bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer's disease subjects have smaller non‐jugular venous drainage system compared to cognitive normal population
Authors: Prado Keshet , Khasminsky Vadim , Keret Ophir , Beninger Felix , Goldberg Ilan , Auriel Eitan , Glik Amir
Published: January 2025

Background

The Internal Jugular Veins (IJVs) and the non‐jugular veins (NJVs) are two pathways responsible for intracranial blood drainage. The NJVs are usually the less prominent drainage system and have been demonstrated to become smaller during aging. This phenomenon may indicate less affective venues drainage and hence less CNS’s waste products clearance as we age.

One of the pathological hallmarks in Alzheimer’s disease (AD) is amyloid betta42 (AB42) accumulation. AB42 accumulation may be the result of overproduction or clearance impairment. NJVs narrowing during aging may cause AB42 accumulation due to clearance impairment and hence plays a role in AD pathology.

Our aim was to compare the venous cross‐sectional area (CSA) in AD vs. cognitive normal (CN) population.

Method

Cognitive impaired patients included AD and mild cognitive impairment (MCI) patients that were recruited prospectively as part of the DIASPORA Horizon‐2020 MesCobrad Project. All patients performed comprehensive neurocognitive evaluation and Brain MRI including Time‐of‐flight sequence for venous demonstration. Venous systems CSA were measured at the jugular foramen level and were done by senior neuroradiologist. CN were defined as subjects without CNS’s known pathology. CN Measurements were taken from a previous study of our group. T‐test was used to compare between groups.

Result

A total of 39 Cognitive impaired patients and 20 CN were included in the study. Mean ages of 68 years (SD, 5.4) and 66 years (SD, 5.5), respectively. The CSA of the IJVs was similar between groups. However, NJVs CSA was significantly smaller in cognitive impaired patients (mean CSA=41.21 mm2 (SD,21.52) vs. CSA=54.5 mm2 (SD,27.3) P=0.045). Table 1.

Conclusion

NJVs are significantly smaller in cognitive impaired patients compared to CN population. NJVs narrowing in AD patients may cause impaired venous drainage hence causing AB42 accumulation in this population. New treatment options for AD patients may rise if larger studies replicate our findings.
Association of serum C‐reactive protein with in vivo cerebral beta‐amyloid deposition in nondemented older adults
Authors: Choi HyeJi , Byun Min Soo , Yi Dahyun , Jung Joon Hyung , Sohn Bo Kyung , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Lee Dong Young ,   the KBASE Research Group
Published: January 2025

Background

C‐reactive protein (CRP) is widely used in clinical practice as a marker for inflammatory condition. Previous studies have examined the association between CRP levels in peripheral blood and Alzheimer’s disease (AD) dementia, but have yielded mixed results. In this study, we investigated the association between serum CRP levels and in vivo cerebral beta‐amyloid (Aβ) deposition in nondemented older adults.

Method

Nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) cohort. All participants underwent 11C‐PiB‐PET/MRI and blood sampling. Serum CRP was measured by using a turbidimetric immunoassay (TIA) method. Since CRP level lower than 3 mg/L is considered as normal range in clinical settings, we classified the participants into two groups as follows: i) CRP < 3mg/L and ii) CRP ≥ 3mg/L. CRP values that deviated more than 3 standard deviations from the mean were considered outliers and excluded from analysis. Global cortical PiB uptake was used for measurement of global Aβ deposition. Both log‐transformed CRP and global PiB SUVR was used for analysis. Multiple linear regression analysis with CRP as an independent variable and global PiB SUVR as a dependent variable was performed adjusting covariates including age, sex, and apolipoprotein E ε4 (APOE4) positivity.

Result

Total 393 nondemented (260 cognitively normal and 133 mild cognitive impairment) older adults were included in the analysis. In CRP <3mg/L groups (N=393), CRP level showed significant negative association with global Aβ deposition, after adjusting age, sex and APOE4 positivity (β[SE] = ‐0.036 [0.015], p=0.018). In contrast, no significant association between peripheral blood CRP level and global Aβ deposition was observed when CRP level was higher than 3mg/L (N=37).

Conclusion

Our finding suggests that CRP in blood inversely relate to Aβ deposition in brain when the levels of CRP are within normal range (i.e., relatively low). However, such relationship appears not persist when CRP levels are higher than normal limit. Further studies are needed to understand the mechanisms underlying the relationship between peripheral CRP and cerebral Aβ accumulation.
Peak width of skeletonized mean diffusivity might be a better neuroimage marker for cognitive functions in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Authors: Lee Wei‐Ju , Huang Fan , Wang Shi‐Ming , Chen Hung‐Chieh , Chen Yi‐Ming , Huang Hsu‐Wen , Huang Chih‐Mao
Published: January 2025

Background

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a monogenic subcortical ischemic vascular dementia (SIVD) caused NOTCH3 gene mutations. Many different neuroimaging methods have been used to investigate the association between neuroimaging changes and clinical symptoms. We investigated the correlation between peak width of skeletonized mean diffusivity (PSMD) values and cognitive functions in preclinical CADASIL patients without a history of stroke or dementia, comparing them to white matter hyperintensities (WMH) volumes.

Method

This study recruited NOTCH3 R544C mutation carriers (n=63) without a history of stroke or dementia and age‐ and sex‐matched non‐carriers (n=35) in Taichung Veteran General Hospital. Brain MRI including T1, Fluid‐Attenuated Inversion Recovery (FLAIR), and diffusion tensor imaging (DTI) data were acquired on 1.5T MRI and neuropsychological assessments were used to evaluate the cognition functions for all participants. The domain‐specific composite Z‐scores were calculated to represent memory, executive function, processing speed, and visuospatial function. We examined the relationships between domain‐specific cognitive functions and both PSMD values and WMH volumes.

Result

In this study, the data from 65 participants carrying NOTCH3 R544C mutation and 35 non‐carriers were analyzed. Mutation carriers have more severe WMH (p < 0.001) and longer PSMD values (p = 0.011) compared to non‐carriers. After adjusting for age, sex, and years of education using partial correlation, the PSMD values are associated with processing speed (r = ‐0.252, p = 0.048) and visuospatial functions (r = ‐0.275, p = 0.03). The correlations between WMH volume and the cognitive functions were not statistically significant.

Conclusion

In summary, the PSMD value might be a better imaging biomarker for the cognitive functions in preclinical CADASIL patients and represent the early subcortical cerebrovascular damage compared to WMH volumes.
Distinct dementia atrophy progression patterns associated with different epidemiological risk factors
Authors: Shapson‐Coe Alexander David , Waters Sheena , Oxtoby Neil P , Marshall Charles R
Published: January 2025

Background

Most evidence about early structural brain change in dementia derives from highly selected disease cohorts. However, at population level, dementia is typically due to mixed pathologies. We aimed to characterise distinct patterns of brain volume change in early all‐cause dementia in a population cohort.

Method

We used the Subtype and Stage Inference (SuStaIn) algorithm to identify distinct subtypes of disease progression based on structural MRI in the UK Biobank cohort of 152 dementia cases, of which 31 were prevalent cases at the time of scanning and 121 were subsequent incident cases that had been scanned during the pre‐diagnosis phase. We compared other characteristics between subtypes to derive insights into potential aetiologies.

Result

Two distinct subtypes of progression were identified by SuStaIn, one that replicated the typical anatomy of Alzheimer’s disease (AD) with early atrophy of hippocampi and temporal cortex (n=82), and a less common subtype (n=34) characterised by early atrophy of the cerebellum, hippocampus and other subcortical structures, and likely to represent mixed AD and vascular pathologies. Individuals with the latter subtype had significantly higher levels of biomarkers associated with vascular disease, including body mass index (p=0.025) and burden of peri‐ventricular white matter hyperintensities (p=0.020). There was no difference in polygenic risk for Alzheimer’s disease or ApoE4 allele frequency between subtypes.

Conclusion

Subtype and Stage Inference provides a data‐driven approach to identifying distinct patterns of dementia progression. Within the UK Biobank cohort of dementia cases, these subtypes appear to be associated with distinct biological risk factors, which may improve our understanding of the earliest stages of dementia.
Characterizing brain structures associated with plasma neurofilament light chain among older adults: variations by sex and APOE gene
Authors: Dong Yi , Song Lin , Hou Tingting , Li Yuanjing , wang yongxiang , Du Yifeng , Qiu Chengxuan
Published: January 2025

Background

Plasma neurofilament light (NfL) has emerged as a promising biomarker to track neurodegeneration in Alzheimer’s disease (AD) and other brain degenerative disorders. We sought to characterize brain structures and white matter lesions associated with plasma NfL among dementia‐free older adults, while taking into account demographic factors and genetic susceptibility (e.g., APOE gene).

Method

This population‐based cross‐sectional study included 844 non‐demented older adults (age ≥60 years, 59.2% women), derived from participants in the baseline assessments of the Multimodal INterventions to delay Dementia and disability in rural China (MIND‐China) study who had plasma NfL measured on the SIMOA platform in 2018 and undertook structural brain magnetic resonance imaging (MRI) scan on a 3T scanner in 2018‐2020. Structural brain measures were assessed using the Computational Anatomy Toolbox on the platform of MATLAB. Data were analysed using the multivariable linear regression models.

Result

Per 1‐SD increase in log‐transformed NfL concentration was significantly associated with multivariable‐adjusted β‐coefficient (95% confidence interval) of 0.09 (0.05 to 0.14) for white matter hyperintensity (WMH) volume, 0.09 (0.05 to 0.14) for periventricular WMH volume, ‐2.71 (‐4.99 to ‐0.43) for grey matter volume, ‐0.03 (‐0.06 to ‐0.01) for entorhinal cortex volume, ‐0.04 (‐0.07 to ‐0.01) for parahippocampal volume, ‐0.22 (‐0.37 to ‐0.07) for AD‐signature volume, and ‐0.02 (‐0.03 to ‐0.01) for AD‐signature cortical thickness. The associations of plasma NfL concentration with the MRI markers of neurodegeneration were statistically evident mainly among males (P for plasma NfL×sex interaction<0.05) or APOE ε4 allele carriers (P for plasma NfL×APOE ε4 allele interaction<0.05).

Conclusion

Brain structures associated with increased plasma NfL in older adults are characterized by reduced grey matter volume, entorhinal cortex volume, parahippocampal volume, and AD‐signature volume, especially among men or carriers of the APOE ε4 allele.
Plasma p‐tau181 is associated with brain amyloid deposition and predicts MCI conversion to AD
Authors: Lin Yung‐Shuan
Published: January 2025

Background

Plasma phosphorated tau 181 (p‐tau181) was found to change in concordance with amyloid PET and well before tau PET, suggesting that the secretion of p‐tau181 may represent a physiologic reaction to β‐amyloid plaques. Our study aimed to evaluate the relationship between amyloid PET plasma p‐tau181 and whether p‐tau181 predicts amnestic MCI to AD conversion.

Method

We included 98 participants (43 demented and 55 nondemented) who underwent florbetaben amyloid PET scan. Amyloid PET was interpreted by visual assessment based on brain amyloid plaque load score (BAPL). The plasma p‐tau181 level were tested using Simoa assays. Another longitudinal cohort of 37 amnestic MCI patients were tested plasma p‐tau181 level at baseline were followed up at for at least one year. ANOVA and logistic regression were used to evaluate p‐tau181 level between amyloid and cognitive status. Cox regression was used to examine p‐tau181 level and MCI conversion to AD.

Result

Brain amyloid deposition was found in 51% (21/43) of the demented participants, and 11% (6/55) in the nondemented. The plasma p‐tau181 level was significantly higher in the amyloid positive individuals (p<0.001). P‐tau181 alone discriminates amyloid status with an AUC of (0.889, 95% CI 0.826–0.951). In the longitudinal amnestic MCI cohort, 49% (18/37) converted to AD during follow‐up. A P‐tau181 cutoff at 2.545 alone was able to predict conversion where higher Ptau181 has shorter conversion free survival (median survival time in month, 35.0 vs 14.0, p=0.029).

Conclusion

Higher plasma p‐tau181 was associated with brain amyloid deposition and MCI conversion to AD. Plasma p‐tau181 could be a surrogate blood‐based biomarker for amyloid positivity and predicts prognosis in MCI.
Building Care Partner Capacity Through Education on Behaviour Change in Dementia
Authors: Hickman Kathy
Published: January 2025

Care Partners (family and friends) providing direct care to people living with dementia are 1.6 times more likely to report distress if the person they are supporting is experiencing behaviour changes according to the Canadian Institute for Health Information. These carers are a critical part of the care team and yet they are often not provided education needed to support high quality care and more effectively contribute to the care team.

The Alzheimer Society of Ontario has developed a 6‐hour workshop (U‐First!® for Care Partners) for carers who are providing direct support to someone experiencing behaviour changes as a result of dementia or other cognitive impairment. This education is adapted from a similar program for direct health care providers and is intended to increase care partner confidence and skills to understand and respond to behaviour changes in order to i) reduce frequency and severity of behaviour changes; ii) enhance well‐being of care partners and people with dementia; iii) improve collaboration among all team members by creating common knowledge, language and approach to care. The program uses an interactive approach grounded in adult learning theory that has participants reflect on their experiences, engage with new content, practice using a variety of methods and plan how to implement what they have learned. Learners receive a participant workbook and an interactive application tool (U‐First!® Wheel), that helps them to think through potential causes of behaviour changes and supportive care strategies.

Evaluation results show lasting impacts. Even at 6 months following completion of the program, participants reported increased ability and confidence to identify, flag and respond to behaviour changes, increased ability to identify risks, increased wellbeing for themselves (including reduced stress) and for the person they are supporting. In addition, they felt the program increased their ability to have positive interactions with the person they are supporting, other care partners and health care providers. Participants with perceived high levels of stress and/or low well‐being prior to the program experienced the greatest benefits in these areas and care partner perceptions of degree of concern about behaviour changes was positively impacted by participation in the program.
Alzheimer disease ATN imaging biomarkers across type 2 diabetes mellitus stages in diverse populations
Authors: Pillai Malavika , Ances Beau , O'Bryant Sid E. , Meeker Karin L.
Published: January 2025

Background

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD) and disproportionately impacts under‐represented groups including Mexican Americans/Hispanics (MAs) and African Americans/Blacks (AAs) compared to non‐Hispanic Whites (NHWs). However, it remains unclear how amyloid, tau, and neurodegeneration (AT(N)) AD imaging biomarkers and cognitive functioning differ across diabetic stages including non‐diabetes, pre‐diabetes, and T2DM in a diverse community‐based cohort.

Method

Data were obtained from the well‐characterized Health and Aging Brain Study: Health Disparities (HABS‐HD) cohort, including MAs (n=612), AAs (n=676), and NHWs (n=725) with clinical, amyloid and tau positron emission tomography (PET), and cortical thickness measures from magnetic resonance imaging (MRI) scans. Diabetic stage was categorized by HbA1c values: non‐diabetes=HbA1c<5.7%; pre‐diabetes=HbA1c 5.7‐6.4%; and T2DM=HbA1c>6.4%. Differences in continuous measures of AT(N) imaging biomarkers and cognitive functioning (Mini‐Mental State Examination) across diabetes stage were determined using multivariate analyses of covariance (MANCOVAs). The interactive effect of diabetes stage and ethno‐racial group on AT(N) biomarkers and cognitive functioning was also assessed. Age, sex, white matter hyperintensity volume, and Clinical Dementia Rating (CDR) Sum of Boxes were included as covariates.

Result

The AD cortical thickness signature was significantly decreased in pre‐diabetes compared to non‐diabetes (p=0.001), and T2DM compared to non‐diabetes (p<0.001) and pre‐diabetes (p=0.04). Cognitive functioning was also decreased in pre‐diabetes compared to non‐diabetes (p=0.005), and T2DM compared to non‐diabetes (p<0.001) and pre‐diabetes (p=0.002). Amyloid and tau PET did not significantly differ across diabetes stages (p’s>0.05). Amyloid burden was significantly increased in NHWs compared to MAs and AAs (p’s<0.001). Cognitive functioning was significantly decreased in MAs compared to AAs and NHWs, and in AAs compared to NHWs (p’s<0.001). Tau PET and cortical signature did not significantly differ by group (p’s>0.05). MAs and AAs had higher incidences of pre‐diabetes/T2DM, but no interactions between diabetes stage and ethno‐racial group were observed for AT(N) biomarkers and cognitive functioning.

Conclusion

AD‐related neurodegeneration and cognitive functioning worsen in the earliest stages of diabetes. Although under‐represented groups have higher T2DM rates, the deleterious effects of higher HbA1c levels are ubiquitous across diverse populations. Treatment of T2DM may alleviate downstream AD decline and should be considered in AD clinical settings, studies, and trials.
Digitally Assessed Sleep Disturbances for Early Diagnosis of Alzheimer’s Disease
Authors: Krix Sophia , Odeh Joud , Lentzen Manuel , Val‐Guardiola Andrea , Martínez Neus Falgàs , Atreya Alankar , Conde Pauline , Doherty Aiden , Vairavan Srinivasan , Muurling Marijn , de Boer Casper , Curcic Jelena , Grammatikopoulou Margarita , Nikolopoulos Spiros , Brem Anna‐Katharine , Coello Neva , Narayan Vaibhav , Wittenberg Gayle , Duijn Cornelia M Van , Hinds Chris , Aarsland Dag , Sanchez‐Valle Raquel , Fröhlich Holger
Published: January 2025

Background

Alzheimer’s Disease (AD) is associated with sleep disturbances. Moreover, individuals with sleep disturbances have been reported to have a higher risk for developing AD. The measurement of sleep behavior therefore opens the opportunity for a potential digital biomarker of AD.

Method

We modeled sleep patterns coming from the RADAR‐AD cohort from two sleep monitoring devices (Table 1). We applied a stochastic modeling approach, multi‐state models, and analyzed the times spent in each sleep state before transitioning and transition probabilities in and between sleep states. We further applied statistical analysis of sleep monitoring data and sleep questionnaires (ESS, PSQI) from the RADAR‐AD study (Fitbit Charge 3, DREEM) and preliminary data from the ADIS study (MotionWatch8) (Table 1), using a likelihood ratio test with the aim to assess the diagnostic potential of sleep monitoring devices compared to traditional sleep questionnaires.

Result

Modeling of digital device data showed that preclinial (preAD), prodromal (proAD) and mild‐to‐moderate (mildAD) AD patients spent more time in the light sleep and awake state, and less time in the REM sleep states compared to healthy controls (HC) before transitioning to the next state, showing non‐linear associations between diagnostic stage and sojourn times (Figure 1A). ProAD and mildAD patients had a higher probability to transit to a light sleep phase compared to HC and to subsequently wake up (Figure 1B). Based on our current and partially still preliminary data, only digital sleep monitoring via Fitbit allowed for a separation between HC and preclinical AD at nominal significance (preAD) but findings were not significant when adjusting for multiple testing (Table 2A). A significant distinction between HC and proAD (p < 0.001) as well as between HC and mildAD (p < 0.01) was possible using Fitbit sleep monitoring data, whereas traditional sleep questionnaires were only able to distinguish HC from mildAD (p < 0.05) (Table 2).

Conclusion

Sleep patterns assessed via tested digital devices were able to separate proAD from HC – in case of Fitbit ‐ which was not possible by traditional sleep questionnaires. Digital sleep monitoring has thus the potential to support the early diagnosis of dementia.
Cerebrospinal Fluid Neurofilament Dynamic Profiles Predict Cognitive Progression in Individuals with de novo Parkinson’s Disease
Authors: Sheng Ze‐Hu , Ma Lingzhi , Guo Fan , Liu Jia‐Yao , Tan Lan
Published: January 2025

Background

Neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) reflects the severity of neurodegeneration, with its altered concentrations discovered in Parkinson's disease (PD) and Parkinson's disease dementia (PD‐D).

Method

A total of 259 people were recruited in this study, including 85 healthy controls (HC) and 174 neonatal PD patients from the Parkinson's Progression Markers Initiative (PPMI). Multiple linear regression and linear mixed effects models were used to examine the associations of baseline/ longitudinal CSF NfL with cognitive decline and other CSF biomarkers. Kaplan‐Meier analysis and log‐rank test were used to compare the cumulative probability risk of cognition progression during the follow‐up. Multivariate cox regression was used to detect cognitive progression in de novo PD.

Result

We found PD patients with mild cognitive impairment (PD‐MCI) was higher than with normal cognition (PD‐NC) in terms of CSF NfL baseline levels (P = 0.003) and longitudinal increase rate (P = 0.034). Both baseline CSF NfL and its rate of change predicted measurable cognitive decline in de novo PD (MoCA, β = ‐0.010, P = 0.011; β = ‐0.0002, P < 0.001, respectively). The predictive effects in de novo PD patients aged > 65, male, ill‐educated (< 13 years) and without carrying Apolipoprotein E ε4 (APOE ε4) seemed to be more obvious and reflected in more domains investigated. We also observed that CSF NfL levels predicted progression in de novo PD patients with different cognitive diagnosis and amyloid status. After an average follow‐up of 6.66 ± 2.54 years, higher concentration above the median of baseline CSF NfL was associated with a future high risk of PD with dementia (adjusted HR 2.82, 95% CI: 1.11‐7.20, P = 0.030).

Conclusion

Our results indicated that CSF NfL is a promising prognostic predictor of PD, and its concentration and dynamics can monitor the severity and progression of cognitive decline in de novo PD patients.
Chronic treatment with a metabotropic glutamate receptor 2 camelid nanobody accelerates amyloidogenesis in Alzheimer’s disease
Authors: Lafon Pierre‐André , Liu Jianfeng , Perrier Veronique , RONDARD Philippe
Published: January 2025

Background

Immunotherapy of Alzheimer’s disease (AD) is a promising approach to reducing the accumulation of beta‐amyloid, a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGluR2 and mGluR3, could be important in controlling Aβ production, although their respective contribution remains unclear due to the lack of selective tools.

Method

5xFAD mice were chronically treated by a brain penetrant camelid single domain antibody (VHH or nanobody) that is an activator of mGluR2. Abeta amyloids after this treatment were measured by FRET‐based technologies (HTRF). HTRF techniques were also developed to measure the direct interaction between APP and mGluR2 or mGluR3 at the surface of transfected cells. Other resonance energy transfer techniques were also used to measure the influence of the nanobody on mGluR2 and mGluR3 internalization.

Result

Enhancing mGluR2 activity increases Aβ1‐42 peptide production whereas activation of mGluR3 has no effect. We show that such a difference likely results from the directly interaction of APP with mGluR3, but not with mGluR2, that prevents APP degradation to Aβ1‐42 peptides. We then show that chronic treatment with a brain‐penetrating mGlu2 potentiating nanobody of the AD model 5xFAD mice accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice.

Conclusion

A selective mGluR2 activation exacerbates AD disease development suggesting that therapeutic benefices could be obtained with blockers of this receptor.
Development of blood biomarker for Alzheimer disease using neuron‐derived extracellular vesicles
Authors: Kudo Takashi , Akamine Shoshin
Published: January 2025

Background

We have developed a technology for isolating extracellular vesicles (EVs) released from the central nervous system present in plasma.

Method

Initially, we differentiated induced pluripotent stem cells (iPS) into neurons to examine the membrane surface molecules of neuron‐derived EVs in culture media. Our analysis revealed a specific interest in neuron‐specific APLP1. Subsequently, when we fractionated plasma using an iodixanol density gradient, we identified CD63, CD9, and Syntenin1 in the fraction containing APLP1. This confirmed the presence of APLP1‐positive EVs in plasma. Our protocol for isolating nerve‐derived EVs involves first separating total EVs from plasma using size exclusion chromatography, followed by isolating nerve‐derived EVs through immunoprecipitation with an anti‐APLP1 antibody. Using this method, we successfully isolated nerve‐derived EVs from plasma obtained from Alzheimer's disease patients and analyzed their protein content using digital ELISA.

Result

Tau in EVs measured by digital ELISA was significantly correlated with Alzheimer's disease biomarkers in cerebrospinal fluid.

Conclusion

Neuron‐derived EVs obtained through our developed method could serve as potential biomarkers for Alzheimer disease.
Cortical Myelination, Cognition, and Cardiovascular Fitness: New Insights using Advanced Magnetic Resonance Relaxometry
Authors: Guo Alex , Faulkner Mary E , Gong Zhaoyuan , Bae Jonghyun , Laporte John P , Bouhrara Mustapha
Published: January 2025

Background

Alterations in grey matter (GM) are known to contribute to cognitive decline in aging and dementia. Recent evidence suggests that individuals with higher cardiorespiratory fitness (CRF) may have a lower risk of GM atrophy and subsequent cognitive decline. However, the role of cortical myelination in cognitive decline and its association with CRF remains elusive. We used two microstructure MRI measures: MWF, which is a direct measure of myelin content, and R1, which is sensitive to lipids, the main constituents of myelin, to first, investigate the relationship between myelination and longitudinal changes in cognition, and second, determine whether higher CRF is associated with higher myelination in cortical regions.

Method

123 participants (55.1±20.4 years) underwent our BMC‐mcDESPOT MRI protocol for MWF and R1 mapping with mean values calculated in 6 GM regions (Table 1). Cognitive performance scores were obtained retrospectively at the time of MRI and before. VO2max, the gold standard measure of CRF, was also measured using our established treadmill protocol. The association between each MRI measure and changes in cognition was evaluated using a linear mixed‐effects model. The association between VO2max and each MRI measure was assessed using a multiple linear regression model. Relevant covariates were included in both models (Figure 1. caption & Figure 2 caption).

Result

Lower myelin content in various GM regions, indicated by lower MWF and R1 values, is associated with a steeper decline in all cognitive domains (Figure 1). These associations were prominent with processing speed and executive function (Table 1A). Moreover, higher VO2max was associated with higher myelin content in several GM regions (Table 1B). An interaction between age and VO2max revealed a steeper positive slope in the older age group, suggesting that the beneficial effect of VO2max on MWF is more pronounced at older ages; and a negative slope in the lower VO2max group, indicating that lower VO2max levels are associated with more rapid demyelination with advanced ages (Figure 2, Table 1B).

Conclusion

These original findings highlight the importance of cortical myelination in cognitive functioning, and suggest that improving CRF could represent a non‐pharmaceutical intervention toward better myelination and offset subsequent cognitive decline.
Pragmatic considerations in clinical biomarker testing for Alzheimer disease
Authors: Schindler Suzanne E. , Paczynski Madeline , Ellington Dawn , Snider B. Joy
Published: January 2025

Background

With the traditional FDA approval of lecanemab for treatment of early symptomatic Alzheimer disease (AD), there has been a surge in demand for clinical AD biomarker testing. While amyloid PET, cerebrospinal fluid (CSF) biomarkers, and AD blood tests are all clinically available, each have different benefits and limitations affecting their real‐world use.

Methods

Pragmatic issues affecting usage of different AD biomarker testing modalities have been experienced in a large specialty memory clinic in St. Louis, MO, USA, that has been scaling up clinical AD biomarker testing, particularly in patients who are candidates for lecanemab treatment.

Results

The high and/or uncertain cost of amyloid PET has limited its use to a small number of patients. CSF biomarkers are the major modality used for AD biomarker testing. The number of lumbar punctures (LPs) has increased from ∼5/month in 2018‐2022 to ∼25/month after the approval of lecanemab. Most patients are willing to undergo LP, the procedure is tolerated well, the cost to patients is reasonable, and insurers are accepting a positive CSF test as sufficient evidence of amyloid pathology for initiation of lecanemab. However, reimbursement for LP is inadequate and LP clinics are burdensome to staff and patients. Approximately 200 AD blood tests have been performed in clinic patients over the past three years. Factors limiting use of AD blood tests include the cost to patients and private insurers not accepting AD blood tests for initiation of lecanemab (Medicare is accepting AD blood tests). More broadly, clinical use of AD blood tests has been complicated by the availability of tests with varying levels of accuracy and interpretability.

Conclusions

Because the major indication for clinical AD biomarker testing is now confirmation of amyloid pathology in patients who are candidates for lecanemab, insurance decisions about which biomarkers are acceptable are driving which AD biomarker modalities are performed. When high accuracy AD blood tests are reimbursed by insurance and accepted as evidence of amyloid pathology, it is likely they will become the dominant modality of AD biomarker testing due to lower burden on staff and patients.
Alzheimer’s disease blood tests of amyloid‐beta 42/40, %p‐tau217, 181, and 205 ratios and MTBR‐243 in real‐world populations: Results from SEABIRD and BioFINDER2
Authors: Bateman Randall J. , Li Melody , Barthélemy Nicolas R. , Bollinger James G. , He Yingxin , Horie Kanta , Koppisetti Rama , Ovod Vitaliy , Schindler Suzanne E. , Sutcliffe Siobhan , Babulal Ganesh M. , Benzinger Tammie L.S. , Lenze Eric J. , Gordon Brian A. , Hansson Oskar , Li Yan
Published: January 2025

Background

Alzheimer’s disease (AD) blood tests that can identify and quantify amyloid plaques, tau tangles, and cognitive and clinical decline are needed in clinical practice, including primary care. However, these tests require validation in diverse groups and real‐world settings. The Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) enrolled 1,122 participants to determine the accuracy and validity of AD blood biomarkers, including amyloid‐β (Aβ) and phosphorylated tau (p‐tau) tests, in a diverse, community‐based sample of older adults compared with amyloid PET and cognitive and clinical measures to determine the impact of key factors (age, race, education, cognition, APOE genotype, and medical conditions).

Method

SEABIRD measured blood plasma Aβ42/40, %p‐tau217, %p‐tau181 and %p‐tau205 ratios by immunoprecipitation‐mass spectrometry. Measures of cognitive and clinical impairment included the AD8® dementia screen, Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR®). 26% of participants completed amyloid PET for comparison to the blood tests. The novel plasma endogenous microtubule binding region of tau with 243 residue (E‐MTBR‐tau243) was measured in a separate cohort, the Swedish BioFINDER2 study, and compared to tau PET for tau tangle assessment.

Result

Of the 1,122 participants enrolled in SEABIRD, 23.5% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 32.1%, as expected for a general population (Table 1). The classification accuracy (ROC AUC) of plasma measures for amyloid PET status was evaluated in a subset of participants: Aβ42/40 0.88, %p‐tau217 ratio 0.96, %p‐tau181 ratio 0.79, and %p‐tau205 ratio 0.83 (Figure 1). The classification accuracy for tau PET status was evaluated in amyloid PET positive participants in BioFINDER2: plasma E‐MTBR‐tau243 0.98, %p‐tau217 ratio 0.87, p‐tau217 concentration 0.89 (Figure 2).

Conclusion

In a diverse population with high comorbid disease burden, AD blood tests using ratios had similar accuracies to those reported in AD research cohorts. Our findings support the clinical use of these tests for detection of both amyloid and tau AD pathologies in the general population. Further, screening with AD blood tests can accelerate enrollment of more diverse cohorts into clinical trials, enabling treatments to demonstrate effectiveness in representative populations.
A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in Alzheimer’s Disease
Authors: Malik Rubina , Beaton Derek , Saykin Andrew J. , Nho Kwangsik , Finger Elizabeth
Published: January 2025

Background

Apathy in patients with Alzheimer’s disease (AD) is associated with significant morbidity. We examined whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with mild cognitive impairment (MCI) and AD.

Method

For 1162 participants in the Alzheimer’s Disease Neuroimaging Initiative, including those with AD, MCI and cognitively normal individuals, a partial least squares correspondence analysis (PLS‐CA) modeled interactions between single nucleotide polymorphisms (SNPs), structural whole‐brain imaging variables, and apathy.

Result

An interaction between apathy, the possession of an APOE (apolipoprotein E) ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and brain atrophy.

Conclusion

The results point to an association of a dopaminergic genetic marker and apathy in AD and may inform future design of clinical trials of apathy, as well as new treatment targets.
Genetically determined higher circulating plasminogen levels contribute to an increased risk of Alzheimer’s disease
Authors: Guo Xingzhi , Li Rui
Published: January 2025

Background

Alzheimer's disease (AD) is the most common form of dementia, characterized by cognitive impairment and memory loss. Previous studies have demonstrated that plasminogen, a key molecule in the fibrinolytic system, is implicated in the pathophysiology of AD. However, it is yet unknown whether the relationship between blood plasminogen and AD is causal.

Methods

Leveraging instrumental variables (IV) from genome‐wide association studies (GWAS), we performed a two‐sample Mendelian randomization (MR) analysis to investigate the causal relationship between plasminogen levels and AD risk. Summary‐level data on blood plasminogen levels was from a GWAS on human blood plasma proteome, and summary statistics on AD were from the International Genomics of Alzheimer's Project (IGAP, N=63,926). Inverse variance weighted (IVW) was used as the primary approach to calculate the estimate, which was further validated using the following sensitivity analyses, including MR‐Egger, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR‐PRESSO), weighted median, simple mode, and weighted mode methods. Additionally, tests for pleiotropy and heterogeneity were conducted to further assess the stability of the MR estimates.

Results

Using the IVW approach, our findings revealed a significant association between higher genetically determined plasminogen levels and an increased risk of AD (odds ratio [OR] = 1.10, 95%CI = 1.04‐1.16, P =0.008), which was further confirmed in sensitivity analyses (Figure 1A). The leave‐one‐out analysis plot revealed that the causal estimate between plasminogen levels and AD was not driven by any single instrumental variable (Figure 1B). The findings from the MR‐Egger intercept test and Cochran's Q test revealed an absence of significant directional horizontal pleiotropy and heterogeneity, suggesting a high level of stability in the current MR study.

Conclusions

According to our research, there is a direct causal link between increased circulating plasminogen levels and a higher risk of AD. Further studies are warranted to evaluate the underlying mechanism of our findings.
Development of a Cognitive Impairment Discrimination Model through Acoustic Analysis of Speech Sounds
Authors: Jeon Jin Yong , Lee Haram , Yoon Hyowon , Roh Sungwon , Ahn Donghyun
Published: January 2025

Background

This study investigates the impact of cognitive impairments on the acoustic characteristics of speech and explores the development of a non‐invasive AI model for the diagnosis of Mild Cognitive Impairment (MCI).

Method

Specifically, using conversational speech data from MCI patients and healthy controls in the DementiaBank, the autocorrelation function (ACF) of the speech signal according to delay time was analyzed. Through such analysis, key acoustic indicators of the speech signal such as τ1, ϕ1, and τe, were calculated, and these were used to employ the concept of pitch strength in the diagnosis of MCI. Additionally, by analyzing four instances of speeches given by former President Reagan at five‐year intervals, the study investigated the changes in speech that occur during the development of cognitive impairment.

Result

The results indicated statistically significant differences in the vocal data of MCI patients compared to the healthy control group, suggesting that cognitive decline affects the periodicity and pitch characteristics of speech.

Conclusion

However, findings from DementiaBank data, which involved responses to memory and cognitive‐function‐related queries in conversations between medical personnel and patients, were not observed in speech acoustic analysis data from simple reading tasks. This highlights the need for further experiments analyzing responses to semi‐structured questions, which involve cognitive brain activity, to confirm the utility of speech data in diagnosing patients with cognitive impairments.
Association between metabolic age and dementia risk: the role of genetic background
Authors: Wang Jiao , Guo Jie , Huang Huijie , Dove Abigail , Miao Yuyang , Ma Xiangyu , Xu Weili
Published: January 2025

Background

Growing evidence indicates that people with neurodegenerative diseases have altered metabolic status, but the association between metabolic age (MetAge), as assessed by circulating plasma metabolomics, and dementia remains unclear. We aimed to investigate the association between MetAge and risk of dementia and to explore whether genetic background plays a role in these associations.

Method

From the UK Biobank, 153,436 dementia‐free adults aged ≥55 (mean age 62.08±4.07 years; 52.54% female) at baseline were followed up to 16 years to detect incident dementia. Dementia was diagnosed based on information from patient registry following international criteria. Nuclear magnetic resonance spectroscopy was used to measure 249 metabolites from plasma samples collected at baseline. MetAge (in years) was calculated based on these metabolites using the XGBoost machine learning algorithm (25.04 to 93.11 years) and tertiled (younger 25.0‐55.7 years, middle‐aged 55.7‐62.7 years, and older 62.7‐93.1 years). AD‐related polygenic risk score (PRSAD) was categorized as low, moderate, and high. Data were analyzed using Cox regression and Laplace regression.

Result

During the follow‐up (median: 14.5, interquartile range: 13.6 – 15.3 years), 4,521 (3.0%) participants developed dementia. MetAge (as continuous variable) was dose‐dependently associated with dementia risk (hazard ratio [HR] and 95% confidence interval [CI] per 5‐year increase: 1.04 [1.02, 1.06]). Compared with younger MetAge, the HR (95% CI) for dementia was 1.13 [1.03, 1.23]. Older MetAge was also associated with earlier onset [10th percentile difference [95% CI]: ‐0.89 [‐1.27, ‐0.50] years) of dementia. In joint‐effect analysis, the HR of dementia was 2.43 (95% CI 2.08, 2.83) among participants with older MetAge and moderate‐to‐high PRSAD, compared to those with younger MetAge and low PRSAD. There was an additive interaction between older MetAge and moderate‐to‐high PRSAD on dementia (attributable proportion: 0.16 [0.01, 0.31]).

Conclusion

Older MetAge is associated with a moderately increased risk of dementia and accelerates dementia onset by nearly 1 year, particularly among people with a high genetic susceptibility for dementia.
CSF and Plasma Proteomics in the AT groups. What is beyond amyloid and p‐tau?
Authors: Benedet Andrea L. , Ashton Nicholas J. , Pola Ilaria , de Bastiani Marco Antônio , Brum Wagner Scheeren , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Therriault Joseph , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R. , Rosa‐Neto Pedro , Zetterberg Henrik
Published: January 2025

Background

The research on Alzheimer’s disease (AD) has substantially advanced in relation to plasma biomarkers, such as pTau217, for the detection of amyloid (Aβ) pathology which identify, with high accuracy, individuals in the AD biological continuum. However, as these biomarkers become abnormal very early in the disease, biomarkers identifying more advanced disease stages and proxying pathophysiological processes beyond amyloidosis are still needed. Therefore, we have conducted a proteomic study, on plasma and CSF, aiming at identifying proteins reflecting pathological changes in AD.

Methods

Participants from the TRIAD cohort, including CU, MCI or dementia, and with available Aβ and tau PET data, had their plasma samples analyzed with NULISAseq CNS panel (Alamar Biosciences). Participants were grouped according to their Aβ ([18F]‐AZD4694>1.55) and tau ([18F]‐MK6240>1.19) statuses in AT groups (A‐T‐ (n=242), A+T‐ (n=27) and A+T+ (n=113); discordant participants were not evaluated (n=28)). LIMMA models evaluated the differential protein expression between groups adjusting for age and sex. Additional WGCNA was implemented aiming to evaluate protein modules associated with these AT groups.

Results

When comparing protein expression according to the Aβ status on participants without evidence of tau pathology (A‐T‐ vs A+T‐), the LIMMA analysis unveiled proteins previously associated with Aβ pathology such as pTau217, pTau231 and GFAP, with the addition of two interleukins (Figure 1). However, when contrasting tau pathology status amongst Aβ+ individuals, additional proteins were evidenced such as NPTX1 and NPTX2, NEFL, MAPT, IL6 and IL13. The WGCNA analysis identified one significant protein module that negatively correlated with group A‐T‐ and positively correlated with A+T+ group, recapitulating findings from the initial LIMMA analysis (Figure 2).

Conclusion

In this plasma proteomic study, analysis focusing on Aβ+ groups unveiled proteins that have been largely reported as associated with amyloid pathology and proteins related to immune regulation. However, when the addition of tau pathology was accounted for, proteins associated with tau pathology, inflammation, neurodegeneration and synaptic dysfunction were differentially expressed in the peripheral fluid. These findings will soon be complemented with CSF data, and we will be able to confirm the link between central and peripheral proteomics to brain pathology.
Advancing Alzheimer's Diagnosis: Creating the Gold Standard pT217‐Tau Antibody for Enhanced Sensitivity
Authors: Park Ji‐Seon , Park Heeseon , Cho Mi‐Hyang , Hwang Kyung‐Hoon , Kim Min‐Seok
Published: January 2025

Background

While numerous blood biomarkers have been proposed for Alzheimer’s disease (AD), only a few have demonstrated definitive diagnostic value. Recently, a set of phosphorylated Tau proteins, particularly pT217, have emerged as promising candidates with superior diagnostic performance. Given the development of pT217 antibodies by major global pharmaceutical companies, our goal is to create the best‐in‐class pT217 antibody, establishing it as the gold standard for diagnostics. To address common practical challenges encountered in applying antibodies to patient blood samples, including plasma or serum, we implemented specific strategies from the initial screening of antibodies targeting pT217. We then compared the performance of our various antibody clones against those of other companies.

Methods

To develop antibody specifically targeting pT217 Tau, we obtained antibody clones from mice immunized with an antigen including epitope targeting pT217 sequence. Using several Tau fragment peptides containing pT217 sequence, we compared the binding efficiency of the pT217 antibody clones by ELISA analysis. Additionally, we explored diagnostic potential of the clones for AD in human plasma samples.

Results

Our antibody clones exhibited a threefold enhancement in the lower limit of quantification (LLOQ) for pT217 Tau fragments compared to antibodies from Company‐L. Additionally, the LLOQ for different lengths of pT217 Tau fragments was improved fourfold with our antibody clones when contrasted with Company‐L's antibodies. These results unequivocally underscore the significantly higher sensitivity of our antibody candidates compared to those from Company‐L.

Conclusions

Our study has demonstrated the successful development of pT217 antibodies with superior sensitivity in comparison to global competitors' pT217 antibodies. These antibodies exhibit robust and specific binding to the pT217 Tau peptide, a pivotal component in Alzheimer's disease diagnosis and research. The heightened sensitivity of our antibodies positions them as strong contenders in advancing Alzheimer's disease diagnostics, potentially enabling earlier and more accurate disease detection. These findings hold substantial promise for enhancing early Alzheimer's disease diagnosis and contributing to the development of more effective treatment strategies.