other MS4A family members, MS4A4A modulates calcium mobilization and receptor signaling. An MS4A4A‐targeting antibody regulates the surface expression of key microglial receptors and induces lipid raft remodeling, which may provide a mechanistic explanation for enhanced TREM2 signaling, ultimately resulting in improved myeloid cell function.
The Biochemical Characterization of LINC00298; a Genetic Risk Factor for the Development of Alzheimer’s Disease
Authors: Whitaker Rachel A Hellmann
Published: December 2023

Background

Long non‐coding RNAs (lncRNAs) are ubiquitous throughout the human system, yet many of their biological functions remain unknown. LINC00298 RNA, a long intergenic non‐coding RNA (lincRNA), is known to be a genetic risk factor for the development of Alzheimer’s disease, but until now, it had not been biochemically characterized.

Method

Computational Modeling was used to develop secondary and tertiary structures of LINC00298 RNA. Liquid Chromatography (LC) and Mass Spectrometry (MS) (LC/MS) was used to identify the protein binding partners of LINC00298 RNA.

Result

Structural analysis of LINC00298 RNA indicated it is mostly comprised of stem‐loop secondary structural motifs, with an elongated tertiary structure that is dynamic, making it an ideal binding partner for numerous cellular proteins. Biological analysis of LINC0028 RNA indicated that it has 24 protein binding partners, which include: Histone H1.4, Histone H2AX, Histone H4, Pyruvate kinase, Alpha‐enolase, 40S Ribosomal proteins SA, S18, and S3, 60S Ribosomal proteins L31, L13, L13a, 60S acidic ribosomal protein P0 and P2, Prohibitin 1, ATP Synthase subunit alpha and subunit e, Heat Shock Protein HSP 90‐beta, Heterogeneous Nuclear Ribonucleoprotein A/B, Heterogeneous Nuclear Ribonucleoprotein U, Cofilin‐1 Elongation factor 2, Eukaryotic Initiation Factor 4A‐I, Dihydropyrimidinase‐related protein 2, and ADP/ATP Translocase 2.

Conclusion

Through analysis of these 24 protein binding partners, it was concluded that LINC00298 RNA may play significant roles in protein translation, as well as neuronal development, proliferation, and cellular organization. Furthermore, analysis of LINC00298 RNA’s interactome, indicated that LINC00298 RNA has dual localization in the nucleus and the cytosol. This biochemical characterization of LINC00298 RNA highlights the essential role it plays in many biological processes and the important need for continued research on LINC00298 RNA’s pathogenic role in the development of Alzheimer’s disease.
Production pathway of APP669‐x peptides in the cultured cells
Authors: Tomita Taisuke , Yokoyama Miyabishara , Kaneko Naoki , Matsuzaki Masaya , Kobayashi Honoka , Yoshizawa Yota , Naito Hiroki , Sekiya Sadanori , Iwamoto Shinichi , Tanaka Koichi
Published: December 2023

Background

We have identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS), and revealed that the composite biomarker using APP669‐711/Aβ1‐42 ratio correlates with amyloid PET status (Kaneko et al., 2014; Nakamura et al., 2018). We also recently found that A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) is responsible for the APP669‐site cleavage of APP (Matsuzaki et al., Mol Psychiatry 2023). Here, we analyzed the production pathway APP669‐x peptides from the C‐terminal stub c102 of APP, which is c99 with 3 extra N‐terminal amino acid residues (i.e., the cleaved APP fragment at APP669‐site).

Method

We established the endo‐specific antibody against the N terminus of APP669‐x peptide, an anti‐c102 antibody. We analyzed the effect of ADAMTS4 on the production of Aβ‐related peptides from the APP‐expressing HEK293 cells using IP‐MALDI‐MS.

Result

We successfully detected the endogenous C‐terminal fragment of APP specifically reacted with anti‐c102 antibody in A549 cells. We found that the overexpression of the recombinant c102 resulted in the production of a series of APP669‐x peptides by the γ‐secretase. No Aβ starting at the 1st nor 4th position was generated from c102‐expressing cells irrespective of ADAMTS4 expression. Co‐expression of ADAMTS4 with APP increased the production of both APP669‐711 and Aβ4‐40. However, the addition of extracellular ADAMTS4 to HEK293 cells expressing APP resulted in the increase in the Aβ4‐40, but not APP669‐711 nor Aβ1‐40, suggesting that no further N‐terminal trimming of c102 is occurred within the cells after ADAMTS4‐mediated APP669 cleavage.

Conclusion

These results indicated that ADAMTS4 cleaves APP in the secretory pathway to generate c102, which is a direct substrate for the γ‐secretase.
Cerebellar atrophy in pathological subtypes of Alzheimer’s disease and related dementias
Authors: Chen Yu , Spina Salvatore , Callahan Patrick , Grinberg Lea T. , Seeley William W. , Kramer Joel H. , Miller Bruce L , Rankin Katherine P
Published: December 2023

Background

The cerebellum is differentially affected in various neurodegenerative diseases (Gellersen et al., 2017), but associations of cerebellar atrophy with specific neuropathologies have not been systematically analyzed. We used brain imaging to examine cerebellar grey matter volume with patients with all major pathological subtypes of Alzheimer’s disease and related dementias (ADRD).

Method

We applied voxel‐based morphometry to the earliest structural magnetic resonance imaging scans of autopsy‐proven ADRD cases (n = 309), and age‐, sex‐, and education‐matched healthy controls (n = 80). Seventy‐seven AD cases, 74 cases with mixed Lewy body disease and AD (LBD‐AD), and 158 frontotemporal lobar degeneration (FTLD) cases were included in this study. Patients with FTLD were further classified into FTLD major molecular classes and subtypes: FTLD‐TDP [FTLD‐TDP type A (TDP‐A) (n = 21), FTLD‐TDP type B (TDP‐B) (n = 21), FTLD‐TDP type C (TDP‐C) (n = 26)] and FTLD‐tau [Pick’s disease (n = 25), corticobasal degeneration (CBD) (n = 32), progressive supranuclear palsy (PSP) (n = 33)]. Clinical function was assessed with the Clinical Dementia Rating Scale (CDR) (Morris, 1993; Hughes et al., 1982) at the time of MRI scan, with global score ranging from 0 (normal), 0.5 (very mildly impaired), 1 (mildly impaired), 2 (moderately impaired) to 3 (severely impaired).

Results

Compared with controls, distinct patterns of cerebellar atrophy were observed in all pathological subtypes spanning bilateral hemispheres and vermis (PFWE‐corr<0.05, >100 contiguous voxels). Significant cerebellar grey matter changes were even found in the early stage (CDR ≦ 1) of all subtypes, with the exception of TDP‐B, and in the very early stage (CDR 0‐0.5) of AD, LBD‐AD, TDP‐A and PSP. Degree of cortical atrophy positively predicted degree of cerebellar atrophy in all subtypes.

Conclusion

This study is the first to identify distinct early patterns of cerebellar atrophy across pathological subtypes of ADRD, and to show a direct relationship between cerebellar and cortical grey matter volume. These results clarify the cerebellar involvement in ADRD and underscore the potential for cerebellar neuroimaging to be a non‐invasive biomarker for differential diagnosis among pathologies and disease monitoring.
The Effect of Home‐based Cognitive Training Using Workbook and Tablet PC in Presenile Dementia Patients
Authors: Kwon Jay Cheol , Lee Kyungsoo
Published: December 2023

Backgrounds

Although the effectiveness of cognitive training has previously been established, adherence or maintenance to these program is difficult to achieve due to the lack of validated and convenient tools and programs. Furthermore, presenile dementia patients are usually physically no impairment but their welfare systems are overlooked compared to senile patients. The aims of this study are to evaluate the effects of home‐based cognitive training and usefulness of workbook (e.g. regular paper book) and tablet personal computer (e.g. GALAXY pad) focusing on presenile dementia patients.

Materials and Methods

We enrolled 48 dementia patients who met the predefined inclusion criteria from two dementia outpatient clinics. Finally, 34 presenile dementia patients (age; 63.03±4.58, 16 men and 18 women, educational attainment; 10.03±4.30 years, CDR sum of box; 3.21±1.97, MMSE; 21.74±5.24, ADAS‐Cog_total; 20.12±8.13, K‐IADL; 0.43±0.36) were randomly assigned to a 12‐week scheduled cognitive training program using either an workbook (W‐group, age; 62.53±4.03, 9 men and 10 women, educational attainment: 10.05±3.05, CDR_SOB; 3.68±2.07, MMSE; 21.42±5.46, ADAS‐Cog_total 20.95±8.49, K‐IADL; 0.50±0.40) or tablet personal computer (T‐group, age; 63.67±5.26, men 7 and women 8, Education; 10.00±5.63, CDR_SOB; 2.60±1.71, MMSE; 22.13±5.11, ADAS‐Cog_tatal; 19.07±7.81, K‐IADL; 0.33±0.29). All patients underwent 1 hour/day for 5 days/week of training with support with their caregiver. During the program, levels of difficulties were adjusted according to rater’s measurement at regular visits. Before and after the training program, all patients were tested for MMSE, CDR‐SB, IADL and ADAS‐Cog.

Results

On ADAS‐cog tests, patients showed improvement post training (p = 0.021). T‐group showed more improvement in CDR‐SB than W‐group (P = 0.01). In subgroup analyses including subdomain, there were no significant differences between pre and post tests. All patients and caregivers were well‐tolerated for 12 weeks.

Conclusion

We suggest that cognitive training using workbook and tablet personal computer is a well‐tolerated and comparable tool for presenile dementia patients and their caregivers.
Microglial zinc finger protein 335 mediates LPS‐induced neurodegeneration and memory loss as a transcriptional factor for lymphocyte antigen‐6M
Authors: Ni Junjun , Quan Zhenzhen , Qing Hong
Published: December 2023

Background

Zinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge.

Method

We used wild‐type (WT) and Zfp335 knock‐down (Zfp335+/−) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT‐PCR, RNA‐sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2‐month‐old mice after LPS treatment.

Result

Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS‐induced microglia‐mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor‐kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen‐6M (Ly6M).

Conclusion

Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia‐mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.
Real‐world one‐year estimation of the candidates for lecanemab in a South Korean memory clinic
Authors: Sun Kyunghwa , Lee Sun Min , Park Sun Ah , Moon So Young
Published: December 2023

Background

Results from an 18‐month Phase 3 clinical trial showed that lecanemab reduced markers of amyloid on early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. As the lecanemab recently received accelerated approval by the US Food and Drug Administation, consideration for prescribing it in the right person, at the right dose and in a very carefully monitored way in a real‐world practice is necessary now.

Method

In this study, we aimed to estimate the candidates for lecanemab in a South Korean memory clinic based on one‐year clinical data. We reviewed retrospectively the medical records of a total 344 patients (211 females, 69.7±9.3 years old) who visited the memory clinic and took the amyloid PET at the department of Neurology, Ajou University Hospital in 2022. We tried to find the patients whose clinical characteristics fit with the inclusion as well as exclusion criteria from the Phase 4 clinical trial of lecanemab.

Result

The patients consisted of 14 subjective cognitive complaints, 139 mild cognitive impairments (MCI), 107 Alzheimer’s disease (AD) dementia, or 84 other neurodegenerative diseases whose amyloid positivity was 28.6%, 43.2%, 72.0%, or 10.7%, respectively. Among patients with evidence of amyloid deposition, 4 MCI and 38 AD dementia were within the exclusion criteria because they scored less than 22 at the Mini‐Mental State Examination (MMSE). Other 7 patients with AD dementia would be also excluded because they scored both Global Clinical Dementia Rating (CDR) score greater than 1 and <22 at the MMSE. One more AD dementia patient had no data of cognitive test. Finally, 56 patients with MCI and 31 patients with AD dementia met the criteria for using the lecanemab.

Conclusion

Our study showed that amyloid PET was already integrated in the real‐world Korean practice. In addition, the amyloid‐positivity data from real‐world practice in a South Korean memory clinic matched well with previous research data. It is expected that this pattern of the Korean practice might contribute to give real‐world data for prescribing the lecaemab in the future.
Regional glymphatic abnormality in behavioral variant frontotemporal dementia
Authors: Jiang Deming
Published: December 2023

Background

The pattern of glymphatic inflow overlaps with the geographic pattern of behavioral variant frontotemporal dementia (bvFTD). The glymphatic function has not yet been explored in bvFTD. The spatial correlation between regional glymphatic function and bvFTD remain unknown.

Method

A total of 60 patients with bvFTD and 61 age‐ and sex‐matched healthy controls (HCs) were selected from two independent cohorts (discovery dataset from Xuanwu Hospital and replication dataset from the Frontotemporal Lobar Degeneration Neuroimaging Initiative study). All participant underwent neuropsychological assessment. Glymphatic measures evaluated from multimodal neuroimaging data, including choroid plexus volume, diffusion along perivascular space (DTI‐ALPS) index, and coupling between blood‐oxygen‐level‐dependent signals and cerebrospinal fluid signals (BOLD‐CSF coupling), were compared between the two groups. To evaluate glymphatic regional function, DTI‐ALPS and BOLD‐CSF coupling were further divided into anterior, middle, and posterior parts. BvFTD‐related metabolic pattern was identified using spatial covariance analysis based on [l8F]‐FDG‐PET.

Result

Patients with bvFTD showed higher choroid plexus volume (P < 0.001); middle DTI‐ALPS (P < 0.001); and weaker anterior BOLD‐CSF coupling (P < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI‐ALPS was negatively associated with the expression of the bvFTD‐related metabolic pattern (r = ‐0.51, P = 0.029) and positively related with regional standardized uptake value ratios of [l8F]‐FDG‐PET in bvFTD‐related brain regions (r = 0.44–0.60, P range: 0.008–0.039). Worse glymphatic function is associated with more severe global cognition decline, disease severity, and neuropsychiatric symptoms. In addition, anterior DTI‐ALPS was higher than posterior DTI‐ALPS (P < 0.001), whereas anterior BOLD‐CSF coupling was lower than posterior BOLD‐CSF coupling (P < 0.001).

Conclusion

Our findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD.