bluuebunny/crossref_metadata_2025 huggingface dataset:
Beta‐amyloid regions related to amyloid positivity using a feature selection method
Authors: Ko Hyunwoong
Published: June 2023

Background

Cerebral beta‐amyloid (Aβ) is a hallmark of AD. Few studies have revealed which of the regional Aβ markers are associated with abnormal levels of Aβ status. The aim of the current study was to identify multivariate regional Aβ markers predicting Aβ positivity (Aβ+).

Method

Seven hundred and sixty‐five participants from the ADNI‐2 cohort at baseline visit were included in the study. We used regional Aβ uptake as predictors in a predictive model. Flobetapir PET images were classified as Aβ‐positive if the standard uptake value ratio was over 1.1. The least absolute shrinkage and selection operator (LASSO) model with 1,000 bootstrap was implemented to identify regional Aβ traits to predict cortical amyloid burden from participants.

Result

Out of 116 predictors, 27 markers in cortical thickness significantly predicted Aβ+ among participants at baseline. After bootstrapping, 2 phenotypes had 95% confidence intervals that did not overlap zero: left precuneus (β = 0.684) and right rostral middle frontal region (β = 0.605).

Conclusion

These results demonstrated that several brain regions are related to abnormal levels of cerebral Aβ. These markers suggest robust sign that may capture AD pathology. To this end, this research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program (IITP‐2022‐2017‐0‐01630) supervised by the IITP (Institute for Information & communications Technology Promotion).
Brain responses to energy intake and its association with cognition in Alzheimer’s Disease
Authors: Li Runzhi , Xu Jun , Yao Zeshan , Wang Yanli , Jiang Jiwei , Li Wenyi , Zhang Yuan , Jia Ziyan
Published: June 2023

Background

To evaluate the brain response to energy intake using cerebral blood flow(CBF) in Alzheimer’s disease (AD), mild cognitive impairment (MCI) and healthy controls (HC) and its relationship with cognition.

Method

A self‐comparison design was used to test the effects of energy intake on brain activity in participants with AD (n = 30), MCI participants (n = 32), and HC (n = 30) and its relationship with cognitive function. Brain perfusion was measured using arterial spin labeling (ASL) functional brain imaging. Participants arrived at the site in the morning and underwent the ASL‐MRI with at least 10 hours fasting overnight. Then the second ASL‐MRI at 30 minutes after eating a standard breakfast was performed. Energy response ΔCBF was computed by subtracting the fasting CBF from the postprandial CBF obtained from ASL‐MRI. Whole brain grey matter voxel‐wise paired T test and linear regression analyses were used for statistical analysis.

Result

AD and MCI group had different energy response ΔCBF pattern with HC group. In AD group, energy intake induced a significantly decreased CBF in temporal lobe including lateral inferior and superior temporal gyrus, right superior temporal gyrus, parietal lobe including bilateral superior and inferior parietal lobe, postcentral gyrus and precuneus, most of occipital lobe and frontal lobe including right rolandic operculum, right precentral gyrus and left middle frontal gyrus. (q < 0.05, false discovery rate corrected). MCI had similar energy intake response pattern with AD. HC group had no significantly changed CBF response to energy intake. Energy response ΔCBF in the vicinity of the superior temporal gyrus showed significant negative correlation with Minimum Mental State Examination (MMSE) in all AD, MCI and HC groups.

Conclusion

The different energy response ΔCBF pattern may help to characterize the energy disorder in AD and may indicate the different brain energy rescue effect in the three groups. Energy response ΔCBF in the superior temporal gyrus is an indicator of cognitive function in AD.
Examining disease‐modifying roles of neurons in Alzheimer’s disease using a novel stem‐cell‐based human‐mouse chimeric transplantation model
Authors: Qu Wenhui , Lam Matti , Menon Vilas , Hargus Gunnar
Published: June 2023

Background

Alzheimer’s disease (AD) and AD‐related dementias (ADRD) are fatal neurodegenerative diseases that impair the cognitive function of more than 40 million people worldwide without effective treatments. Despite the high prevalence of AD and ADRD, molecular mechanisms of neurodegeneration are only partially understood. Emerging evidence supports the physiological relevance of using induced pluripotent stem cell (iPSC) to model AD and related dementias. This study is set to determine neuron‐autonomous changes in AD iPSC‐derived neurons in vitro and in vivo.

Method

In vivo and in vitro characterization of iPSCs. We have differentiated human iPSC‐derived neural cells carrying the familial AD V717I (London) mutation in the amyloid precursor protein (APPV717I) into mature neurons in vitro and employed Seahorse assay, whole transcriptomic profiling, mass spectrometry for 150 key metabolites of the intermediary metabolism, immunostainings, and biochemical assays. We have also transplanted human AD iPSC‐derived neural cells into the brains of adult immunocompromised mice. We then microdissected human grafts and employed single nucleus RNA sequencing (snRNA‐seq) to better understand the transcriptomic changes in transplanted cells at single‐cell resolution. We will then compare the transcriptomic data of the graft with preliminary or published snRNA‐seq data on post‐mortem brain tissue from AD patients.

Result

we have also observed reduced baseline respiration in APPV717I neurons compared with their isogenic controls. Alterations of metabolic pathways were also observed in AD neurons, both in the pathway analysis of whole transcriptome profiles and in metabolomics studies. To further explore the molecular changes of iPSC‐derived AD neurons and to confirm key findings, AD or control neural cells were transplanted into the brains of immunocompromised mice and they showed robust survival and differentiation into neurons. snRNA‐seq on microdissected grafts is underway to better understand the transcriptomic changes in transplanted cells at single‐cell resolution.

Conclusion

Preliminary results show cell‐autonomous changes of AD iPSC‐derived neurons in vitro and successful transplantation of human iPSC‐derived AD neural cells in vivo suggest the feasibility of modeling AD using this innovative in vivo human stem cell model.
Safety profile of lycopene, ellagic acid and hesperetin combination regimen in the brain of balb c mice
Authors: Adeyemo Oluwatobi Adewumi , Ajiboye Oyedele Ebenezer , Osinowo Princess Boluwatife , Awogbindin Ifeoluwa Oluleke , Olayinka Ebenezer Tunde
Published: June 2023

Background

The pathophysiology of neurodegenerative diseases, particularly Alzheimer’s disease is multifactorial. However, with scientific evidences suggesting that various antioxidants possess different protective mechanisms, thus hypothetically/theoretically no single natural compound can adequately abrogate these plethora of neurodegenerative cascades. Hence, there is a need for a paradigm shift from the usual monotherapy directed management of neurodegeneration. Therefore, this study investigated the effects of combined administration of three antioxidants namely; hesperetin, lycopene and ellagic acid in the brain of balb c mice.

Method

Thirty (30) male balb/c mice were grouped and administered orally with respect to each of their weights for Twenty eight (28) days as follows: Group I (Control)‐ Dimethyl sulfoxide (DMSO) in olive oil, Group II‐ Lycopene (5mg/kg body wt), Ellagic acid (15mg/kg body wt), Hesperetin (20mg/kg body wt) dissolved in DMSO and olive oil, Group III‐lycopene(10mg/kg body wt), Ellagic acid (30mg/kg body wt), Hesperetin(40mg/kg body wt) dissolved in DMSO and olive oil.

Result

The combination regimen at both doses show no significant difference in the concentration of nitric oxide (NO), protein carbonyl (PC), reduced glutathione (GSH), hydrogen peroxide (H2O2), malondialdehyde (MDA) level, activity of catalase (CAT) in the brain. Furthermore, the numbers of spared pyramidal and purkinje neurons of the cortex (sensorimotor cortex, hippocampus) and cerebellum at both doses were increased respectively but not significant when compared with their age‐matched control. Also, neuronal nuclei (NeuN) immunohistochemical staining revealed a slightly elevated matured neuronal population, as well as decreased ionized calcium binding adaptor molecule 1 (Iba1) expressions.

Conclusion

In conclusion, this study suggests that the combined regimen is not only safe, but also enhanced cell viability in normal condition and could be promising in the management of neurodegenerative diseases.
High concordance between plasma amyloid β biomarkers by IP‐MALDI‐MS and visual assessment of amyloid PET
Authors: Kaneko Naoki , Nakamura Akinori , Yoda Ritsuko , Kato Takashi , Sekiya Sadanori , Ito Kengo , Iwamoto Shinichi , Tanaka Koichi
Published: June 2023

Background

Abnormal amyloid‐β (Aβ) deposition in the brain has been defined as the earliest pathological change of Alzheimer disease (AD). We combined immunoprecipitation (IP) with MALDI‐TOF MS to develop IP‐MALDI‐MS, which is an analytical technique for plasma Aβ. This technique has previously revealed that APP669‐711/Aβ1‐42 ratio, Aβ1‐40/Aβ1‐42 ratio, and a combination of these two biomarkers (a composite biomarker) in human plasma correlates highly with SUVR obtained from amyloid PET (Nakamura et al., Nature, 2018). In this work, we validated a concordance between plasma Aβ biomarkers by IP‐MALDI‐MS and visual amyloid PET status with an independent dataset from the previous report.

Method

Plasma samples were obtained from 41 Aβ+ and 55 Aβ‐ subjects classified using PET with PIB tracer in National Center for Geriatrics and Gerontology. Aβ‐related peptides were immunoprecipitated from the sample spiked by stable isotope‐labeled (SIL) Aβ1‐38 using beads coupled with anti‐Aβ antibody. After the IP was performed two times consecutively, Aβ‐related peptides eluted from the antibody beads were applied to MALDI‐TOF MS. SIL‐Aβ1‐38 was used as an internal standard for normalizing an intensity of each Aβ‐related peptide. APP669‐711/Aβ1‐42 ratio and Aβ1‐40/Aβ1‐42 ratio were calculated from those intensities and then the composite biomarker was generated as previous reported.

Result

APP669‐711/Aβ1‐42 ratio, Aβ1‐40/Aβ1‐42 ratio and the composite biomarker were significantly higher in the Aβ+ group than the Aβ‐ group (p < 0.001). IP‐MALDI‐MS discriminated Aβ‐PET positivity with high AUC in APP669‐711/Aβ1‐42 ratio (92.8%), Aβ1‐40/Aβ1‐42 ratio (95.7%) and the composite biomarker (95.8%). Furthermore, an accuracy of the three biomarkers was 89.6‐92.7% in the Aβ+/‐ classification.

Conclusion

Our results demonstrated high concordance of plasma Aβ biomarkers with visual amyloid PET status. The measurement by IP‐MALDI‐MS can provide the biomarker values highly associated with Aβ‐PET positivity.
Association of short tandem repeats with neuropathological features in late‐onset of Alzheimer’s disease brains
Authors: Lee Annie J , Klein Hans‐Ulrich , Schneider Julie A , Bennett David A , De Jager Philip L , Narzisi Giuseppe , Zody Michael , Vardarajan Badri N
Published: June 2023

Background

Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. Short tandem repeats (STRs), which are hyper‐mutable sequences in the human genome could explain some of the missing heritability in LOAD. STRs are involved in several neuro‐degenerative disorders. We systematically evaluated the impact of 31 disease‐associated STRs on neuropathological LOAD features.

Method

From whole‐genome sequencing (WGS) data in for 1,134 unrelated individuals of European ancestry from Religious Orders Study (ROS) and Rush Memory and Aging project (MAP) cohorts, we identified known pathogenic STRs in 31 loci using ExpansionHunter. WGS was generated from DNA extracted from blood and brain tissues. We tested the association of STRs with a) neuropathological LOAD status, b) beta‐amyloid levels, c) neurofibrillary tangle (NFT) burden, d) global measure of pathology based on the scaled scores of 5 brain regions and e) estimated slope of global cognition using longitudinal measurements. Regression models adjusting for age, sex and first three principal components. Subsequently, we examined if STRs influenced gene expression in dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC) and the anterior cingulate (AC) and tested if the association of STRs with neuropathological traits were mediated by altered gene expression.

Result

TGC repeat in ATXN1 was associated with cognitive decline (b = ‐0.007, p = 0.014) and risk of clinical AD (b = 0.126, p = 0.03). Variation in CAG repeats in ATN1 was associated with cognition (b = 0.004, p = 0.022) and risk of pathological AD (b = ‐0.069, p = 0.035). Longer Repeats at ATXN1 increased gene expression in DLPFC (b = 0.012, p = 0.049) and PCC (b = 0.019, p = 0.006) and repeats in ATN1 altered DLPFC (b = 0.01, p = 0.016) and PCC (b = 0.01, p = 0.026) expression. Mediation analysis determined that the effect of the CAG repeats in ATN1 on tau was mediated by gene expression in PCC (p = 0.004).

Conclusion

We demonstrate that disease causing STRs influence the underlying gene expression in brain and are associated with neuropathological and cognitive endophenotypes of AD. This suggests that STRs could explain some of the missing heritability in LOAD.
Financial Behaviors and Experiences of Financial Loss in those with Alzheimer’s disease and Frontotemporal Dementia: Preliminary findings from a survey
Authors: Narayan Claudine K. , Stein Colin M. , Ake Jeannie M. , Benavides Andrea , Huey Edward D. , Goldman Jill , Mejia Arlene , Chapman Silvia , Joyce Jillian L. , Stern Yaakov , Cosentino Stephanie , Sunderaraman Preeti
Published: June 2023

Background

Older adults are increasingly experiencing financial loss, with annual costs estimated to be about $2.9 billion. The risk of experiencing financial loss is magnified in those with neurodegenerative conditions, including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). However, limited information exists on the frequency and amount of money lost, and the behaviors that contribute to such loss in these conditions. The current study sought to characterize the nature of financial losses in AD and FTD, and to identify risk factors in an effort to prevent or mitigate financial loss.

Method

Survey data were collected from ten caregivers of individuals clinically diagnosed with AD or FTD recruited via the Neurodegeneration‐Associated Psychiatric Syndromes study and caregiver support groups at Columbia University Medical Center. Survey items queried demographic information, details of financial loss, level of concerns experienced by care partners and patients, and financial behaviors resulting in financial losses (Table 1).

Result

Caregivers had known the patients on average for 46 years. Out of 10 patients, 6 experienced financial loss. See Table 2 for detailed results. While the same number of patients with AD and FTD lost money, those with FTD lost money more frequently and to a larger amount than those with AD. Caregivers of FTD patients expressed a higher degree of concern relative to those with AD. Moreover, most AD patients were described as being concerned about their financial ability, as compared to none of the FTD patients having concern for their financial ability. Additionally, 3 of 5 FTD patients were reported to have engaged in repetitive spending as compared to none of the AD patients.

Conclusion

Preliminary data indicate a high prevalence of financial loss (60%) in AD and FTD. The intensity of financial loss and related caregiver burden appears higher in FTD, with caregivers describing repetitive spending and less concern about difficulties, likely tied to the lack of insight which is a core feature of this disease. These findings can guide caregiver supervision and interventions to preserve family funds.
Subjective memory complaints, white matter hyperintensities, and cognitive decline in a population‐based cohort study
Authors: Dhana Anisa , Decarli Charles , Dhana Klodian , Krueger Kristin R , Desai Pankaja , Evans Denis A , Rajan Kumar B
Published: June 2023

Background

Subjective memory complaints (SMCs) are associated with a faster cognitive decline and dementia; whether this relationship results from irreversible structural brain alterations, such as white matter hyperintensities (WMH), requires investigation. We aimed to determine the association of SMCs with WMH and cognitive decline and investigate the role of WMH on the relationship between SMCs and cognitive decline.

Method

We studied 917 participants (63% African Americans and 60% women) from the population‐based Chicago Health and Aging Project (CHAP), who responded to questions about SMCs, underwent magnetic resonance imaging of the brain, and had valid cognitive data on two or more visits during the follow‐up period. SMCs were obtained by self‐report questionnaire, and based on frequency and severity of concerns, we categorized participants into three groups: not concerned, moderately concerned, and very concerned.

Result

Of 917 participants eligible for the study, 158 (17.2%) had no SMCs concerns, 671 (73.2%) had moderate concerns, and 88 (9.6%) were very concerned. SMCs were associated with larger WMH volumes and faster cognitive decline. Compared to participants with no concerns, those very concerned had 0.833 (95%CI 0.203, 1.463) units higher WMH volumes and 174% faster cognitive decline (‐0.049; 95%CI ‐0.076, ‐0.022). The association between SMCs and cognitive decline was statistically significant only among individuals with large WMH volumes; that is, very concerned individuals with large WMH volumes had 428% faster cognitive decline annually (‐0.077; 95%CI ‐0.144, ‐0.011) than participants with no concerns. In participants with low volumes of WMH, SMCs were not associated with a faster cognitive decline (P‐value = 0.595).

Conclusion

Our study suggests that SMCs, frequently reported by the elderly, are an important sign of cognitive impairment, especially in people with brain atrophies, such as large WMH volumes.
Towards clinical implementation: Establishing standardized operating procedures to limit the pre‐analytical sample handling effects on the novel Alzheimer’s disease blood‐based biomarkers
Authors: Gouda Mariam , Teuling Mark M.Den , Hussainali Zulaiga , van Leeuwenstijn Mardou S. S. A. , ’t Veld Sjors G.J.G. in , Pijnenburg Yolande A.L. , Edelmayer Rebecca M. , Teunissen Charlotte E. , Verberk Inge M.W.
Published: June 2023

Background

Clinical implementation of novel blood‐based biomarkers for Alzheimer’s disease (AD) will aid in accurate, less‐invasive diagnosis. However, variation in blood handling may affect the accuracy of biomarker’s measurement. Establishing standardized operating procedures (SOPs) to mitigate these effects is essential for implementing novel blood‐based biomarkers into clinical use. We aim to provide an evidence‐based SOP specific for AD blood‐based biomarkers by studying the effects of multiple pre‐analytical variations in blood samples from AD and healthy controls (HCs). Here, we show the first results obtained, addressing the effect of biomarker’s adsorption to lab plastics, during sample processing.

Method

Blood samples are being withdrawn from 150 volunteers (AD and HCs) and treated according to one of ten pre‐analytical experimental protocols. Several aliquots per sample are being obtained, to be shared and analyzed among labs, focusing on labs with novel P‐tau plasma tests. Preliminary results are acquired for the effect of 1x, 2x and 4x tube transfers in fresh polypropylene tubes with fresh pipet tips at every transfer, compared to no tube transfer, as a reference condition. Sample analysis was performed on Simoa using the Simoa neurology 4‐plex E assay (Aβ1‐42, Aβ1‐40, GFAP, NfL), and the P‐tau181 V2 assay. A variation in the median value of one of the measured biomarkers of at least 10% from the reference condition was regarded as a significant change.

Result

Formally, medians of all tube transfers for all biomarkers measured (Aβ1‐42, Aβ1‐40, GFAP, NfL and Ptau‐181), stayed within the predefined range, for both AD and HC. However, the levels of Aβ1‐42 and Aβ1‐40 showed an obvious tendency to decrease at the 4th tube transfer. For Aβ1‐40, levels in HCs were more affected compared to those in AD (median 92%; AD: median = 95%). For Aβ1‐42, both AD and HCs showed a similar decrease (median: 91% and 93%). This decrease is not so apparent with the Aβ1‐42/Aβ1‐40 ratio.

Conclusion

In line with the results, 4 tube transfers or less should have no influence on the accuracy of the measured biomarkers. For Aβ peptide measurements, using the Aβ1‐42/Aβ1‐40 ratio appears to stabilize the effect of tube transfer.
Pilot study of social and structural determinants of health (SSDOH) measures in the UPENN Alzheimer’s disease research center
Authors: Stites Shana D. , Midgett Sharnita , Visco Alexis , Mechanic‐Hamilton Dawn
Published: June 2023

Background

To mitigate health and healthcare disparities in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) research and care, scientists must be able to characterize and measure social and structural determinants of health (SSDoH) that may help explain heterogeneity in cognitive, functional, and interventional outcomes in AD/ADRD.

Method

Participants (n = 70) were members of the UPENN ADRC clinical cohort with unimpaired cognition who completed the SSDoH measures via an online survey. SSDoH measures were chosen based on content and psychometric properties. Self‐report measures are in the following categories: (1) Education, (2) Occupation, (3) Economic Status and Strain, (4) Stressors and Subjective Stress, (6) Subjective Social Support and Status, and (7) Sociodemographic data, which included self‐report of age, race, language, disability, neighborhood, sex, sexual orientation, and gender identity questions.

Result

Results describe piloting the measures, the gaps and strengths of measures, and plans for future collection and analysis. The response rate was 74% (52 out of 70 participants started the survey). Most participants completed the survey within 25 to 30 minutes. Most participants reported being satisfied with the battery, and a few reached out to ADRC staff to express interest in volunteering additional data. Some revision to the longitudinal record of neighborhoods was needed.

Conclusion

A multidomain battery of SSDoH measures was feasible to implement in the UPENN ADRC clinical cohort. Routine collection of SSDoH may help researchers better understand factors that create disparities in AD/ADRD outcomes and develop interventions to mitigate them.
A prototype robot‐mediated reminiscence therapy (RMRT) for people with dementia
Authors: Yuan Fengpei , Shved Jonathan , Bahour Abdurhman , Crane Monica , Duzan Joshua , Boltz Marie , Bilal Dania , Zhao Xiaopeng
Published: June 2023

Background

Approximately 6.2 million older Americans are living with Alzheimer’s Disease and Alzheimer’s Disease related dementias (AD/ADRD). Reminiscence therapy (RT) has shown a positive impact on the mood, cognition, communication, and quality of life of people with AD/ADRD (PLWD). Traditional RT is usually delivered by professional facilitators, limiting the accessibility of RT to PLWD. Robotics has the potential to facilitate RT, enabling accessible, home‐based, personalized RT.

Method

A prototype of robot‐mediated reminiscence therapy (RMRT) was implemented using a humanoid social robot, Pepper. A multimedia file, including pictures, audio, and video, was created as a source of prompts for memory stimulation. The file consisted of nine topics, including pets, cars, holidays, hobbies, chores, movies, music, sports, and local scenes. In each topic, the robot displayed a memory trigger on the left side of its tablet and engaged in a conversation with PLWD. The robot started the conversation with background information relevant to the memory trigger and then provided appropriate prompts (e.g., questions) to encourage PLWD to talk. The PLWD can control the robot by clicking buttons and using voice input.

The prototype RMRT was tested with two female participants (one with mild dementia due to AD, aged 75‐85 and one with mild cognitive impairment, aged above 85). They used the topics, holidays, movies, and music. Questionnaires were used to assess their acceptance and user experience.

Result

Both participants reported a positive user experience with the RMRT. The robot was easy to use, its appearance was pleasing, and talking with the robot was relaxing. Participants preferred to control the robot using both the tablet and voice input. One participant suggested that the user icon should match the user’s gender. Both participants would like to use the RMRT in the future and would recommend it to others.

Conclusion

The two participants had a positive experience interacting with the RMRT and made suggestions for improving its design. Our next step is to address the participants’ suggestions for improving the design of the robot and test its usability with a larger sample of PLWD to assess the effectiveness, efficiency, and user experience during RMRT.
Sleep apnea and cognition in older APOE4 carriers and non‐carriers
Authors: Halter Colt M , Woodard John L.
Published: June 2023

Background

Sleep apnea (SA) is common in late life and has received much attention as a possible risk factor for Alzheimer’s disease (AD). However, cross‐sectional findings suggest little, if any, relationship between SA and impaired cognition in Apolipoprotein E ε4 (APOE4) allele carriers and non‐carriers. Preclinical AD detection is essential, and the relationship between SA, APOE4, and cognitive impairment merits further analysis in a large sample. Therefore, we investigated whether SA and APOE4 carrier status were related to neuropsychological functioning using the National Alzheimer’s Coordinating Center (NACC) database. We predicted an interaction between SA and APOE4 carrier status, such that APOE4 carriers with SA would show the most significant impairment in cognition.

Method

Participants were at least 65 years of age with normal cognitive status. Sample sizes ranged from 1902 to 1945, depending on available neuropsychological data. SA presence or absence was clinician‐determined. Participants completed nine cognitive measures, including semantic memory (verbal category fluency), executive functioning (verbal letter fluency), visual scanning and executive functioning (Trails A and Trails B), global cognitive functioning (total Montreal Cognitive Assessment [MoCA]), and memory (MoCA–delayed recall and Benson Complex Figure Copy – delayed). We compared non‐carriers (ε3/ε3) and heterozygous carriers (ε3/ε4) using three‐way ANOVAs and ANCOVAs, while considering sex and age.

Result

There were no main or interaction effects of SA, carrier status, or sex on participant age (p>.05). Therefore, age was used as a covariate in three‐way ANCOVAs to enhance the power to detect a significant effect if present. Contrary to our hypotheses, there were no main or interaction effects involving SA (p>.05) with sex or carrier status. An APOE4 main effect was observed only for MoCA total and delayed recall scores.

Conclusion

Past cross‐sectional studies report a weak or null relationship between SA and cognitive performance. We found no main or interaction effects involving SA with sex or APOE4 carrier status on neuropsychological functioning in a large sample of older adults. Our large sample size helps provide more evidence for these null relationships and is consistent with other large‐sample studies.
White matter hyperintensity, neurofilament light chain, and cognitive decline
Authors: Dhana Anisa , Decarli Charles , Krueger Kristin R , Dhana Klodian , Desai Pankaja , Evans Denis A , Rajan Kumar B
Published: June 2023

Background

White matter hyperintensity (WMH), assessed by magnetic resonance imaging (MRI), is a marker of cerebrovascular disease. Neurofilament light chain (NFL), assessed in the blood, is a biomarker of neurodegeneration. While both measures, WMH and NFL, are associated with cognitive impairment, we aimed to evaluate which of the two measurements is most advantageous in determining the risk of cognitive impairment.

Method

We conducted this investigation in Chicago Health and Aging Project (CHAP), a prospective population‐based cohort study in the United States. The study included 1,323 participants with data on NFL serum concentrations and 923 who underwent an MRI scan and had data on WMH volumes. NFL was measured using an ultrasensitive immunoassay, single‐molecule array technology. MRI scans of the brain were acquired using 1.5‐T systems. Global cognitive function was created as a composite measure of 4 neuropsychological tests, standardized and averaged to z‐scores. Linear mixed‐effects models were used to examine associations of the NFL, WMH, and cognitive decline adjusting for age, sex, race, education, and APOE e4.

Result

Of 1,323 participants, 808 (61%) were African Americans, and 38% were men, with an average age of 78.5 years. WMH and NFL were associated with faster cognitive decline in a multivariable‐adjusted model. Individuals in the third tertile of WMH had a faster cognitive decline by 0.029 (95%CI ‐0.052, ‐0.006) units per year compared to the first tertile. Also, compared to the first tertile of NFL, individuals in the third tertile had a faster cognitive decline by 0.029 (95%CI ‐0.046, ‐0.011) units per year. The stratified analysis by the tertiles of WMH showed that NFL was associated with a cognitive decline only in participants in the lowest tertile of WMH (‐0.089; 95%CI ‐0.159, ‐0.02). Similarly, when we stratified analysis by the tertiles of the NFL, we found a significant association of WMH with cognitive decline only participants in the lowest tertile of the NFL (‐0.052; 95%CI ‐0.008, ‐0.024).

Conclusion

While both biomarkers, NFL and WMH, are associated with cognitive decline, our findings suggest that within individuals with low values of NFL, WMH may identify people with a faster rate of decline in cognitive functioning.
Does informing people about modifiable dementia risk factors lead to improved behavioral risk profiles?
Authors: Bartlett Larissa , Doherty Kathleen , Farrow Maree , Eccleston Claire , Bindoff Aidan D , Kitsos Alex , Vickers James C
Published: June 2023

Background

The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) is a large, online, prospective public health cohort study with nested interventions targeting modifiable dementia risk. The objective of ISLAND is to investigate the effectiveness of public health strategies aimed at increasing knowledge about behavioral and lifestyle factors associated with dementia, and to encourage behavior change to reduce future risk profiles at individual and population level.

Method

Commencing October 2019, Tasmanian residents aged 50 and over were invited via a rolling media campaign to join ISLAND. Online surveys administered at baseline were repeated annually to enable tracking of changes in physical and mental health, social functioning, dementia risk knowledge, motivations and behaviors. After each survey wave, participants were provided a personal Dementia Risk Profile (DRP), a traffic‐light style report of their own risk level against nine domains, together with WHO recommendations for achieving ‘low risk’ status. For analyses, the DRP provides individual domain scores and a cumulative risk score, computed by summing domain scores (low = 0, medium = 0.5, high = 1). Newsletters and study information included prompts for participants to join the PD‐MOOC, a free, 4‐week online course about preventing dementia, which runs three times each year.

Result

Participants who provided full data at baseline and the October 2021 annual surveys (n = 2,935) reported a significant and moderate‐sized reduction in their cumulative DRP scores (βs = ‐.36 [95%CI ‐.40, ‐.31]. Within this sample, the participants who engaged with the PD‐MOOC (1,208, 42%) reported a small additional independent benefit (βs = ‐.08 [95%CI‐.11, ‐.05]). General knowledge about dementia risk reduction increased across all respondents (βs = .11 [95%CI .06, .15]) and amongst PD‐MOOC participants, the effect was stronger (βs = .61 [95%CI .53, .70]). The results of mediation models testing the role of knowledge and motivations in observed DRP changes will be presented.

Conclusion

These preliminary findings support the core hypothesis of ISLAND, that increasing knowledge about modifiable dementia risk factors is associated with action‐taking to change key risk behaviors. Future work will link dementia‐risk knowledge and behavioral patterns over time with cognitive and blood‐based markers of neurodegeneration, to understand the long‐term effects of this online public health project.
Association of tamoxifen and raloxifene therapy with cognitive performance, odds of mild cognitive impairment, and neuroimaging markers of neurodegeneration
Authors: Kara Firat , Lohse Christine M. , Castillo Anna , Tosakulwong Nirubol , Lesnick Timothy G. , Jack Clifford R. , Petersen Ronald C. , Olson Janet E. , Couch Fergus J. , Ruddy Kathryn J. , Kantarci Kejal , Mielke Michelle M.
Published: June 2023

Background

Tamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone receptor‐positive breast cancer. Raloxifene, another SERM, has been used for the treatment of osteoporosis in post‐menopausal women. The aim of this cross‐sectional study was to examine whether a history of tamoxifen or raloxifene use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or structural neurodegenerative MRI markers.

Method

The study included women with and without a personal history of breast cancer enrolled in the Mayo Clinic Study of Aging (MCSA). A history of breast cancer and use of SERMs before the MCSA enrollment visit was abstracted using the Rochester Epidemiology Project medical‐linkage system. Participants had a diagnosis of MCI (prevalent) at the time of enrollment into the MCSA. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive measures z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), hippocampal volume, and Alzheimer’s disease signature cortical thickness.

Result

Among the women aged ≥ 50 at enrollment in the MCSA, 151 had a history of breast cancer, and 2235 had no prior history of any cancer. Of the 151 women with a history of breast cancer, 42 (28%) had taken tamoxifen and 109 (72%) had not at enrollment in the MCSA; 54 had neuroimaging data (tamoxifen = 16; no tamoxifen = 38). Among the women without prior history of cancer at enrollment in the MCSA, 76 (3%) had taken raloxifene and 2159 (97%) had not; 755 had neuroimaging data (raloxifene = 25; no raloxifene = 730). No significant associations between tamoxifen with global or domain‐specific cognition or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders (Table 1). Likewise raloxifene was not significantly associated with global or domain‐specific cognition or odds of MCI in women without a history of cancer after adjusting for confounders (Table 2). We did not find significant associations between SERMs and any neuroimaging outcome (Table 3).

Conclusion

Our results suggest use of tamoxifen or raloxifene is not significantly associated with cognition in postmenopausal women.
Differences between healthy adults and mild cognitive impairment patients in Category Fluency performance: A scoring method based on words’ Serial Recall Order and item‐level features
Authors: Marco Matteo De , Blackburn Daniel J , O'Malley Ronan , Venneri Annalena
Published: June 2023

Background

Semantic Memory (SM) alterations occur very early in preclinical AD. Category Fluency (CF) is the most widely‐used measure of free SM recall but is not effective at detecting subtle SM changes. Its score based on word‐count, in fact, is also influenced by other abilities such as processing speed and executive functioning.

We thus designed an alternative, item‐level scoring method less susceptible to these intervenient variables. This quantifies “how difficult” each CF word is based on 9 semantic features. Additionally, the Serial Recall Order (SRO) is established. This is an ordinal variable that tags the position of each word within the recalled list. Participant‐specific correlations are then calculated between SRO and each semantic feature. These capture the tendency of each participant to recall increasingly difficult words.

We previously showed that, in healthy adults, these correlational indices are associated with neurocognitive mechanisms of semantic processing and control, but are statistically independent of processing speed and executive functioning (https://doi.org/10.3389/fnagi.2021.678588; https://doi.org/10.3389/fpsyg.2021.777838).

This study tests whether these indices differ between normal adults and patients with mild cognitive impairment (MCI) at risk of progressing to AD.

Method

CF performance from 60 MCI patients and 60 matched controls was scored following the above methodology. ANCOVAs were run to test the effect of diagnosis on z‐converted correlational indices, controlling for age, educational attainment, and number of CF entries at the basis of the correlations.

Result

Of the nine indices, ‘SRO‐dominance’ was the only one differing between diagnoses. This correlation was ≈‐0.204 in controls and ≈‐0.362 in patients. Words 1‐8 were of similar dominance between groups. A difference was found instead for Words 9‐12.

Conclusion

‘Dominance’ is the ‘degree of control/power’ conveyed by a word. While the general tendency of CF performance is that of recalling words that are increasingly dominant, this trend is significantly more pronounced in MCI. This suggests a different use of semantic‐control resources between groups when the target category is explored in more depth. Although preliminary, these findings indicate that the SRO of CF words can help profile SM in patients with suspected AD. More work is needed, however, to study diagnostic statuses informed by biomarkers.
Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals
Authors: Xie Long , Wisse Laura EM , Das Sandhitsu R. , Lyu Xueying , de Flores Robin , Yushkevich Paul A. , Wolk David A.
Published: June 2023

Background

Neurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD). However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.

Methods

420 CN (A‐/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1‐weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta‐amyloid status was determined with PET by standard cut‐offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Partial Pearson’s correlation, controlling for age, sex, and MRI‐PET date difference, was performed between MTL tau burden and structural atrophy measurements. Intracranial volume and MRI follow‐up time were additional covariates for cross‐sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A‐ subgroups.

Results

Tau burden was significantly associated with cross‐sectional left BA35/36 thickness in the whole cohort and bilateral posterior hippocampus volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A‐ CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta‐amyloid PET SUVR.

Conclusions

The results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.
Predicting biological brain age using deep learning methods
Authors: Dartora Caroline , Marseglia Anna , Mårtensson Gustav , Muehlboeck J‐Sebastian , Kern Silke , Zettergren Anna , Schiöth Helgi , Ferreira Daniel , Skoog Ingmar , Westman Eric
Published: June 2023

Background

The interplay of genetic and environmental factors can trigger a cascade of neuropathological changes leading to individual differences in brain aging. The apparent age of the brain (brain age) can differ from chronological age, potentially reflecting different resilience mechanisms. Brain age has also the potential as biomarker to predict future cognitive impairments and dementia. In this study, we developed a biological measure of brain age, based on the differences between predicted brain age (PBA) and chronological age (CA) using deep learning model (DLM).

Method

The sample included 16734 T1‐w MRI from multiple time‐points of 15115 healthy individuals, aged 32‐96 yrs., from: 1) ADNI (n = 1489); 2) AIBL (n = 957); GENIC (n = 406); 4) UK Biobank (n = 13882). Healthy status was defined as absence of dementia/cognitive impairment, neuro‐psychiatric disorders, and/or self‐report of good health. Medical diagnoses were collected through physician‐/self‐reports or medical records following the International Classification of Diseases. A DLM based on convolutional neural networks was trained to develop an algorithm to predict brain age from raw MRI images registered to the MNI space using training (90%) and hold‐out test (10%) sets. To assess the model generalizability, we applied the algorithm in the Gothenburg H70‐Birth Cohort 1944 (n = 792 septuagenarians).

Result

The hold‐out method achieved a mean absolute error (MAE) error, between PBA and CA, of 3.04 yrs. In the H70 cohort the mean PBA was 73.9±1.49 [64.7‐86.1] years.

Conclusion

The model shows accurate predictions, comparable with those from previous studies using other computation methods. As next steps, we will evaluate hyperparameter optimization and implementation of a cross‐validation methodology. We also seek to include further cohorts of healthy individuals with heterogeneous age‐span to increase the model reliability and generalizability. This will enable to address e.g., differences between normal and pathological aging as well as exploring resilience mechanisms.
Evolution of circulating metabolites through lifespan according to gender and APOE
Authors: Bonnechère Bruno , Liu Jun , Amin Najaf , Kaddurah‐Daouk Rima F. , Van Duijn Cornelia M
Published: June 2023

Background

There is increasing interest in blood‐based metabolic biomarkers for Alzheimer’s disease (AD). Studies show consistently that at branched chain amino acids (BCAAs) and a large scale of lipids are changed in patients with AD. Little is known of how these metabolites associate to age, genes and apolipoprotein E (APOE). This study aims to study these metabolites over the lifespan and determine the influence of age, sex and APOE.

Method

We conducted this study in UK Biobank, a large prospective cohort of 459,227 subjects with extensive genotypic and phenotypic data. Using the Nightingale nuclear magnetic resonance technology, 249 metabolites (165 directly measured metabolites and 84 derived measures) have been determined in the blood of 118,071 participants. We used mixed‐effect models to study the effect of age, sex and APOE on metabolite levels and adjust for lifestyle factors and medication.

Results

APOE*4 is the major determinant of total of 216 metabolic of the Nightingale platform using a FDR < 0.05. We find that 41 were also associated to dementia in the population 60+ years old. Also, APOE*2 is associated with 226 metabolites (FDR<0.05) including 41 dementia associated metabolites. Concerning gender differences, significant differences were found for the metabolites at the FDR 0.05. Overall, we find a significant interaction between age^2 and APOE*4 for valine and BCAA. When stratifying for gender, for most of the metabolites concentrations in blood remain stable over age in men. For amino acids, we observed a decreased concentration level with age in me. For females, we find that the metabolite levels increase over age, reaching a plateau around 55 years old.

Conclusion

This study shows that AD associated metabolite levels in blood are determined by sex and APOE. In women, the levels of metabolites in women are also associated to age up until menopause.
AD‐Associated Variants Directly Impair Surface Interactions Between the Hydrophobic Site of TREM2 and the Hinge Region of ApoE
Authors: Dean Hunter B , Greer Rory A , Kober Daniel L , Roberson Erik D , Brett Thomas J , Song Yuhua
Published: June 2023

Background

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and Apolipoprotein E (ApoE) are two of the strongest genetic risk factors for late‐onset Alzheimer’s disease (AD), but while their interplay in the microglial response to AD pathology is hotly studied, surprisingly little is known about the mechanism by which their variants impair this role.

Method

To define the structural mechanism by which AD‐associated variants impair the TREM2‐ApoE interaction, we used sequence‐based in silico methods to predict the binding site between TREM2 and ApoE, validated the predicted binding site with biolayer interferometry (BLI), then constructed initial models of TREM2‐ApoE complex structures using the identified binding site between TREM2 and APOE as restraints for unbiased molecular docking methods. The top four initial models were re‐ranked by comparing the effect of key residue mutations in the TREM2‐ApoE complex on binding affinities calculated from molecular dynamics‐molecular mechanics Poisson‐Boltzmann surface area (MD/MM‐PBSA) binding free energy analyses with binding affinities measured by BLI. The final validated TREM2‐ApoE complex structure model provides for further investigating the molecular and structural effects of AD‐associated TREM2 variants on interactions between hydrophobic site of TREM2 and hinge region of ApoE.

Result

Our iterative MD/MM‐PBSA–BLI procedure generated an all‐atom model of the TREM2‐ApoE complex that replicates the binding effects of both engineered mutations in TREM2 and AD‐associated variants in both TREM2 and ApoE. The validated model shows the interaction centered on the apical hydrophobic site of TREM2 and the hinge region of ApoE. The interaction sites in the TREM2‐ApoE complex model are consistent with regions affected by AD‐associated variants in simulations of the individual proteins, with biophysical studies using truncated constructs of the two proteins, and with a recently reported minimal active peptide of TREM2 that is sufficient to stimulate its cytoprotective and cytokine regulating roles in primary microglia.

Conclusion

Iterative molecular modeling and biophysical binding affinity assays show the hydrophobic site of TREM2 binding the hinge region of ApoE, an interaction which is impaired by AD‐associated variants and which can be targeted to generate novel therapeutics for AD.