bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuron‐derived small extracellular vesicles as a ‘liquid biopsy’ to assess brain insulin signaling deregulation in Alzheimer's disease pathogenesis
Authors: Cleary Jacob Alexander , Kumar Ashish , Su Yixin , Kim Susy , Singh Sangeeta , Harrison William , Hayden Kathleen M. , Lee Jingyun , Espeland Mark A. , Furdui Cristina M , Ding Jingzhong , Craft Suzanne , Deep Gagan
Published: January 2025

Background

Insulin signaling deregulation in the brain is a critical risk factor for Alzheimer's disease (AD); however, molecular changes in this pathway during AD pathogenesis cannot be currently accessed in clinical setting due to lack of brain tissues. Here, we propose small extracellular vesicles (sEV) characterization as a non‐invasive approach to assess the status of insulin signaling in the AD brain.

Method

In postmortem brain tissues of cognitively normal (CN) and AD (n=5 each) subjects, expression of 84 genes, involved in insulin signaling and resistance was analyzed using pathway specific PCR array. Next, the level of key miRNAs (miR185‐5p, miR‐210‐3p, and miR342‐3p), that regulate the expression of insulin signaling genes, was assessed by TaqMan‐based qPCR in brain tissues and secreted sEV in their microenvironment. The expression of these miRNA was also analyzed in the neuron‐derived sEV (NDE) isolated from the plasma of 28 CN (18 female and 10 male) and 28 dementia (11 female and 17 male) subjects, all with type‐2 diabetes. These highly specific NDE were isolated by sequential immunoprecipitation using CD171 and synaptophysin surface markers, and the expression of studied miRNAs was correlated with corresponding clinical measures (MMSE score, Aβ1‐40 and Aβ1‐42 levels).

Result

AD brain tissue revealed significant deregulation of genes involved in insulin signaling and resistance (e.g., AKT2, GSK3β, INSR, KRAS, PIK3R1, IGF1R, PTPN1, BRAF, GCK, UCP1, LDLR, NPY, and RRAS2). We also observed a significant increase in the expression of miRNAs (miR185‐5p, miR‐210‐3p, and miR342‐3p) involved in regulation of these genes. Interestingly, the expression of these miRNAs in the brain tissues as well as their secreted sEV showed a high degree of concordance. Most importantly, NDE in the plasma of individuals with dementia also showed a similar change in the expression of miRNAs regulating insulin signaling in the brain, suggesting suitability of sEV application as liquid biopsy for the brain tissue. Lastly, this increased expression of NDE miR‐185‐5p in dementia showed significant inverse correlation with MMSE Score.

Conclusion

NDE in plasma offer critical molecular information about insulin signaling and resistance in the brain, which could be valuable in making diagnostic and treatment decisions in AD.
Microglial‐targeted nSMase2 inhibitor fails to reduce tau spread in the animal model of Alzheimer’s disease
Authors: Huang Meixiang , Tallon Carolyn , Zhu Xiaolei , Huizar Kaitlyn , Piccirillo Silvia , Thomas Ajit G , Tenora Lukas , Liyanage Wathsala , Roda Francesca , Gualerzi Alice , Kannan Rangaramanujam M , Bedoni Marzia , Rais Rana , Slusher Barbara S
Published: January 2025

Background

Cognitive decline associated with Alzheimer’s disease (AD) correlates with hyperphosphorylated tau (pTau) propagating between neurons along networks connected by synapses. It has been hypothesized this transcellular transmission occurs partially by extracellular vesicles (EVs). Both genetic and pharmacological inhibition of nSMase2 has been found to inhibit EV biogenesis and pTau propagation. However, the lack of suitable nSMase2 inhibitors for clinical development has been a challenge. In our lab, a highly selective and nM potency nSMase2 inhibitor, termed DPTIP, was identified through a high‐throughput campaign. However, it has poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To improve its PK properties, we conjugated it to a hydroxyl‐PAMAM dendrimer delivery system, creating dendrimer‐DPTIP (D‐DPTIP), which selectively targets microglia. In previous studies, using a murine AAV‐hTau brain injection propagation model, we showed that administration of D‐DPTIP significantly inhibited tau spread. In this study we extended those studies to evaluate D‐DPTIP in Tau P301S (PS19) transgenic mice.

Method

PS19 mice were chronically dosed for 20 weeks. Subsequently cognitive function was evaluated using the Y‐maze and Novel Object Recognition tests, and hippocampal volume was measured through MRI. Total tau and pTau levels were quantified by immunoblotting. Immunofluorescent staining and fluorescence‐activated cell sorting (FACS) were employed to identify cell types in the brain responsible for D‐DPTIP internalization. nSMase2 target engagement assays were conducted in both CD11b+ (microglial) and CD11b‐ (non‐microglial cells). Surface plasmon resonance imaging (SPRi) was used to characterize the origin of brain extracellular vesicles (EVs) released into plasma in PS19 mice ± D‐DPTIP treatment.

Result

Total tau, pTau, cognitive deficits, and hippocampal volume loss were not altered by D‐DPTIP treatment in the PS19 mice. D‐DPTIP was found to be co‐localized with microglia and selectively decreased nSMase2 activity in the CD11b+ cells. SPRi analysis showed a decrease in levels of activated microglia‐derived plasma EVs following treatment.

Conclusion

D‐DPTIP selectively targets and inhibits nSMase2 activity in microglia. Consequently, in the AAV‐hTau seeded model where microglial EVs play a central role, D‐DPTIP successfully inhibits tau propagation. However, its effectiveness is limited in PS19 mice, where neuronal‐mediated tau propagation is thought to be predominant.
Exploring the protective potential of bilobalide against amyloid beta peptide 1‐42‐induced toxicity in BE(2)‐M17 cells: insights via cell viability and cellular energetics
Authors: Chakraborty Manas , Dhiman Kunal , Gupta Veer
Published: January 2025

Background

Reliable treatment approaches for addressing early cognitive impairment and Alzheimer’s disease (AD) are currently lacking. Given the multifactorial nature of AD, therapeutic strategies need to focus on disease‐specific biochemical pathways. Given the significance of metabolic pathways in cognitive impairment, it is essential to investigate alternative disease modifiers capable of targeting multiple metabolic pathways, such as phytochemicals. This research project aims to identify alterations in bioenergetics and viability resulting from amyloid pathology in cell models. Additionally, it will assess the therapeutic potential of a of bilobalide a biologically active terpenoid extracted from Ginkgo biloba. in alleviating these changes.

Method

The Neuroblastoma cell line BE(2)‐M17 cells were utilized to establish an in vitro model of Alzheimer’s disease (AD). These cells underwent differentiation into mature human neurons through treatment with 10 µM retinoic acid. Prior to treatment with amyloid beta 1‐42 (20 µM) for 24 hours, the cells were pre‐treated with varying doses of bilobalide (1 µM, 5 µM, 10 µM, 15 µM, and 20 µM) for 24 hours. To assess the impact of bilobalide pretreatments on cell viability, a Cell Titer Glo assay was performed. The oxygen consumption rate, Total Reactive Oxygen Species (ROS), and 2',7'‐dichlorofluorescin diacetate (DCFDA) assays were conducted to evaluate cellular responses. Additionally, Seahorse analysis was employed to further investigate the oxygen consumption rate.

Result

The successful differentiation of the BE(2)‐M17 cells has been achieved and confirmed through morphological changes. The cell viability results indicate a substantial impact of bilobalide in mitigating the amylopathic changes induced by the amyloid beta insult. While the cell energetics evaluation is still underway, the preliminary results from the pilot study strongly suggest a significant impact of bilobalide in alleviating the amylopathic changes induced by the amyloid beta insult

Conclusion

The observed amelioration of amylopathic changes points towards the potential therapeutic effect of bilobalide in the context of Alzheimer’s disease. These initial findings provide promising indications of the potential effectiveness of bilobalide in influencing cellular energetics in the context of Alzheimer’s disease.
Counterfactual reasoning‐based intervention effect estimation for longitudinal cognitive decline
Authors: Kang Sohyun , Song Yeong‐Hun , Seong Joon‐Kyung
Published: January 2025

Background

After the landmark approval of the Aβ‐lowering antibody for treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease (AD), it has intensified the need to stratify patients based on the likelihood that they will benefit from any amyloid‐lowering treatments currently in the pipeline. We therefore seek to identify individuals most likely to benefit from Aβ‐lowering drugs by estimating intervention effect based on counterfactual reasoning for longitudinal cognitive decline at the individual level.

Method

We utilized 3,542 T1‐weighted magnetic resonance images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), involving 3,103 Alzheimer’s patients and 439 cognitively normal individuals. Cortical thickness data, processed with FreeSurfer v7.0 and the Desikan‐Killiany atlas, underwent W‐score correction for age, sex, and education to address confounding effect. Amyloid positivity, determined by ADNIMERGE AV45 (>=1.11), was considered. Patients were stratified based on the clinical dementia rating sum of boxes (CDRSB) decline rate into fast or slow decliners. Our framework integrates counterfactual reasoning and intervention effect estimation through a deep explainable AI method rooted in causality. The framework comprises 1) amyloid‐neurodegeneration‐cognition encoding, 2) counterfactual map generation, and 3) intervention effect estimation, illustrated in Figure 1.

Result

The encoder achieved a 5‐fold cross‐validation accuracy of 0.9230 ± 0.0101, with corresponding F1 score and mAUC values of 0.8948 ± 0.0140 and 0.9454 ± 0.0108, respectively (Figure 2). Individual counterfactual neurodegeneration maps targeting slow decliners to fast decliners revealed positive amyloid changes and worsened cognitive outcomes (Figure 3). On the other hands, targeting fast decliners to slow decliners exhibited negative amyloid changes and improved cognitive outcomes. The correlation between cognitive deterioration probabilities (indicating fast decliner status) and amyloid intervention (counterfactual amyloid level) was positive and significant (r=0.2109, p<0.0001) (Figure 2).

Conclusion

Although this work focuses on the fundamental counterfactual reasoning for predicting the rate of longitudinal cognitive decline in the AD spectrum, it also has major potential clinical implications in the era of Aβ‐lowering therapies. By editing the patient‐tailored counterfactual reasoning process, we accurately estimate intervention effect at the baseline timepoint, so that maximize clinical benefit through optimized personalized treatment.
Locus Coeruleus Neuroimaging compared Voxel by Voxel to Histology‐ a postmortem human validation study
Authors: LaMore Tia , Huang Shuo , Marinho Pedro Burlacchini S. , Chen Yuheng , Li Song Hua , Lee Wing Hung , Carreira Luzia Lima , Rodriguez Roberta Diehl , Otaduy Maria Concepción Gracía , Shi Yonggang , Grinberg Lea T.
Published: January 2025

Background

Neuropathological studies indicate that locus coeruleus(LC) volume decreases in Alzheimer’s disease(AD) by 8% at each stage, (from Braak 0‐1), whereas in normal aging, the LC remains unchanged. These changes make LC volumetry by neuroimaging a promising way to track AD progression even before symptoms appear. However, LC’s small size and location make it prone to imaging artifacts. To assess the accuracy of neuroimaging sequences designed for LC volumetry, we used an in‐house histological computational method to compare histology and neuroimaging on a voxel‐by‐voxel basis.

Method

We investigated three cases (two Braak 1s, and a Braak 5). The whole brain underwent 7T MRI postmortem, pre‐autopsy, at the University of Sao Paulo. Upon autopsy, the brains were processed at UCSF and the histological LC was 3D reconstructed. In parallel, the GRE and TFL MRI sequence LCs were segmented (Figure 1). We applied affine& spline registration to match histology to MRI‐T1 volumes (voxel size=0.75mm)(Figure 1). To measure registration accuracy, we calculated DICE coefficients using T1 visible structures (Figure 2). Next, we analyzed the percentage overlap of voxels to investigate how accurately MRI sequences detected histology LC borders.

Result

Overall, the DICE values for brainstem registration are high. Table 1 shows the overlapping percentages that are quite low, from 2.5%‐23%. For our Braak 1 cases, the least overlap of GRE MRI and histology LC borders is in rostral region, while in both TFL and GRE sequence for the Braak 5 case, the least LC overlap was in the caudal region (Table 1).

Conclusion

These results suggest that accurately detecting LC borders using MRI remains a challenging task due to small size, imaging artifacts, and neuromelanin dependency, which is low at baseline in caudal LC. However, our overlap results did match previous findings on specific regional LC volume loss seen rostrally in early AD, despite no neuronal loss, and in later stages of AD, volume loss caudally. This points to the MRI LC signal being potentially clinically useful for disease monitoring. Our study will continue to examine the MRI signal picked up in the LC across Braak as regions of LC degeneration shift compared to the histology counterpart.
Association between hippocampal subfield volume estimated from ultra‐high field scans and cognitive and clinical symptoms in patients with late‐life depression and healthy controls
Authors: Hu Xiaochen , Zeyen Philip , Bischof Gérard N , Elmenhorst David , Andrassy Gregory , Aktas Beyza , Schruttke Neele , Lee You Na , Mokhtari Niloofar , Berron David , Giehl Kathrin , Onur Oezguer A. , Stirnberg Rüdiger , van Eimeren Thilo , Drzezga Alexander , Dafsari Forugh S , Stoecker Tony , Jessen Frank
Published: January 2025

Background

Late‐life depression (LLD) is a risk factor for Alzheimer's disease (AD) dementia. Previous morphological studies have often associated LLD with atrophy within the medial temporal lobe (MTL), including the hippocampus. A number of previous studies have demonstrated the changes in several MTL subfields in LLD, such as the perirhinal cortex (PrC), cornu ammonis (CA), dentate gyrus (DG), subiculum and entorhinal cortex (EC), but with inconsistent results, which may be explained by the relatively low image resolution of the 3T scanner used in the previous studies.

Method

A total of 93 individuals over the age of 60 were included in this study, of which 23 LLD patients and 29 normal controls without a history of depression underwent T1 and T2tse scans on a 7‐Tesla MRI scanner. Images were pre‐processed and roughly segmented into CA1‐3, DG, SUB, EC, and PrC (area 35, 36) using the Automated Segmentation Hippocampal Subfields (ASHS) and further separated into anterior and posterior (head and body). All segmented images were manually edited. Group comparisons of MTL subfield volumes were made, adjusting for age, sex, and years of education. Cognitive and clinical scores were correlated with the volume of each subfield.

Result

LLD and controls did not differ in total hippocampal volume. LLD showed reduced volume in the head portion of the right DG (p=0.05) and a trend towards reduced ratio between left and right EC (p=0.07). No other group differences were observed. Correlational analyses revealed a significant association between bilateral hippocampal volume and TMT‐A speed, as well as the anxiety subscale of the Geriatric Depression Scale (GDS). Subfield analyses revealed significant associations between the anxiety subscale of the GDS and bilateral DG head volume (left: r=‐0.36, p=0.006; right: r=‐0.42, p=0.002) and between the left CA1 body and the cognition subscale of the GDS (r=0.29, p=0.03).

Conclusion

Using ultra‐high field MRI, we demonstrated an anterior‐posterior differentiation along the hippocampal long axis in the involvement of cognitive and clinical symptoms in LLD. Future work should investigate the relationship between AD pathological changes and behavioral symptoms in LLD and whether MTL subfields may play a mediating role.
CSF profiling of impaired Blood‐brain barrier individuals: novel putative biomarkers discovery
Authors: Santis Giovanni De , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J.
Published: January 2025

Background

Blood‐brain barrier (BBB) integrity is crucial for brain homeostasis and maintenance. This is a pilot study to investigate cerebrospinal fluid (CSF) levels of several proteins implicated in BBB integrity, such as aquaporin‐4 (AQP4), platelet‐derived growth factor (PDGFRβ), human major facilitator superfamily domain containing protein 2A (MFSD2A), matrix metalloproteinase (MMP)‐9, Matrix metalloproteinase (MMP)‐2, and Fibrinogen, for assessing BBB integrity.

Method

CSF samples were collected from 100 participants (36 [36%] female and 64 males [64%]; mean [SD] age, 73,34 [9,05] years). Participants were stratified according to their CSF/serum albumin concentration ratio (Q‐Alb); intact BBB (Q‐Alb <9, n = 25), mild BBB damage (Q‐Alb 9‐14, n = 25), modest BBB damage (Q‐Alb 14‐30, n = 24), and severe BBB damage (Q‐Alb >30, n = 25). AD CSF biomarkers (p‐Tau181, total‐Tau, Aβ42/40 ratio) were assessed by LUMIPULSE G1200. Protein levels were quantified using ELISA Kits (CUSABIO, Thermofisher, Bioss Antibodies). Correlation analyses were conducted between protein levels and albumin CSF/serum ratios with R (Kruskal‐Wallis test with pairwise comparison, Bonferroni method, was performed).

Result

CSF AQP4 and PDGFRβ levels were significantly higher in individuals with severe BBB damage (Figure 1). No significant differences are highlighted in the levels of MMP9, MMP2, MFSD2A and Fibrinogen; whereas, in both MFSD2A and Fibrinogen it is shown a notable difference in the levels of protein between the modest and intact groups, with a subsequent decline in the severe group. A positive correlation (Figure 2) between PDGFRB and AQP4 with Q‐Alb (PDGFRB, r = 0,273, P < 0,0001; AQP4, r = 038, P < 0,001) was found, where AQP4 seems to best reflect albumin stratification (Figure 3).

Conclusion

In this pilot study, we show that CSF concentration of some blood‐brain barrier‐related proteins increases with severity of BBB damage. This highlights their potential as novel biomarkers for monitoring BBB integrity. Remarkably, the presence of high concentrations of Fibrinogen in the CSF could be an important feature to further investigate.
Are exercise classes for older people, including those with dementia, located in areas with the greatest need in the North East of England?
Authors: Ardle Ríona Mc , Foster Lucy , Long Annabelle , Alcock Lisa
Published: January 2025

Background

Approximately 944,000 people are living with dementia in the UK (∼0.8% of the population). The World Health Organisation consider dementia a public health priority. Efforts to prevent dementia and to decelerate its progression to dependency/disability are vital.

Promoting physical activity (e.g. exercise classes) can support dementia prevention and once diagnosed, support independence. Previous research indicates that most exercise classes for older adults in the East Midlands of England are in areas with small percentages of older inhabitants and only 2% are cited as suitable for dementia. As older adults in the North East (NE) of England have worse health outcomes, greater socioeconomic deprivation and lower life expectancy, we aimed to identify the geographical distribution and population characteristics of exercise classes in NE of England.

Method

For preliminary analysis, one county in NE of England was selected, Tyne and Wear, an area of 538km2 with an estimated population of 1,136,371 (19% aged ≥65 years) in 2021. The area is primarily urban (∼98%). Exercise classes were identified via a comprehensive Google search undertaken in December 2023 and geocoded. Data were input into a geographic information system (ArcGIS, Esri). Spatial analysis tools in ArcGIS calculated number and percentage of classes with respect to population age, socio‐economic status and population density.

Result

427 exercise classes were identified as suitable for older adults; <1% (n = 2) were advertised as appropriate for people with dementia. 5.4% were situated in areas where the predominant age group are aged ≥65years (Fig. 1), 20.6% in areas with the greatest socio‐economic deprivation (Fig. 2; based on Index of Multiple Deprivation) and 98% in urban areas (Fig. 3).

Conclusion

Results highlight that there are limited opportunities for people with dementia to participate in exercise classes in Tyne and Wear, England. Additionally, most exercise classes are in urban areas where a low percentage of the population are aged ≥65years, limiting their accessibility to older people. Addressing this issue may contribute to health equity and disability‐free life expectancy in NE, supporting both dementia prevention and dementia post‐diagnostic support. Further work will consider the rest of NE of England (Northumberland, Durham) for a more representative analysis.
Cognitive reserve: Resting‐state functional connectivity moderates the association between white matter hyperintensity and executive function in older adults with subcortical ischemic vascular cognitive impairment
Authors: Gu Yi , Hsu Chun Liang , Silva Nárlon Cássio Boa Sorte , Tam Roger , Alkeridy Walid Ahmed , Lam Kevin , Liu‐Ambrose Teresa
Published: January 2025

Background

Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. White matter hyperintensities (WMH) are hallmarks of SIVCI and are associated with impaired executive function. Cognitive reserve is a property of the brain that moderates an individual’s ability to maintain cognitive performance given brain injury or pathology. The neural correlates of cognitive reserve remain elusive; however, resting‐state functional connectivity (rs‐FC) in networks such as the fronto‐executive network (FEN), fronto‐parietal network (FPN) and default mode network (DMN) have been proposed as potential candidates. The role of these networks in mitigating the impact of SIVCI‐related pathology on cognition remains unclear. Therefore, we investigated whether intra‐network rs‐FC in the FEN, FPN, and DMN moderated the negative impact of WMH on executive function in older adults living with SIVCI.

Method

We conducted a cross‐sectional study among 38 community‐dwelling older adults with SIVCI. Executive function was assessed by the Trail Making Test (B‐A). WMH volume was quantified by T2‐weighted and proton density‐weighted structural magnetic resonance imaging (MRI) using a seed‐based method and log‐transformed before analyses. The rs‐FC was computed via a 5‐min resting‐state functional MRI scan with priori‐selected region‐of‐interest masks. A moderation analysis was conducted to assess whether intra‐network rs‐FC in the FEN, FPN and DMN moderated the association between WMH volume and executive function, adjusting for age, sex, and Montreal Cognitive Assessment (MoCA) score.

Result

The participants had a mean age of 74.1 years (SD = 5.5) and 71% were female; the mean MoCA score was 21.29 (SD = 2.66). Compared with individuals with lower intra‐network rs‐FC of DMN, those with greater intra‐network rs‐FC of DMN (non‐standardized b = ‐2913.64, p = 0.000) showed better Trail Making Test performance under greater WMH load. In contrast, individuals with lower intra‐network connectivity of FEN (b = 2050.34, p = 0.007) and FPN (b = 1790.81, p = 0.005) had better Trail Making Test performance under greater WMH load.

Conclusion

The strength of intra‐network connectivity in the FEN, FPN, and DMN moderates the impact of WMH on executive function in older adults with SIVCI. The results shed light on the potential neural basis of cognitive reserve against WMH.
Combining blood‐based biomarkers and accessible measures for the prognosis of cognitive decline in older primary care patients
Authors: Kleineidam Luca , Oezdemir Selçuk , Martino‐Adami Pamela , Chatterjee Madhurima , Pentzek Michael , Weyerer Siegfried , Bickel Horst , Wiese Birgitt , Riedel‐Heller Steffi G. , Scherer Martin , Zetterberg Henrik , Blennow Kaj , Jeromin Andreas , Wagner Michael , Ramirez Alfredo , Schneider Anja
Published: January 2025

Background

Combining plasma phosphorylated Tau 217 (pTau217), with cognitive assessments allows for predicting incident dementia in mild cognitive impairment (MCI). However, the performance of this approach in primary care as well as the added value of other blood‐based biomarkers (BBM) in this setting is unclear.

Methods

We examined 833 older primary care patients from the AgeCoDe/AgeQualiDe study (median age=83). Plasma ALZpath pTau217 and other blood‐based biomarkers (BBM; pTau181, GFAP, NfL, Abeta‐42/40) were measured using single‐molecule arrays. Subjective cognitive decline (SCD) and the Mini‐Mental State Examination (MMSE) were assessed at baseline. We evaluated the performance of BBM, MMSE, and SCD reports for predicting the development of any cognitive impairment (MCI or dementia) or conversion to dementia at 3.5 and 7 years of follow‐up using time‐dependent ROC analysis with death as competing risk.

Results

Plasma pTau217 improved the prognosis of developing any cognitive impairment at follow‐up beyond age, sex, and renal function (base model; Figure 1) and showed a high prognostic value at 7 years of follow‐up (p<0.001, AUC=0.809; 3.5 years prognosis: p<0.001; AUC=0.767). Adding SCD and MMSE to the model provided only a small improvement in short‐term prediction (3.5 years prognosis: p=0.002; AUC=0.785) while no significant improvements were observed by considering other BBM.

For predicting incident dementia, pTau217 also increased the prognostic value beyond the base model (3.5 years: p=0.044, AUC=0.689; 7 years: p=0.002; AUC=0.697). However, this increase was smaller as compared to the prognosis of any cognitive impairment since individuals developing MCI but not dementia showed similar pTau217 levels at baseline. Furthermore, considering MMSE and SCD reports resulted in a considerable increase in prognostic value beyond pTau217 (3.5 years: p<0.001, AUC=0.791; 7 years: p=0.002; AUC=0.749). Plasma pTau217 in turn improved the long‐term prediction beyond SCD reports and MMSE (p<0.001, AUC=0.749 vs 0.724). Again, other BBM did not increase the prognostic value.

Conclusions

In our sample, pTau217 showed a high ability to discriminate between older primary care patients who will stay cognitively stable over seven years from patients developing any cognitive impairment, in contrast to other BBM. Assessments of SCD and cognition can further improve the identification of patients at increased short‐term risk for dementia.
The role of biofluid markers in predicting near‐term cognitive impairment
Authors: Yakoub Yara , Gonzalez‐Ortiz Fernando , Ashton Nicholas J. , Karikari Thomas K , Strikwerda‐Brown Cherie , St‐Onge Frédéric , Ourry Valentin , Schöll Michael , Geddes Maiya R. , Ducharme Simon , Rosa‐Neto Pedro , Soucy Jean‐Paul , Breitner John C.S. , Zetterberg Henrik , Blennow Kaj , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: January 2025

Background

PET biomarkers have proven valuable for identifying cognitively unimpaired (CU) individuals at‐risk of near‐term clinical progression. Given the increasing interest in plasma biomarkers to detect Alzheimer’s pathology, we assessed levels of amyloid (Aβ42/40) and tau (p‐tau217 and p‐tau181) biomarkers in plasma (A+T+plasma) in CU individuals as predictors of clinical progression to mild cognitive impairment (MCI). We then repeated these analyses using cerebrospinal fluid (CSF) and PET biomarkers.

Method

We studied 218 participants from the PREVENT‐AD cohort with cognitive follow‐up (mean 5.34 years, range 1–10 years) and plasma biomarkers available while CU. Cognition was assessed annually using the RBANS. Plasma biomarkers were measured using IP‐MS for Aβ42/40 and in‐house single molecular arrays for p‐tau217 and p‐tau181. An overlapping 71 participants had Aβ42/40 (Mesoscale Discovery assay) and p‐tau181 (Innotest immunoassay) CSF data available, and 135 participants had Aβ (18F‐NAV4694) and tau (18F‐florbetapir) PET data. We also performed receiver operating characteristic (ROC) curves to compare the performance of plasma (Aβ42/40 and p‐tau217; Aβ42/40 and p‐tau181), CSF (Aβ42/40 and p‐tau181) or PET (Aβ‐ and tau‐PET) biomarkers in predicting progression to MCI. We examined an additional model including only Aβ‐PET, given the importance of this technique as a stand‐alone marker for recruitment in anti‐Aβ trials.

Result

The proportion who progressed from CU to MCI was 62% in individuals with A+T+plasma217; and 41% with A+T+plasma181; 56% with A+T+CSF181 and 100% with A+T+PET (Figure 1). Cox proportional hazard models indicated a faster progression rate in all A+T+ groups compared with their matched A‐T‐ biomarker groups (Figure 2). Considering longitudinal RBANS scores, all A+T+ groups declined faster than the other groups, except for the plasma181 group. Finally, the PET (Aβ and tau‐PET) and CSF models were superior to the plasma or Aβ‐PET alone in identifying progressors, with no meaningful difference between the Aβ‐PET and the biofluid models (Figure 3).

Conclusion

CU individuals with A+T+ based on plasma biomarkers are at increased risk of cognitive decline and clinical progression. Nevertheless, the proportion who progressed to MCI in individuals classified with plasma was lower than that found using PET. Thus, the latter should remain the gold standard to identify presymptomatic pathological changes.
Subjective Memory and its Association with Cognitive Performance among Older Adults: Findings from a Cohort Study in Lebanon
Authors: Chaaya Monique , Abdulrahim Sawsan , Elbejjani Martine , McCall Stephen , Sammak Aya El , Nassif Alexandra Abi , Ngwa CH Henry , de Leon Carlos Mendes
Published: January 2025

Background

Rapid aging in low‐to‐middle income countries (LMICs) is expected to lead to exponential growth in dementia. As standard cognitive tools can be time‐consuming and cause fatigue for older adults, health professionals in primary care settings can utilize efficient measures to assess their cognitive performance. To date, there are still inconsistencies in the correlation between subjective memory complaints and cognitive impairment. Moreover, the validity of using a single‐item subjective memory is still not established. The aim of this study is to assess whether a one‐item measure of subjective memory is correlated with objective measures of cognitive performance among older adults in LMICs.

Method

Lebanon Study on Aging and Health (LSAHA) is an ongoing population‐based cohort study of older adults aged 60 years or older, where 1,502 older adults were recruited from a rural district in Lebanon between October to December 2023. Cognitive performance was assessed using four tools: the Cognitive Domain in the ‘Community Screening Instrument for Dementia (CSI‐D)’ the ‘CERAD 10‐word’ immediate and delayed recall and the Informant Questionnaire on Cognitive Decline among the Elderly (IQCODE). Subjective memory was assessed by a single item and responses were categorized as: “good/very good/excellent” and “fair/poor.” Baseline data was analyzed using adjusted linear and logistic regression models to assess the association between subjective memory and cognitive performance measures.

Result

Of the participants that responded to subjective memory and cognitive tools (n = 1,245), more than half (56.3%) reported fair/poor subjective memory. Adjusting for age, gender, and educational level, subjective fair/poor memory recall was significantly associated with higher odds of cognitive impairment based on CSID (OR:1.82 95%CI:1.42‐2.34) and IQCODE (OR:1.78 95%CI:1.33‐2.37) and a lower number of immediate (β:‐1.70 95%CI:‐2.19‐ ‐1.20) or delayed (β:‐0.65 95%CI:‐0.85‐ ‐0.44) word recall.

Conclusion

This study’s findings suggest that a single‐item subjective memory assessment could be used by healthcare providers to identify older adults who may require further evaluation for cognitive impairment, similar to how self‐rated health has been a good marker for mortality and other health conditions. The results of this study warrant further research on this measure across different populations, comparing it with other validated screening tools.
Modifiable and non‐modifiable disparity‐related predictors of cognitive scores in a population‐based cohort: the ELSI‐Brazil
Authors: Borelli Wyllians Vendramini , Da Ros Lucas Uglione , Aguzzoli Cristiano Schaffer , de Bastiani Marco Antônio , Suemoto Claudia Kimie , Zimmer Eduardo R.
Published: January 2025

Background

Social and health‐related disparity factors are important predictors of brain health in low and middle‐income countries (LMIC). Social predictors of cognition have a higher impact on brain health among LMICs than classic demographic factors, such as age and sex. This study aimed to evaluate the impact of modifiable and non‐modifiable social and health‐related factors on cognition in a Brazilian population‐based cohort.

Method

We selected 9,412 individuals from the ELSI‐Brazil cohort, which is a population‐based study conducted with a similar design as the Health and Retirement Study. Complex sample design stratified and clustered distinct geographical regions according to their representation nationally. We included health‐related disparity factors (hypertension, diabetes, cardiovascular disease, and falls), as well as social determinants of health (piped water, access to healthcare, private health coverage, income, food insecurity, and education). Non‐modifiable factors were also retrieved (age, sex, race and region). We evaluated cognition using a global composite of orientation, animal fluency, and memory recall scores. A linear regression model was conducted to identify and stratify predictors of global cognitive scores (R2 adjusted = 0.336).

Result

We included 5,432 individuals above 60 years of age in this analysis (mean age 70.3±7.97 yo). The regression model identified that the most important modifiable predictor of cognition was depression (ß = ‐0.14±0.06, p < 0.001), followed by physical activity (ß = 0.12±0.03, p < 0.001), and private health coverage (ß = 0.09±0.06, p = 0.001). Among non‐modifiable predictors of cognition, northeast region dwelling was the most important predictor (ß = ‐0.16±0.05, p < 0.001), following residing in the north region (ß = ‐0.14±0.10, p = 0.006), and brown race (ß = ‐0.1±0.05, p < 0.001). No health‐related factor reached significance.

Conclusion

Overall, modifiable and non‐modifiable social‐related disparity factors had a significant impact on cognition in this study. Modifiable factors should be addressed in public health policies, while non‐modifiable risk factors may provide insights on compensatory strategies to overcome their negative effects on brain health. Further studies may expand this investigation to other LMIC.
The influence of amyloid on tau deposition in clinically obese participants
Authors: Yu Yang Yang , Nowell Joseph , Edison Paul
Published: January 2025

Background

Obesity is a prevalent comorbid condition that doubles the risk of Alzheimer’s disease. The proposed mechanisms underlying neuronal damage involve chronic low‐grade inflammation, the production of reactive oxidative species, and altered brain glucose metabolism. In Alzheimer’s disease, amyloid is thought to influence tau deposition and glucose metabolism. We explore the impact of amyloid on tau pathology in individuals with obesity.

Method

We processed 267 PET scans (18F‐flortaucipir) from 267 participants with a BMI ≥30 (n=116) and those without obesity (n=151) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to compare tau pathology. Amyloid status was determined from the ADNI database using predefined cerebellum positivity thresholds (SUVR of 1.08 for 18Florbetaben and 1.11 for 18florbetapir). Independent t‐tests and multivariate analysis were employed in subjects with obesity versus those without, in global cortex and specific regions of interests in relation to Alzheimer’s. Amyloid positive and negative subjects were evaluated separately within different cognitive subgroups, namely those with mild cognitive impaired and those who were cognitively normal.

Result

Independent t‐tests were conducted in the obese group with normal cognition and negative amyloid status, revealing higher tau uptake in the parietal lobe and anterior cingulate compared to non‐obese subjects. Multivariate analysis, controlling for age and APOE‐ε4, further confirmed the significance of these findings in these brain regions. This pattern was absent in obese subjects with positive amyloid status and in those with mild cognitive impairment, regardless of amyloid status being positive or negative.

Conclusion

Tauopathy manifests in the obese brain independently of amyloid deposition, even preceding cognitive impairment. These findings suggest that amyloid‐targeting therapies may be less effective in obese patients.
Audiometric hearing level in individuals with SCD, MCI and mild dementia
Authors: Rattanabannakit Chatchawan , Sirikuntharamas Poramad , Suwanwech Triphoom , Prakairungthong Sarun , Nanthasi Witsarut , Senanarong Vorapun
Published: January 2025

Background

Hearing impairment is identified as a risk factor for dementia. This study aimed to investigate audiometric hearing level in individuals across the clinical spectrum of cognitive impairment, from normal cognition (NC) to mild dementia, encompassing subjective cognitive decline (SCD) and mild cognitive impairment (MCI).

Method

135 participants were included in this study. There were 33 NC participants, 36 participants with SCD, 34 participants with MCI, and 33 participants with mild dementia. Demographic data was collected, along with the Montreal Cognitive Assessment (MoCA), and the Cognitive Change Index to capture subjective cognitive complaints from patients themselves (CCI‐S) and their informants (CCI‐I). All participants underwent tonal audiometry to measure the best air‐conduction and bone‐conduction hearing threshold, speech recognition test (SRT) and word recognition score (WRS). Association of audiometric data and cognitive function and their differences between diagnostic groups were analyzed.

Result

The median age of all participants was 61.5 (IQR = 19) years, 77.2% were female, median years of education was 14.5 (IQR = 7) years. There were significant differences in age, education, and visual acuity among groups (all p<0.001) (Table). Air‐conduction and bone‐conduction hearing thresholds demonstrated significant differences between groups (all p<0.001), which the worst performance observed in the mild dementia group (p<0.001), even after controlling for age and education (p = 0.013). 63.2% of all participants were defined as having hearing impairment according to WHO criteria, peaking at 93.94% in mild dementia patients. Individuals with moderate hearing impairment demonstrated lower MoCA score and higher CCI‐I scores, compared to those with mild or no hearing impairment. The higher air‐conduction, bone‐conduction hearing threshold, SRT, WRS were significantly correlated with the lower score of MoCA (r = ‐0.47 to ‐0.36, all p<0.001) and a higher score of CCI‐I (r = 0.31 to 0.39, all p<0.001), but not the CCI‐S. However, these associations became insignificant after controlling for age (all p>0.05).

Conclusion

Our study indicates a link between diminishing audiometric hearing levels and a higher degree of objective cognitive decline, along with an increased level of informant perception regarding individuals' cognitive deficits. Not related to age or education, individuals with mild dementia display significantly worse hearing than those without.
Assessing a Digital Lifestyle Intervention to Reduce Dementia Risk in Older Adults
Authors: Bunyan Maria , Irving Jessica , Barnett Jennifer H , Kawadler Jamie , Bauermeister Sarah , Vassilev Philip , Gallacher John , Koychev Ivan
Published: January 2025

Background

An estimated ∼40% of dementia cases are due to modifiable risk factors which can be targeted in lifestyle interventions. Effective interventions employ face‐to‐face delivery, making them resource‐intensive and burdensome. Digital interventions offer scalability, accessibility and cost‐effectiveness. Engagement and efficacy of digital interventions are unknown, as is whether the ‘human component’ of these interventions must be retained.

Method

The Five Lives app is a digital health solution that combines a CE‐marked dementia risk assessment with a digital coaching programme (DC) to facilitate behaviour changes which could lead to eventual reduced dementia risk. Three groups were compared: DC‐only, DC and access to brief 1‐to‐1 virtual clinician services (DC+VC) and no intervention (control). The study spanned 12 weeks and participants (n = 154) were aged 50‐69 with normal cognition. A lifestyle score was conducted at baseline and exit, which scores participants on behaviour relating to sleep, physical activity, diet, stress & mood and mental stimulation. Engagement was measured as the total number of app activities (brain games, articles, quizzes and lifestyle log) completed during the intervention period.

Result

Participant engagement was high (mean participant activities = 35/week). There was a significantly greater change in lifestyle score between intervention group (DC‐only and DC+VC pooled) and control (F(1,81) = 3.10, p = 0.049), and a trend for significance for a greater change in DC‐only versus control (F(1,24) = 3.96, p = 0.058). The change in lifestyle score between DC‐only and DC+VC was not significant, nor was the difference in app engagement. Total engagement was not predictive of lifestyle score change.

Conclusion

Participant engagement indicates the intervention is feasible in older adults. Results suggest the Five Lives app is a promising tool to facilitate behaviour change to potentially reduce dementia risk, and the VC does not provide significant additional benefits. This study provides initial data to warrant further development of DC interventions to reduce dementia risk. Future analyses should investigate which participants respond best to the intervention, barriers to change, and how engagement interplays with sustained dementia‐targeted lifestyle change.
‘Diet’ deep canonical correlation analysis for high‐dimensional genetics study of brain imaging phenotypes in Alzheimer’s disease
Authors: Yang Shu , Wang Austin , Bao Jingxuan , Mu Shizhuo , Feng Yanbo , Wen Zixuan , Baik Jae Young , Wen Junhao , Hou Bojian , Wang Rongguang , Huang Heng , Saykin Andrew J. , Thompson Paul M. , Davatzikos Christos , Shen Li ,   for the ADNI and AI4AD
Published: January 2025

Background

Understanding the relationship between genetic variations and brain imaging phenotypes is an important issue in Alzheimer's disease (AD) research. As an alternative to GWAS univariate analyses, canonical correlation analysis (CCA) and its deep learning extension (DCCA) are widely used to identify associations between multiple genetic variants such as SNPs and multiple imaging traits such as brain ROIs from PET/MRI. However, with the recent availability of numerous genetic variants from genotyping and whole genome sequencing data for AD, these approaches often suffer from severe overfitting when dealing with ‘fat’ genetics data, e.g. large numbers of SNPs with much smaller numbers of samples.

Methods

Here, we propose to tackle the challenge by integrating an efficient model parameterization approach from Mila’s Diet Network architecture into DCCA to handle high dimensional SNP data in AD imaging‐genetics study (Figure 1). The new method, DietDCCA, was applied to nine datasets derived from 955 subjects in the ADNI data. Each dataset contains 68 FreeSurfer cortical ROIs from the florbetapir (AV45) PET imaging and varied numbers of SNPs from 810 to 11,938 based on different significance thresholds derived from previous studies.

Results

Firstly, we compared our DietDCCA with DCCA on each of the nine datasets to demonstrate the improvement on test correlations (Figure 2). DietDCCA outperformed DCCA by a large margin on all datasets even when the SNPs are as many as ∼10k. Next, we sought to verify if the detected correlations were contributed by meaningful SNPs and extracted the SNP feature that has the largest weight in each neuron of the diet net layer (Figure 3). DietDCCA successfully selected the APOE4 SNP (rs429358) for most cases and also picked out SNPs in other genes (ABCA7, APOC2, CLPTM1, NECTIN2) that were previously reported to associate with AD.

Conclusions

We introduced a novel method, DietDCCA, to handle high‐dimensional SNP features in AD imaging‐genetics study. The initial investigation of DietDCCA on the ADNI data showed promises in detecting correlation signals with AV45 ROIs from biologically meaningful SNPs. The study supplies a novel and effective tool to study the genetic basis of AD imaging phenotypes for future analyses.
Psychological effects of personalized dementia risk disclosure: The Barcelonaβeta Dementia Prevention Research Clinic study
Authors: Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo , Suárez‐Calvet Marc , Gispert Juan Domingo , Fauria Karine , Minguillón Carolina , Molinuevo Jose Luis
Published: January 2025

Background

Approximately 35‐40% of new patients at memory clinics are cognitively intact individuals concerned about their dementia risk. The demand for personalized risk profiling and preventive strategies for those at higher dementia risk is in need of innovative infrastructures. However, disclosing dementia risk estimates raises concerns about potential negative emotional impacts. To address this challenge, the Barcelonaβeta Dementia Prevention Research Clinic, was established to evaluate the risks and benefits of novel prevention infrastructures and the potential impact of dementia risk disclosure. Here we focus on the psychological effects of personalized dementia risk disclosure on cognitively unimpaired individuals with subjective cognitive decline (SCD).

Method

Participants aged 60‐80 with cognitive complaints were pre‐selected using web‐based algorithms. Eligible participants were invited to an in‐person visit and a clinical diagnosis was established after neuropsychological, blood tests and magnetic resonance imaging assessments. Dementia risk over 5 years (%risk) was calculated and disclosed with personalized prevention plans. Impact on depression (CES‐D), anxiety (STAI), and test‐related distress (IGT‐AD) was assessed up to 12 months post‐disclosure. SCD participants were categorized into “high dementia risk” (HDR, %risk>10.8) and “low dementia risk” (LDR, %risk<3.6) groups, based on previous epidemiological evidence. Wilcoxon rank‐sum tests and Spearman’s rank correlation analyzed between‐group differences and correlations at different time points.

Result

The percentage of 5‐years dementia risk was disclosed to 192 participants with SCD. Test‐related distress (IGT‐AD) was consistently higher in HDR (N = 25) vs. LDR (N = 55), while CES‐D and STAI showed no significant differences between groups (Table 1, Figure 1). Similar results were observed in correlation analyses for the entire sample (Table 2). Median CES‐D and STAI‐S values remained below clinically relevant cutoffs for depression and anxiety across all visits.

Conclusion

Disclosure of dementia risk heightened test‐related distress but did not manifest clinically relevant negative effects in anxiety and depression scales. The potential impact of this psychological response on promoting engagement in preventive behaviors warrants further exploration.