bluuebunny/crossref_metadata_2025 huggingface dataset:
The multidomain intervention trial for prevention of dementia among older adults with type 2 diabetes: a multi‐center, randomized, 18‐month controlled trial
Authors: Sugimoto Taiki , Araki Atsushi , Fujita Hiroki , Fujita Kosuke , Honda Keiko , Inagaki Nobuya , Ishida Takeshi , Kato Junichi , Kishi Minoru , Kishino Yoshinobu , Kobayashi Kazuki , Kouyama Kunichi , Kuroda Yujiro , Kuwahata So , Matsumoto Nanae , Noma Hisashi , Ogino Jun , Ogura Masahito , Ohishi Mitsuru , Shimada Hiroyuki , Sugimoto Kazuhiro , Takenaka Toshihiro , Tamura Yoshiaki , Tokuda Haruhiko , Uchida Kazuaki , Umegaki Hiroyuki , Sakurai Takashi ,   J‐MIND‐Diabetes study group
Published: December 2023

Background

The aim of the Japan‐Multidomain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J‐MIND‐Diabetes) was to examine the efficacy of multi‐domain intervention in prevention of cognitive decline in older adults with type 2 diabetes and mild cognitive impairment (MCI).

Method

The J‐MIND‐Diabetes is an 18‐month, multi‐centered, randomized controlled trial. Outpatients with type 2 diabetes aged 70‐85 years with MCI were recruited and randomized into multi‐domain intervention (management of metabolic and vascular risk factors, physical exercise, nutritional guidance, and promotion of social participation) and control groups (general instructions on dementia prevention) at a 1:1 allocation ratio using the stratified permuted‐block randomization methods. The primary outcome was a change from baseline to 18‐month follow‐up in a global composite score combining several neuropsychological tests, which include the MoCA‐J, the MMSE, the Rey‐Osterrieth Complex Figure Test (ROCFT), delayed recall test of a 10‐word list, the Digit Span, the Trail Making Test, the Digit Symbol Substitution Test, and the Letter Word Fluency Test.

Result

Between March 13, 2019, and May 8, 2020, 361 patients were screened and 154 were randomly assigned to the multi‐domain intervention group (n = 81) or control group (n = 73). 110 (71%) participants completed the trial. The full analysis set included 136 patients. In the primary efficacy analysis, there was no significant differences in the change of composite score from baseline to 18‐month follow‐up between the intervention group and the control group (mean difference 0.066 [95% CI ‐0.089 to 0.222]). In the analysis for each neuropsychological test, scores of immediate and delayed recall tests of the ROCFT in the intervention group significantly improved by a mean of 1.627 points and 1.793 points, respectively. The mean difference in the change of score of delayed recall test of the ROCFT between intervention group and control group was significant (mean difference 1.803 [95% CI 0.169 to 3.436]). In subgroup analyses, intervention effect on composite score was significant among patients with moderate to severe white matter hyperintensities (mean difference 0.351 [95% CI 0.088 to 0.614]).

Conclusion

The multi‐domain intervention could improve memory function in older adults with type 2 diabetes and MCI.
The associations between glial biomarkers and cognitive changes in individuals at risk of Alzheimer’s disease
Authors: Warmenhoven Noelle , Sánchez‐Benavides Gonzalo , Escalante Armand González , Milà‐Alomà Marta , Shekari Mahnaz , López‐Martos David , Ortiz‐Romero Paula , Kollmorgen Gwendlyn , Carboni Margherita , Minguillon Carolina , Gispert Juan Domingo , Arenaza‐Urquijo Eider M , Palpatzis Eleni , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Grau‐Rivera Oriol
Published: December 2023

Background

In preclinical Alzheimer’s disease (AD), previous evidence suggests that glial reactivity may affect cognitive performance. This study aimed to test whether glial markers cerebrospinal fluid (CSF) GFAP, YKL‐40, sTREM2, and plasma GFAP are associated with cognitive change in cognitively unimpaired individuals at risk of AD. We hypothesized that higher levels of glial markers may be associated with better cognitive outcomes.

Method

We included 353 individuals from the ALFA+ cohort with available baseline (BL) glial biomarkers and cognition at follow‐up (FU) 3 years later (Table 1). CSF Aβ42/40, pTau181, YKL‐40, GFAP, and sTREM2, were analyzed using the exploratory Roche NeuroToolKit, a panel of automated robust prototype immunoassays. Plasma GFAP was determined with the Simoa HD‐X (Quanterix) platform using the commercial Neurology 4‐Plex E assay (N4PE). Amyloid pathology was studied with Centiloids derived from [18F]flutemetamol PET. Rate of change ([FU‐BL]/time) in the Preclinical Alzheimer’s Cognitive Composite (PACC) and domain‐specific cognitive composites was used as the dependent variable, glial biomarkers at BL as predictors, and age, sex and education as covariates in linear models. Interaction terms between each glial biomarker and different AD pathology were also explored. Aβ+ was defined as CSF Aβ42/40 <0.071.

Result

Higher baseline CSF sTREM2 was associated with a positive PACC rate of change (p = 0.002) (Table 2). These results remained significant after controlling for CSF Aβ42/40, pTau181 and Centiloid levels (all p < 0.01). Moreover, CSF sTREM2 at baseline was associated with a better memory outcome (p = 0.012), independently of amyloid and tau (all p < 0.02), and better executive functioning (p = 0.046), independently of tau pathology (p = 0.011). These positive associations remained in the Aβ‐ group regardless of AD pathology, but not in the Aβ+ group, in which some negative associations were observed when adjusting for Centiloids (YKL‐40, p = 0.024) (Figure 1).

Conclusion

Higher TREM2‐mediated microglial response in individuals at risk of AD is associated with better cognitive performance. These associations were driven by the Aβ‐ group. These results may have important implications for the design of clinical interventions targeting TREM2 in this early stage of AD.
Hemoglobin levels and vitamin B12 deficiency anemia but not iron status are associated with lower verbal fluency in older adults from the Southern region in Mexico
Authors: la Cruz‐Góngora Vanessa De , Rodriguez Aaron Salinas
Published: December 2023

Background

Semantic verbal fluency (SMF) has been identified as an early marker of mild cognitive impairment (MCI). Anemia and some micronutrient deficiencies (MD) have been considered as risk factor for MCI. In Mexico, it has been poorly studied the nutritional drivers associated to MCI. Anemia and MD are frequent in vulnerable Mexican population but controversial exist around the criteria to define such entities in older adults (OA).The aim is to analyse the association between hemoglobin concentration, iron and B12 status, as well as the causes of anemia with SVF in older Mexican adults.

Methods

802 OA from 4 urban localities in Campeche and Yucatan ‐most of them considered themselves as Mayan indigenous‐ donated a capillary and venous blood sample. Hb (g/dL) was measured in capillary blood using Hemocue. Ferritin, vitamin B12, transferrin receptors (stfr), and other biomarkers were analysed in serum. The causes of anemia were classified as: Iron deficiency (ID), B12 deficiency (B12D), inflammatory, renal, multiple and unexplained. We explored the quartiles (Q) of Hb ‐sex adjusted‐, s‐ferritin, and stfr with SVF. Anemia, causes of anemia and MD were modelled separately using multiple linear regression models adjusted by confounders.

Results

Anemia, ID and B12D affected to 35.3%, 5% and 10% of OA, respectively. The mean of SVF was 13‐5±6.5 words. The Q1 [coef = ‐1.4, p = 0.025], Q2 [coef = ‐1.46, p = 0.016] and Q3 [coef = ‐1.13, p = 0.05] of Hb were negatively associated with SVF in comparison with Q4. No association was observed between the quartiles of s‐ferritin, stfr, ID or B12D with SVF. Total anemia (‐0.9, p = 0.047), and particularly B12D anemia (‐3.5, p = 0.018), were associated to lower SVF vs non‐anemics.

Conclusions

Higher Hb values (≥13.3 g/dL for women and ≥14.7 g/dL for men) above the cut‐off of anemia were positively associated with SVF independent of MD. This finding suggests that normal Hb values in those ranges of Hb might hide a declining in brain function secondary to an inadequate delivery of cerebral oxygen. Those with B12D anemia had the worse SVF performance. It is necessary to identify the main drivers for the optimal Hb range where the OA is functional independent to target early interventions.
Hippocampal subfield volumes in COVID‐19: a preliminary multicenter study using 7T MRI
Authors: Santini Tales , Alkateeb Salem , Liou Jr‐Jiun , Li Jinghang , Adeyemi Oluwatobi F , de Erausquin Gabriel A. , Garbarino Valentina R. , Goss Monica , Habes Mohamad , Himali Jayandra Jung , Karmonik Christof , Li Karl , Masdeu Joseph C. , Nair Rejani R , Patel Vibhuti N , Snitz Beth E. , Bowtell Richard , Penny Gowland , Roman Gustavo C , Ganguli Mary , Vahidy Farhaan S , Girard Timothy D. , Jacobs Heidi I.L. , Hosseini Akram A. , Seshadri Sudha , Ibrahim Tamer
Published: December 2023

Background

Hippocampal formation atrophy is a well‐established imaging biomarker of several neurological diseases, including Alzheimer’s disease, temporal lobe epilepsy, and schizophrenia. The hippocampus is divided into subfields that have different functions and vary in sensitivity to different diseases. This study investigates the potential interaction between COVID‐19 and the various hippocampus subfields, which may shed light on the long‐term neurological consequences of the virus.

Method

We obtained high‐resolution T1‐weighted (T1w) and T2‐weighted (T2w) MRI images using 7T scanners located at three sites in two countries: Pittsburgh (n = 14) and Texas (San Antonio and Houston) (n = 40) in the USA, and Nottingham, UK (n = 33). We evaluated the hippocampus subfields using the ASHS package [1‐3]. Imaging sets of 51 subjects with minimal or no manual segmentation corrections (Figures 1 and 2) were included in the analysis. We conducted T‐tests with Bonferroni correction, adjusting for age and intracranial volume to identify the differences in hippocampus subfield volumes across groups.

Result

Participants who needed admission into the ICU due to Covid‐19 showed a significantly lower (p‐value = 0.0034) left CA1 volume compared to participants who did not require ICU (Figure 3). In addition, several other non‐significant trends were observed.

Conclusion

Our preliminary findings suggest that Covid‐19 may impact the hippocampus, particularly in patients who required intensive care. However, the study ‐ as of to date ‐ has a small sample size and lacks a comparison group with patients who were admitted into ICU for acute illnesses other than Covid‐19. Additionally, longitudinal data is needed to track the long‐term effects of the disease on the hippocampal subfields.

Funding: NIH R56AG074467, R01MH111265 and R01AG063525

References: 1. Berron et al. Neuroimage 2017

2. Yushkevich et al. Human Brain Mapping 2015

3. Santini et al. Neuroimage: clinical 2021
Post COVID‐19 cognitive rehabilitation effects on depressive symptoms
Authors: Dutra Letícia Silva , Alves Larissa Scoralich , Shigaeff Nadia
Published: December 2023

Background

More than 600 million people have been infected by Covid‐19 since the beginning of the pandemic. Common cognitive and psychological symptoms in these patients are memory impairment, attention difficulties, anxiety and depression, and neuropsychological rehabilitation is a possible strategy to improve them. In addition, some studies have shown a decrease in depressive symptoms after starting a cognitive rehabilitation program, although this was not the main objective of rehabilitation.

Method

Five patients underwent mood assessment, more specifically, depressive symptoms. For this, the Patient Health Questionnaire‐9 (PHQ‐9) was used. The application was made immediately before and after the cognitive rehabilitation intervention, lasting 20 weekly sessions of about one hour of activity.

Result

The evaluation was performed on five patients with a mean age of 52.5 years (Table 1). These presented measures that indicated the presence of depressive symptoms at the beginning of the study. After 20 sessions of cognitive rehabilitation it was not possible to observe an objective change in depressive symptoms. This can be explained by the reduced number of individuals in the sample, which may have impaired the statistical calculation. But it was observed a clinical improvement of depressive symptoms was observed in 60% of patients and 40% remained stable (Table 2). Clinical improvement was also noted in patients, who reported that they were feeling better and that they resumed activities that they have previously avoided or that they were finding it easier, in addition to perceiving their own evolution throughout the treatment, increasing their sense of self‐efficacy and feeling more hopeful.

Conclusion

Finally, it is noted that cognitive rehabilitation is a possible strategy to improve not only cognitive impairment, but also the clinical manifestations of depressive symptoms in post‐Covid‐19 patients.
Home‐based cognitive interventions for patients with mild cognitive impairment and dementia. A systematic review
Authors: Rodas Andrea C Alvarado , Ulate Mauricio Molinari , Palacios Mateo Orellana , Martin Manuel Angel Franco
Published: December 2023

Background

Currently, there is a search for timely care and intervention on patients with dementia, which have reasonable costs and allow the sustainability and efficiency of national health and social care systems (Livingston et al., 2017). Cognitive interventions delivered in the patient’s home can be an excellent alternative, due to their feasibility(Jang et al., 2021) and accessibility (Rai et al., 2021) to the intervention. The aim of this paper is to describe the evidence on cognitive intervention performed at home for patients with MCI and mild dementia. To describe its characteristics and outcomes, and to address its feasibility and usability.

Method

A systematic review was performed using the PRISMA recommendations. We reviewed 190 records from four databases: PubMed, CINAHL, Web of Science, and PsycInfo.The quality of the studies was assessed using the tool “Assessment (mERA) checklist7” (World Health Organization, 2016)

Result

Ten papers were included. With a mean quality score of 0.76/1 (91.7% agreement).

The sample contains (N = 777) patients (MA 75.9). 80% have an education >7 years. 87.1% have a diagnosis of mild dementia. There are (N = 628) caregivers (MA 64.8). Seventy percent (n = 440) are women.

Positive results were found in: 71% of studies that looked for results on cognition. 66% of the studies that looked for results on mood and behavioral symptoms. 83% of studies that looked for results on functionality/quality of life. 100% of the studies that looked feasibility, and 75% of the studies that looked for results on the caregiver.

Conclusion

Cognitive intervention in the home of patients with MCI and early dementia showed positive results at a cognitive, emotional and behavioral levels. Likewise, in the caregiving relationship, emotional health and quality of life of caregivers.

The use of assistive technologies in the home has some benefits over face‐to‐face care.

Outcome‐cost ratio can be a cost‐effective solution for the sustainability and efficiency of national health and social care systems.
AD/ADRD Data Sources: Access and Utilization to Advance Research for Improving Human Health
Authors: Onyeneho Karyn N
Published: December 2023

Background

Alzheimer’s Disease and Related Dementia (AD/ADRD) cases affect more than 6 million Americans and more than 55 million people globally, leading to the deaths of 1 in every 3 older adults (Alzheimer’s Association, 2023). By 2050, these numbers are projected to climb. The National Institute on Aging is leading efforts to effectively prevent and treat AD/ADRD to improve human health and advance research enabled by accessible, utilizable, and shareable AD/ADRD data sources and investigated the utilization of AD/ADRD genomic datasets for secondary research from generalist and disease‐specific repositories. Multifactorial approaches about the use of the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) and Database of Genotypes and Phenotypes (dbGaP) were investigated to understand efficacies in secondary data use

Method

A correlational study was conducted of AD/ADRD data access requests approved in NIAGADS and dbGaP (2020‐2022). NIAGADS (n = 12) and dbGaP (n = 12) datasets (Figures 1 and 2) were obtained for inclusion in the final analysis. A literature review was also conducted of studies published in PubMed, ScienceDirect, PLOS One, and gray literature (2013‐2023) to understand AD/ADRD data access and utilization key drivers (Figure 3). Hypotheses: H1: There is no difference in the approval rates of data access requests from NIAGADS and dbGaP between 2020‐2022; H2: Utilization of AD/ADRD secondary data sources, NIAGADS and dbGaP, have contributed to growth rates of AD/ADRD publications. Independent two‐sample t‐tests were performed to test the hypotheses.

Result

H1: dbGaP data access requests approved (M = 0.793, SD = 0.036) compared to NIAGADS data access requests approved (M = 0.887, SD = 0.032) demonstrated no significance in approval rates between 2020‐2022, t(9) = 2.26, p = 0.160. H2: Publication rates from dbGaP (M = 18.8, SD = 20.8) compared to NIAGADS (M = 2.33, SD = 6.24) demonstrated a significance in publication growth rates, t(13) = 2.16, p = 0.002.

Conclusion

Researchers trust the use of dbGaP and NIAGADS, and other generalist and disease‐specific data sources (such as ADNI, AlzPathway, ALSOD, dbGaP, NCRAD, OMIM, and UPDB), for secondary data analyses. Researchers utilizing these data sources discovered hidden disease‐gene associations, AD/ADRD pathophenotypes, genetic variants affecting gene transcripts, fMRI functional connectivity changes, relationship modeling of inflammatory factors, candidate gene prioritization, and drug therapies. Researchers recognize the value of using data sources for secondary research.
E2814: an anti‐tau therapy engages its CNS target and affects the downstream tangle‐specific biomarker MTBR‐tau243 in Dominantly Inherited Alzheimer’s Disease
Authors: Zhou Jin , Rawal Sumit , Yagi Takuya , Wildsmith Kristin R , Takahashi Eri , Horie Kanta , Barthélemy Nicolas R. , Aluri Jagadeesh , Lalovic Bojan , Boyd Peter , Bateman Randall J. , Reyderman Larisa
Published: December 2023

Background

E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR‐tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer’s Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in healthy and Dominantly Inherited Alzheimer’s Disease (DIAD) participants for safety, pharmacokinetics (PK), and cerebrospinal fluid (CSF) target engagement.

Method

Seventy‐two healthy participants were enrolled in single and multiple ascending dose cohorts of Study 001 (NCT04231513) and received randomized, double‐blind, placebo‐controlled treatment of E2814. Intravenous infusion of single and multiple doses (once every 4 weeks for three times) were administered. In Study 103 (NCT04971733), 7 DIAD participants with confirmed mutations and mild to moderate cognitive impairment were enrolled and received open‐label treatment of E2814. Four sequential doses were evaluated as intravenous infusion every 4 weeks. Serum and CSF PK, and CSF target engagement (by analyzing both bound and unbound MTBR‐tau299 and MTBR‐tau354 [containing the epitopes of E2814]) were measured in both healthy and DIAD participants, as well as safety assessments. CSF MTBR‐tau243 recapitulating AD tau pathology was also measured in DIAD participants using methods previously described (Horie et al., J Prev Alz Dis 2022).

Result

E2814 was safe and well‐tolerated over a wide dose range. No infusion‐related reactions or other clinically significant safety signals were observed with single or repeated dose administration for up to 15 months. E2814 showed a dose‐related increase in serum and CSF exposure with CSF‐to‐serum ratio of ∼0.2%, comparable between healthy and DIAD participants. CSF target engagement was demonstrated by concentration‐related and sustained MTBR‐tau299 and MTBR‐tau354 binding in healthy and DIAD participants. More importantly, E2814 elicited a rapid and robust reduction on MTBR‐tau243, a neurofibrillary tangle‐specific biomarker, in DIAD participants.

Conclusion

E2814 demonstrated promising safety, PK and CSF target engagement profile in DIAD participants, and showed evidence of downstream effects on tangle‐specific biomarker MTBR‐tau243. Data supports further evaluation in the ongoing Ph2/3 DIAN‐TU Tau NexGen Platform Study in DIAD (NCT05269394) and future exploration in sporadic AD.
APOE and Alzheimer disease risk across age, sex, race, ethnicity, and ancestry: An overview from 68,756 individuals
Authors: Belloy Michael E , Andrews Shea J , Guen Yann Le , Napolioni Valerio , Greicius Michael D
Published: December 2023

Background

APOE*2 and APOE*4 are respectively the strongest protective and risk‐increasing genetic variants for late‐onset Alzheimer’s disease (AD), making APOE status highly relevant towards clinical trial design and AD research broadly. The associations of APOE genotypes with AD are importantly modulated by age, sex, race, ethnicity, and ancestry, but these associations remain unclear, particularly in historically understudied non‐white samples.

Method

The study overview is shown in Figure.1. Various case‐control, family‐based, and longitudinal AD genetic cohorts were available through public repositories and underwent extensive genotype and phenotype quality control. These cohorts contributed data for Non‐Hispanic Whites (NHW), Non‐Hispanic Blacks (NHB), and Hispanics (HISP). Global ancestry was determined using SNPweights v2.1. Case‐control logistic regression models evaluated the AD risk associations of APOE*2 dosage, APOE*4 dosage, and APOE genotype, with regard to APOE*33 as the reference, while adjusting for sex, array/batch/center, and global European, African, and Amerindian ancestry. Different stratified analyses, interaction models, and race/ethnicity heterogeneity tests were evaluated. APOE associations in East‐Asians (EAS) were obtained through meta‐analyses of published AD genetic studies, given the relative paucity of EAS in publicly available genetic cohorts.

Result

Compared to prior literature, we made several novel observations (Figure.2). Notably, the associations of APOE genotypes with AD risk were least pronounced in HISP, which was not explained by global ancestry. Further, not just APOE*4, but also APOE*2 followed a reduced association strength with AD risk according to the pattern of EAS > NHW > NHB > HISP (with the exception of APOE*2 in EAS, which showed no significant association). The sex‐by‐age‐specific association of APOE*34 in NHW, which was shown to be stronger in women, was reproduced here at ages 60‐70 years, and additionally replicated in NHB and HISP. There were no other significant sex‐by‐APOE interactions.

Conclusion

Merited by recent advances in AD genetic cohorts, we provide the largest‐to‐date overview of APOE’s associations with AD risk across important biological and demographic strata. We expect these insights to be critical to guide AD research and clinical trial design. With increased diversity and phenotype harmonization efforts in AD genetics, future extensions on this work are expected to provide additional insights.
Impact of diagnosis timing on AD cost and healthcare utilization
Authors: Yao Wei , Gupta Anya , Shrinath Arjun , Ramesh Viviktha , Yan Jessie , Shah Soham , Prasad Akhilesh , Little Elizabeth , Sharma Vishakha , Alcorn Charles
Published: December 2023

Background

This study aims to detect direct cost savings with early detection of Alzheimer’s disease (AD) and related dementias. We hypothesize that earlier diagnosis of AD can reduce direct healthcare costs and unnecessary utilization. A retrospective case‐control study is conducted using Optum Market Clarity Claims/EHR linked dataset on Medicare Advantage population from Jan 1 2011 to Dec 31 2020.

Method

Based on whether the patient was diagnosed with prior Mild Cognitive Impairment (MCI) before progressing to an AD diagnosis per ICD‐9/10 cm diagnosis codes, AD patients are categorized into early vs. late diagnosis (for those who were identified in the MCI stage vs not). Both groups are compared on annual all‐cause healthcare costs and frequency of encounters longitudinally spanning across 6 years pre‐index period and 3 years post‐index with AD diagnosis date as the index date. To understand the impact of early diagnosis, we estimated total cost, medical service cost and drug cost post‐index within the first 3 years by risk adjustment on baseline demographics, comorbidities, procedures, lab tests, and visits prior to AD diagnosis using propensity score weighting.

Result

Early‐diagnosed patients (N = 421) have a lower utilization rate of inpatient skilled nursing facility, nursing home and hospitalization than late‐diagnosed patients (N = 2817) after being diagnosed with AD. We also observed average medical service cost savings in all 3 years post‐index, ranging from $320 to $2556 per patient per year. Per cost allocation analysis, medical service cost savings are observed in inpatient, emergency room, inpatient SNF, urgent care, nursing home/assisted living, and observation unit. Risk adjusted cost savings with statistical significance are observed in year 3 post‐index. The mean cost difference between late and early diagnoses: total cost ($15472.11), medical service ($15013.7) and medication cost ($1601.61).

Conclusion

The study highlights opportunities for earlier diagnosis and suggests long‐term healthcare savings for AD patients who have been diagnosed at MCI stage compared to patients who were directly diagnosed with AD. Further research is needed to drill down into the driver of cost savings and whether it is attributable to disease management of MCI or other complications.
“Unraveling the Neuroprotective Mechanism of Dioscorea bulbifera (DB) in Alzheimer’s Disease (AD) Caused by Estrogen Loss: An Integrated Network Pharmacology Investigation and Experimental Validation”
Authors: Chowdhury Mayank Roy , Tiwari Anamika , Karamveer Karamveer , Dubey Govind Prasad , Tiwary Basant Kumar , Vijaykumar Sudarshana Deepa
Published: December 2023

Background

Alzheimer’s disease (AD) is a leading cause of dementia, characterized by cognitive decline, and is more prevalent in women, possibly due to estrogen loss after menopause. Dioscorea bulbifera (DB), a medicinal plant, has been proposed as a potential treatment for AD. However, the underlying mechanism of action of DB and its neuroprotective effects in AD, particularly in the context of estrogen loss, remain unclear.

Method

In this study, we employed an integrative network pharmacology approach to predict the mechanism of action of DB in AD. Using a collection of AD‐related genes and predicted DB targets, we identified putative targets, direct regulatory targets, and potential regulatory targets of DB. Pathway‐enrichment analysis was performed to elucidate the pivotal pathways involved in DB’s treatment of AD. Molecular docking was conducted to verify the interactions between the core targets and the active ingredients of DB. In vivo experiments were conducted using ovariectomized rats induced with scopolamine to evaluate the neuroprotective effects of DB. Acetylcholine (Ach) and serum estradiol levels were quantified using ELISA.

Result

Our results identified 132 putative targets, including 68 direct regulatory targets and 25 potential regulatory targets of DB for the treatment of AD. Pathway‐enrichment analysis revealed that neurotransmitter clearance in the synaptic cleft was a crucial pathway in the treatment of AD with DB. Molecular docking further supported the interactions between the core targets (ESR1, APP, GSK3β, BACE1, AChE, and MAOB) and the active ingredients of DB. In vivo experiments using ovariectomized rats induced with scopolamine demonstrated the neuroprotective effect of DB and validated the predicted mechanism of action.

Conclusion

Our findings provide experimental support for the predicted mechanism of action of DB in AD caused by estrogen loss, and validate its neuroprotective effects using behavioral tests and ELISA in ovariectomized rats. DB may hold promise as a potential therapeutic option for AD, particularly in the context of estrogen loss, and further research is warranted to explore its full potential in AD treatment.
A group of pancreatic islet β cell‐like neurons are vulnerable to energy deficiency
Authors: Cai Wenwen , Sang Shaoming , Zhong Chunjiu
Published: December 2023

Background

Alzheimer’s disease (AD) bear resemblance to the diabetes mellitus for that both of them exhibit beta‐amyloid (Aβ) deposition, insulin resistance and glycometabolic disorder. Peripheral islet β cells produce insulin and islet amyloid peptides, but whether there is a group of neurons in the brain like islet β cells is not clear.

Method

Hybridize APP/PS1 transgenic mice and CaMKII‐CreERT2/+
;Tpkfl/fl
strain, with tamoxifen induced Tpk knockout at 6 months of age, to form a model of energy deficiency. Labeling neuron and microglia with NeuN and Iba1 antibody, and immunofluorescence was used to observe Aβ, insulin‐like growth factor expression. TUNEL staining was applied to test cell apoptosis.

Result

We found that layer 5 cortical pyramidal neurons are strongly marked by Aβ antibody, 4G8, in APP/PS1 transgenic mice. Immunofluorescence showed that these 4G8‐positive neurons colocalized with insulin‐like growth factor 1/2 and highly expressed prohormone convertase 2. Further, we conditionally knocked out Tpk gene, a key gene involved in glucose metabolism, in excitatory neurons of APP/PS1 mice. Over time, NeuN and Iba1 labeling showed that the significant loss of neuron and activation of microglia happened in layer 5 cerebral cortex at the earliest. Additionally, the 4G8‐positive neurons in this layer were stained by TUNEL and markedly reduced in the early stage.

Conclusion

We found a group of islet β cell‐like neurons that are vulnerable to glucose energy impairment, suggesting a group of vulnerable neurons in sporadic AD, and implicating the cytological mechanism of association between AD and diabetes.
Quantitative Amyloid‐PET in Real‐World Practice: Lessons from the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study
Authors: La Joie Renaud , Mundada Nidhi S. , Blazhenets Ganna , Mejía‐Perez Jhony Alejandro , Schonhaut Daniel R , Zeltzer Ehud , Soleimani‐Meigooni David N. , Cho Hanna , Ranasinghe Kamalini G , Windon Charles , Yadollahikhales Golnaz , Iaccarino Leonardo , Koeppe Robert , Carrillo Maria C. , Hanna Lucy , Gatsonis Constantine , March Andrew , Siegel Barry A , Hillner Bruce E , Whitmer Rachel A. , Rabinovici Gil D.
Published: December 2023

Background

Amyloid‐PET quantification was developed in research settings using highly selected samples, harmonized acquisition protocols, and MRI‐based preprocessing. We aimed to analyze scans from IDEAS, a large‐scale, real‐world study of amyloid‐PET. Major challenges lie in scans being acquired on various PET/PET‐CT/PET‐MR scanners without standardization of acquisition or reconstruction protocols, and without MRI to preprocess data.

Method

18,295 Medicare beneficiaries with MCI or dementia underwent PET with [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol at 343 facilities. Sites shared 10,700 raw scans with their visual interpretation (positive or negative) by local radiologists/nuclear medicine physicians. Scans were processed using a PET‐only pipeline, which derives Centiloid based on a cortex‐to‐cerebellum tissue ratio in template space. Processed scans underwent standard visual quality control by 2 raters (Fig 1a‐b), and flagged scans were reviewed in a consensus meeting to discuss troubleshooting options. Injected dose and time between tracer injection and PET acquisition start were obtained from DICOM file header.

Result

9,963 scans (93%) were successfully pre‐processed with default parameters (Fig 1a) and 403 additional scans (4%) were included after manual intervention (Fig 1c). 339 scans (3%) were excluded because of technical artifacts or major bilateral lesions (Fig 1c). The final sample (n = 10,361) is described in Table 1, with example scans in Fig 1d. Centiloids showed the expected bimodal distribution (Fig 2a) and differentiated visually positive from negative scans (median = ‐2 versus 74 CL; area under the curve = 0.913, Fig 2b). PET acquisition generally followed tracer‐specific FDA recommendations for injected dose and acquisition time, but major variability was observed (Fig 2c). Centiloid values were independent from injected dose but were higher in patients scanned at later time windows for [18F]flutemetamol, resulting from known slow tracer kinetics (Fig 2c).

Conclusion

MRI‐free, amyloid‐PET quantification in a real‐world setting was feasible, with results conforming to expected distribution of Centiloid values and concordant with visual reads. However, greater standardization of PET acquisition than is currently required by FDA labels will be needed to reliably quantify amyloid PET in clinical practice (e.g., to monitor response to amyloid lowering therapy). The IDEAS dataset will be made available via the Global Alzheimer’s Association Interactive Network in 2023.
Genome‐wide association study on Alzheimer’s disease related cognitive, fluid, and neuropathology biomarkers in the African American population
Authors: Mu Shizhuo , Bao Jingxuan , Wen Zixuan , Yang Shu , Hohman Timothy J. , Huang Heng , Thompson Paul M , Saykin Andrew J. , Davatzikos Christos , Kim Dokyoon , Shen Li ,   for the Alzheimer’s Disease Neuroimaging Initiative and the AI4AD Initiative
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder that progresses over time, but its exact cause remains unknown. While risk genomic loci for AD‐related biomarkers have been identified in previous studies, these findings have mostly been based on European cohorts. As a result, there is limited research on the African American (AA) population. To address this research gap, we conducted a Genome‐Wide Association Study (GWAS) using whole genome sequencing (WGS) data from Alzheimer’s Disease Sequencing Project (ADSP) to identify AD‐related variants in the AA population.

Method

WGS data and harmonized phenotypes from the cognitive, fluid biomarker, and neuropathology domains were downloaded from the ADSP database. Quality control (QC) was performed on the WGS data through removing high missing call rate SNPs, rare genetic variants, genetically closely related subjects, subjects with high missing call rate, and genomic loci that failed the Hardy‐Weinberg equilibrium among cognitive normal cohort. After QC 9,815,631 SNPs and 33,324 subjects were preserved. A total of 5,397 subjects in AA population were selected for the subsequent GWAS analysis. Scalable and Accurate Implementation of Generalized mixed model (SAIGE) was used to perform association tests between genetic variants and 39 phenotypic traits controlled for age, sex, and the first 10 principal components. Functional mapping and annotation (FUMA) was used to perform the post GWAS annotations.

Result

Thirty‐nine phenotypic traits from cognitive, fluid biomarker, and neuropathology domains were screened but only the “infarcts and lacunes”, “PD braak (dichotomous)”, and “whole brain vascular disease” of the neuropathology data had significant GWAS signals. We identified one risk locus for each of the phenotypic traits: lead SNP rs7604487 significantly associated with “infarcts and lacunes”; lead SNP rs7093080 significantly associated with “PD braak (dichotomous)”; and lead SNP rs623123 significantly associated with “whole brain vascular disease” (Figure 1). These associations were insignificant in the ADSP cohort with European ancestry.

Conclusion

Our GWAS on AD related biomarkers identified three genetic loci associated with multiple neuropathological processes among the AA population. These findings have a potential to contribute to a better understanding of the AD genetic risk in the AA population. It warrants further investigation to replicate the discovery in independent cohorts.
Post‐secondary Education as a Modifiable Risk for Dementia: Birth Cohort and Gender Findings from the Health and Retirement Study
Authors: Smith Jacqui , Larkina Marina , Sonnega Amanda
Published: December 2023

Background

Education and gender are well‐known predictors of cognitive functioning after age 60, but multiple mechanisms underlie these associations. Research on dementia prevalence in the United States has highlighted the importance of considering historical changes in the quantity (years) of childhood education in potentially delaying diagnosis. Less attention has been given to gender differences in post‐secondary education despite considerable increases since the 1970s in the completion of university degrees by women.

Method

We examined new data for two cohorts of men and women in the Health and Retirement Study (HRS) about the types and content (field of study) of their college degrees. College information was collected in a Life History Mail Survey (2015‐2017). Cognitive status was assessed on a 27‐point scale in tests conducted in contingent biennial interviews (2016, 2018). Test scores were classified to indicate normal function, cognitive impairment (MCI / CIND) or dementia based on the validated HRS Langa‐Weir algorithm. The analytic sample of 9213 (60% women; 40% men) with complete data included individuals born before 1948 (n = 4662; mean age at cognitive test = 79; age range 69‐107) and Baby Boomers born 1948 to 1959 (n = 4551; mean age at cognitive test = 62).

Results

As expected, compared to the older cohorts, more Baby Boomers had post‐secondary education (44% vs 52%; p <.001). Men in the older cohort were more likely to have a Bachelor or higher‐level degree than women, but gender was not a significant predictor of degree type in the Baby Boomers. Cohort disaggregated analyses predicting cognitive function revealed that having a BA/BSc degree provided more protection against cognitive impairment for Baby Boomer women than for men with the same degree (p < .001). College majors were gendered and significantly accounted for variance in late‐life cognitive status depending on specialization.

Conclusions

The birth cohort and gender disparities in post‐secondary education revealed in our analyses provide new insight into modifiable aspects of education beyond childhood. Future research should consider the quality and timing of college education and subsequent employment histories as life course factors that differentiate trajectories of cognitive aging and transition to dementia.
Polygenic risk for Alzheimer’s disease is associated with increased cerebrospinal fluid levels of amyloid‐beta‐40
Authors: Howard Erica , Moody Jena N , Hayes Jasmeet P
Published: December 2023

Background

Alzheimer’s disease (AD) is associated with the accumulation of neuropathological beta‐amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab‐40 and Ab‐38 due to their high solubility, may be indicative of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. The apolipoprotein E (APOE) e4 allele, which is the strongest genetic risk factor for AD, has been linked to impaired Ab clearance and disruption of the amyloid precursor protein (APP) pathway that is responsible for Ab production. However, the association between early Ab dysregulation and other genetic risk variants remains understudied. Thus, we aimed to explore whether genetic risk for AD is related to early markers of Ab overproduction by examining associations between polygenic risk scores (PRS) and CSF Ab‐40 and Ab‐38 in an AD‐vulnerable population.

Method

We selected 88 non‐demented Veterans (Age: M = 68.22, SD = 3.75 years) from the Alzheimer’s Disease Neuroimaging Initiative‐Department of Defense (ADNI‐DOD) database with available genetic markers and CSF measures for Ab‐40 and Ab‐38. Genetic propensity for AD was assessed using genome‐wide PRS, both with and without the APOE region, employing a p‐value threshold < 0.01. CSF Ab concentrations were measured using a 2D‐UPLC‐tandem mass spectrometry method outlined by ADNI‐DOD. Partial spearman’s correlations related PRS to CSF Ab‐38 and Ab‐40 levels adjusting for age.

Result

CSF Ab‐40 levels were positively associated with PRS for AD (rhopartial = 0.22, p = 0.037). When variants in the APOE region were excluded from the score, the relationship between CSF Ab‐40 and PRS remained significant (rhopartial = 0.23, p = 0.035). The relationship between PRS for AD and CSF Ab‐38 levels was not significant, regardless of whether APOE regions were included in the score (all p’s > 0.1).

Conclusion

Genetic risk for AD may lead to early Ab overproduction, as evidenced by elevated CSF Ab levels, particularly Ab‐40. Other genetic variants, in addition to APOE, may play an integral role in disrupting the APP pathway and dysregulating Ab production.
AB1601 Phase 2 Study of ABvac40, an Anti‐Aβ40 Vaccine: Safety and Immunogenicity of a Cross‐Over Extension
Authors: Pascual‐Lucas María , Lacosta Ana María , Canudas Jesús , Montañés María , Allué Jose A , Sarasa Leticia , Molina Elisabet , Castillo Sergio , Sarasa Manuel , Terencio Jose , Boada Mercè
Published: December 2023

Background

Amyloid‐β (Aβ) immunotherapy is a promising strategy for treating Alzheimer’s disease (AD). Previous studies suggested that Aβ40 could have an important role in AD, especially in relation to amyloid deposition in blood vessels in AD. The AB1601 (NCT03461276) is a multicenter, randomized, double‐blind, placebo‐controlled, phase 2 study in patients with amnestic mild cognitive impairment (a‐MCI) or very mild AD (vm‐AD) which investigated the safety, tolerability and immunogenicity of repeated subcutaneous injections of ABvac40, a vaccine targeting Aβ40. The 24‐month study (Part A) showed that ABvac40 was safe, well‐tolerated and highly immunogenic. Here, an additional 18‐month cross‐over study (Part B) was conducted to evaluate safety, tolerability and immunogenicity of ABvac40 in patients randomized to placebo in Part A (Delayed start group), and to assess safety and immunogenicity of a delayed booster of ABvac40 in ABvac40‐treated patients in Part A (Booster group).

Method

A total of 124 patients with a‐MCI (N = 80) or vm‐AD (N = 44) were initially included in Part A. Seventy‐seven out of 101 patients who completed Part A transitioned to Part B. Safety assessments included the frequency of amyloid‐related imaging abnormalities (ARIA). Immune response was assessed by quantification of specific anti‐Aβ40 antibodies in plasma samples.

Result

ABvac40 continued to show a favorable safety profile. Specifically, no ARIA‐E was reported and ARIA‐H incidence was low, equally distributed in both groups, and similar to the placebo group (Part A). Delayed start group showed a strong and specific immune response, with a time course equivalent to the ABvac40 group in Part A. A delayed booster of ABvac40 elicited a large increase in anti‐Aβ40 antibody plasma levels, exceeding the concentrations observed throughout the active dosing phase of Part A.

Conclusion

The cross‐over extension of the AB1601 Phase 2 study confirmed the excellent safety and tolerability profile of ABvac40, making this vaccine a potential candidate to be combined with other disease‐modifying therapies. Results on immunogenicity supported those obtained in Part A, demonstrating that ABvac40 elicited a strong, specific, sustained and boostable immune response. This could have important implications for long‐term treatments, especially in the context of preventive approaches. Additional exploratory efficacy results of Part B are expected in Q4‐2023.
Plasma pTau217: single vs multiple phospho‐site assays.
Authors: Benedet Andrea L. , Pola Ilaria , Triana‐Baltzer Gallen , Molfetta Guglielmo Di , Arslan Burak , Rahmouni Nesrine , Tissot Cécile , Therriault Joseph , Servaes Stijn , Pascoal Tharick A. , Kolb Hartmuth C. , Jeromin Andreas , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Rosa‐Neto Pedro
Published: December 2023

Background

Blood biomarkers have gained much attention in recent years given their increasing ability to indicate amyloid pathology and excellent performance in distinguishing diagnostic groups in the context of Alzheimer’s disease (AD). Plasma pTau217 has been considered the best candidate biomarker to serve as diagnostic and prognostic tool for clinical trials. However, biomarker assays targeting tau phosphorylation on Thr217 may differ because of their composition (e.g., targeting multiple or single phosphorylation sites) which may lead to distinct associations with pathology. Thus, we aimed to compare two plasma pTau217 immunoassays that differ in regard to their target specificity.

Method

Participants from the TRIAD cohort with available cross‐sectional plasma and imaging data, incorporating within the AD spectrum, were included in this study (Young = 25;CU‐ = 107;CU+ = 32;MCI+ = 42;AD+ = 47;MCI‐ = 19). Plasma pTau was quantified using the assays from Janssen (pTau217+; which exhibits enhanced signal with co‐phosphorylation of pTau212) and from ALZpath (single phosphorylation on pTau217), both performed on the Simoa platform. Amyloid and tau pathologies were indexed by PET using [18F]AZD4694 and [18F]MK6240, respectively. ANCOVA compared biomarker values across groups, Spearman rank tested the correlations between them. Linear regression models (LM) evaluated the association between plasma and PET biomarkers globally and at the voxel level.

Result

Biomarker levels (fold mean of CU‐) were comparable across diagnostic groups, showing the expected increases in amyloid positive groups. Both plasma assays were highly correlated with amyloid (Fig.1), which was also observed on the LM adjusted by age and sex, and on the voxel‐wise analysis (Fig.2). Associations with tau PET SUVR (medial temporal) were also significant and showed similar distribution between the two pTau assays. When neocortical tau was evaluated, however, pTau217+ had a better association as well as higher correlation coefficients within amyloid+ (Fig.3) and neocortical tau+ groups than did ALZpath pTau217.

Conclusion

In general, pTau217 assays with different antibody specificity showed very similar associations with PET. However, pTau217+ achieved a better association with neocortical tau as compared to ALZpath pTau217. A biomarker targeting multiple phosphorylation sites might be a better proxy of advanced tau, therefore may offer improved ability to detect and exclude participants with advanced AD pathology for clinical trials.