bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic heterogeneity of Alzheimer’s disease: Evidence for disease‐relevant and disease‐specific clustering
Authors: Elman Jeremy A. , Schork Nicholas J. , Rangan Aaditya V
Published: December 2023

Background

Alzheimer’s disease (AD) demonstrates heterogeneity across domains of cognitive impairment, atrophy, and pathological accumulation. This has led to speculations that AD may comprise several disease subtypes. AD is under substantial genetic influence, thus searching for genetic clustering may provide insight towards the origins of this phenotypic variability.

Method

Genotyping data from 2,739 AD cases and 5,478 age and sex‐matched controls from the UK Biobank were used as the discovery data. A principal components analysis (PCA) was applied to AD‐associated variants (p<0.05 in the IGAPS2 GWAS of AD) to assess disease‐relevant structure. A novel biclustering algorithm was then applied to find disease‐specific genetic signatures of AD. This algorithm searches for subsets of subjects and variants that are present in cases, but importantly, not in controls. Pathway analysis was used to characterize the biological pathways implicated by disease‐relevant and specific clustering. Data from 476 AD cases and 591 controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used to test replication of clusters.

Result

PCA revealed 3 distinct clusters. Each cluster contained a mix of cases and controls but these clusters only became apparent when restricting to AD‐associated variants, suggesting disease‐relevant structure. Examining clusters separately, we found 2 significant disease‐specific biclusters comprising sets of variants found more frequently in a subset of AD cases than in controls. When projecting ADNI data on UK Biobank principal components, there was almost perfect overlap of disease‐relevant clusters. Disease‐specific biclusters significantly replicated (p<0.05) across a range of parameter choices.

Conclusion

These findings demonstrate a hierarchy of heterogeneity for AD genetic risk. At the first level, the three disease‐relevant clusters may indicate that different pathways are more vulnerable for different groups of individuals, but additional risk factors or insults are required to substantially increase risk for AD. At the next level, individuals assigned to the biclusters may represent subtypes of AD with different genetic signatures that significantly increase risk for AD. Replication in ADNI demonstrates that this hierarchical structure is a generalizable aspect of AD genetic risk. More broadly, this study illustrates an approach that can be extended to investigate genetic heterogeneity of other complex diseases.
Associations of Neighborhood Disadvantage, Cardiometabolic Risk, and Cognition in a Community‐Dwelling Cohort
Authors: Krishnamurthy Sudarshan , Craft Suzanne , Bateman James R. , Lockhart Samuel N.
Published: December 2023

Background

Social determinants of health (SDoH) are important environmental factors in cardiometabolic risk and cognitive aging. Area Deprivation Index (ADI) is a measure of neighborhood‐level socioeconomic disadvantage and has been studied in normal cognition (NC), but relatively less is known about impact in those with mild cognitive impairment (MCI).

Method

This study explores, in participants with NC and MCI enrolled in the Wake Forest ADRC Clinical Core, baseline measures of metabolic risk (Oral Glucose Tolerance Testing of blood glucose 120‐minute post‐challenge; OGTT‐120), cognition (Preclinical Alzheimer’s Cognitive Composite; PACC), demographics (age, education, diagnosis, race, sex), and participant national ADI rank (using baseline home address). Consensus diagnosis of NC and MCI was adjudicated by a panel of experts.

Result

Demographics of community‐dwelling adults enrolled as a convenience sample in the Wake Forest ADRC with metabolic and cognitive measures by cognitive status is listed in Table 1. MCI participants, compared with CN, were older, more likely male and white, with lower education and PACC, and higher ADI (higher = more disadvantaged). Significant differences in ADI were observed when participants were stratified by race (Figure 1); post‐hoc tests indicate significantly higher ADI in Black compared to white participants, and to some degree, by higher ADI among Black participants compared with Asian participants. OGTT‐120 in participants with NC (n = 265) and MCI (n = 156) was not significantly associated with ADI national rank (Figure 2A); when controlling for age, sex, education, and diagnosis, there was still no association between OGTT‐120 and ADI. Higher ADI was significantly associated with lower PACC scores in individuals with NC (p = 0.044), but not MCI (Figure 2B); this association remained significant (p = 0.004) independent of age, sex, education, and diagnosis (all covariates p<0.001).

Conclusion

Among community‐dwelling older adults, ADI national rank differs by participant race. OGTT‐120 does not correlate with ADI in participants with NC or MCI. PACC scores correlate negatively with ADI national rank in participants with NC, but not MCI; this relationship remained when controlling for covariates. Further analyses are necessary to examine the association between cardiometabolic risk and ADI.
A model for direct support of people with rare dementias, their families and practitioners
Authors: Zimmermann Nikki , Wood Olivia K , Waddington Claire , Williams Millie van der Byl , Tapson Karen , O'Hara Trish , Harding Emma , Fox Nick C , Barker Suzie , Brotherhood Emilie V , Crutch Sebastian J
Published: December 2023

Rare Dementia Support (RDS) is a UK‐based collaborative service led by the UCL Dementia Research Centre, which aims to empower, guide and inform people living with a rare dementia diagnosis and those who care about them. RDS covers familial Alzheimer’s disease (FAD), frontotemporal dementia (FTD), familial frontotemporal dementia (fFTD), posterior cortical atrophy (PCA), primary progressive aphasia (PPA), Lewy body dementia (LBD) and young‐onset Alzheimer’s disease (YOAD). Following self‐referrals and clinical referrals from memory services and specialist neurology clinics across the UK, we provide one‐to‐one support and facilitate regular opportunities for members to meet each other and the team, through large and small support groups, themed programmes and regional support groups.

We will describe the practices of the one‐to‐one Direct Support Team, which provides free information, advice and support from pre‐diagnosis navigation through to post‐bereavement support. This specialist emotional and practical support encompasses compassionate listening; solution focussed outcomes (to complement the diagnosis, treatment and monitoring); helping people to understand and adapt to their condition; empowering people to use their strengths to live fulfilled lives; designing strategies and interventions to manage complex situations (including issues of safeguarding, deprivation of liberty, etc); legal rights and financial support; and supporting transitions into later stages and end of life.

We will also relate the practices of direct support to the broader principles of RDS as a whole (see Figure 1), including the implications of never discharging anyone from our service, and balancing person‐centred and disease‐specific approaches (the importance of knowing which disease each person has, and what person the disease has).

An evaluation of the service will be presented, including characterisation of the current 4797 members, plus data from individual support consultations in 2022 (N = 1449) relating outcomes to personal (social connectedness, wellbeing, knowledge of condition and services), disease (diagnosis, severity) and service (support usage, intensity of discussion) factors.

We will conclude by discussing existing examples of and new opportunities for partnership working – with local, national and international charities, clinical services, academic institutions and funding organisations – to improve access to specialist support for those with atypical, inherited and young onset dementias.
Applications of hybrid structure light three‐dimensional scanning in neurodegenerative disease autopsy brain banking
Authors: Barannikov Savannah , Keating Mallory , Seshadri Sudha , Bieniek Kevin F
Published: December 2023

Background

Postmortem magnetic resonance imaging (MRI) and three‐dimensional (3D) printing has been demonstrated to be a feasible approach for the creation of tissue matrices to aid in postmortem brain dissection. We aimed to extend this approach using hybrid structure light technology (visible and infrared) 3D scanning to generate brain models as a digital resource and operational tool for human neurodegenerative disease brain banks.

Method

A consecutive series of 56 brains accessioned into the Glenn Biggs Institute Brain Bank were imaged using an EinScan H handheld 3D scanner. Five brains were selected for generation of tissue matrices, with infratentorial structures removed using 3D object post‐processing software tools. Matrices were printed using a Raise3D Pro2 printer and 1.75‐mm polylactic acid premium filament.

Result

Each scan was approximately an hour to complete, including capture and alignment of a lateral and a medial surface scan for each brain. Raw scan files (DAT and BRAP‐PRJ) averaged 5.47 GB and 3D object files were 12,991 KB for 3MF and 18,067 KB for OBJ file types. For cases with tissue matrices, average print time was 42 hours with an average filament consumption of 338 g. Brain cutting with the tissue matrices was performed in a standardized manner, with superb control for section thickness and planar orientation compared to brains cut without a matrix.

Conclusion

3D scanning of postmortem autopsied brains is a simple and useful strategy to generate models with utility in guided tissue sectioning and storage (practice), surface area volumetric analysis (research) and virtual reality/augmented reality neuroanatomy training (education) for Alzheimer’s disease and related dementias.
Inhibition of BMP signaling delays tauopathy and cognitive deficits in P301S mouse model
Authors: Affaneh Amira , Tunc‐Ozcan Elif , Peng Chian‐Yu , Kessler John A
Published: December 2023

Background

Aging is the highest risk factor for sporadic Alzheimer’s disease (AD). Expression of bone morphogenic protein 4 (BMP4) increases 10‐fold with age, while expression of the BMP antagonist, noggin, decreases. We have observed that activating BMP signaling in induced human neurons increased levels of phosphorylated tau. The increase of p‐tau has been correlated with the activated non‐canonical BMP pathway leading to p38 activity. We hypothesized that modulating BMP signaling in an AD mouse model of tau would rescue disease phenotype.

Method

P301S (PS19) mice were injected with lentivirus overexpressing noggin (LV‐noggin) or lentivirus mcherry (LV‐mcherry) control in the dentate gyrus. Cognitive behavioral testing was run at 7 months of age and brain tissue was collected for protein and immunofluorescent imaging.

Result

We observe that levels of BMP4, as well as BMP signaling, are increased in the brains of PS19 mice compared to littermate wildtype mice. Analysis of noggin injected PS19 brains show downregulation of BMP signaling in the DG shown by decreased pSMAD1/5/8, as well as non‐canonical signaling through p38 kinase activity. Inhibition of BMP signaling through overexpression of noggin improves cognitive ability shown through Barnes maze testing. Downregulation of BMP signaling in P301S mice led to a decrease in tau phosphorylation seen both in immunoblotting, as well as immunocytochemical analysis in the DG.

Conclusion

PS19 model of tauopathy show increased levels of BMP signaling. We have shown that increased levels of BMP signaling lead to increased tau phosphorylation and reduced degradation of p‐tau. We show that by inhibiting BMP signaling in vivo we can delay cognitive behavioral deficits seen in these mice by decreasing tau phosphorylation. This suggests that the age‐related increase in BMP signaling may participate in the initiation and progression of AD pathology and help to explain why age is the largest risk factor for AD.
Fast accumulators of tau have higher levels of plasma pTau and stronger associations with amyloid in later Braak regions at baseline
Authors: Servaes Stijn , Tissot Cécile , Therriault Joseph , Lussier Firoza Z , Ashton Nicholas J. , Benedet Andrea Lessa , Karikari Thomas K , Wang Yi‐Ting , Stevenson Jenna , Rahmouni Nesrine , Stevenson Alyssa , Pallen Vanessa , Arias Jaime Fernandez , Macedo Arthur C. , Nazneen Tahnia , Hosseini Seyyed Ali , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Pascoal Tharick A. , Gauthier Serge , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro
Published: December 2023

Background

Accumulation of tau neurofibrillary tangles in Alzheimer’s disease (AD) follows a stereotypical pattern, known as Braak staging. As individuals show different rates of tau accumulation, depending on their initial stage, this potentially biases drug effects on tau pathology over time. We hypothesized that amyloid would be a driving force behind tau deposition in later Braak regions for those that were at earlier stages of the disease.

Method

79 individuals (CU: 57, MCI: 21, AD: 1) were recruited from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort. All individuals underwent baseline and 2‐year follow‐up amyloid ([18F]AZD4694) and tau ([18F]MK6240) PET imaging, as well as baseline plasma pTau181, pTau217, and pTau231 assessments. Differences in standardized uptake value ratios between the two timepoints in Braak I‐IV were used to separate fast accumulators of tau from slow accumulators, using the standard deviation of a Young group (n = 13).

Pearson R’s were calculated between tau deposition in Braak regions IV‐VI and the neocortical amyloid load at baseline, within both these groups. Furthermore, a voxelwise analysis was performed to identify specific regional differences in amyloid SUVR between slow and fast progressors, while correcting for age, sex, ApoE4 carriership, as well as the individual’s Braak stage. In addition, an independent t‐test was performed to compare the levels of each pTau species at baseline.

Result

Fast accumulators had stronger increases (p < 0.01) in tau accumulation in Braak region V and VI, compared to slower accumulators. Furthermore, the level of tau deposition in Braak region IV and V was positively associated (p < 0.01) with the amyloid load in the neocortex, but only in the fast accumulator group (figure 1). The voxelwise analysis confirmed that faster progressors had stronger associations with amyloid‐PET (figure 2). Furthermore, those who accumulated tau at a faster rate also had higher levels of plasma pTau at baseline (figure 3).

Conclusion

Tau deposition in later Braak regions is associated with a higher amyloid load and increased values of pTau181, pTau217 and pTau231 at baseline in individuals in early Braak stages that accumulate tau at a more rapid rate.
Distinct CSF biomarker‐associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
Authors: Wang Lily , Zhang Wei , Young Juan I. , Gomez Lissette , Schmidt Michael A. , Lukacsovich David , Varma Achintya , Chen Xi , Kunkle Brian W. , Martin Eden R.
Published: December 2023

Background

Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease and that DNAm differences can be detected in the blood of AD subjects. Because access to human brain tissues is primarily limited to postmortem samples, most studies have correlated blood DNAm with clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Thus, the association of blood DNAm with changes in AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.

Method

CSF biomarkers are well‐established AD endophenotypes and correlate significantly with neuropathology scores measured on postmortem brain samples. In this study, we performed a comprehensive analysis to identify blood DNA methylation associated with CSF pathological biomarkers for AD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 cognitively normal, 79 AD cases).

Result

We identified a number of novel associations between blood DNAm and CSF Aβ42, pTau181, and total tau biomarkers, demonstrating that changes in various pathological processes in the CSF are also reflected in the blood epigenome. Overall, the CSF biomarker‐associated DNAm is relatively distinct in cognitively normal (CN) and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our pathway analysis of CSF biomarker associated‐DNAm from CN subjects revealed that biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood.

Conclusion

Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.
Associations between Verbal Memory Performance and Regional Brain Volumes Differ by APOE4 Carrier Status in Midlife Women
Authors: Wugalter Katrina A , Thurston Rebecca C , Wu Minjie , Schroeder Rachel A , Aizenstein Howard J , Derby Carol A. , Maki Pauline M
Published: December 2023

Background

APOE4 genotype is a stronger risk factor for Alzheimer’s disease (AD) in women than men, and its influence on memory and AD biomarkers differs by disease stage. Among cognitively normal older APOE4 carriers, APOE4 status influences memory similarly in males and females but adversely influences hippocampal volume in males. The effect of APOE4 status on regional brain volumes earlier in life, and in relation to memory, are less well understood. We examined whether associations between verbal memory performance and regional brain volumes differed by APOE4 status in cognitively normal midlife women. We hypothesized that APOE4 carriers would show weaker associations between memory performance and brain volumes than non‐carriers, particularly in the temporal lobe.

Method

Participants were enrolled in MsBrain, a cohort study of midlife women. Verbal memory was assessed with the California Verbal Learning Test (CVLT‐II). Cortical thickness was measured and segmented by FreeSurfer using individual T1w MPRAGE images. Multiple regressions were conducted to determine associations between memory (learning, free recall) and regional brain volumes by APOE4 status (carriers versus non‐carriers), controlling for age, education, and race.

Result

In 148 cognitively normal postmenopausal women (mean age = 59.17 years, 84.4% white, n = 37 APOE4 carriers), APOE4 status had no main effect on CVLT‐II measures or brain volumes, except the volume of the left supramarginal gyrus. However, APOE4 status modified the magnitude of association between verbal memory and brain volumes, specifically the association between: a) verbal learning and volume in the left caudal middle frontal gyrus (CMFG), left isthmus cingulate gyrus, left parahippocampal gyrus, left insula, right precuneus, right lateral orbitofrontal gyrus (LOG), and right temporal pole (TP); and b) free recall and volume in the left CMFG, right LOG, right posterior cingulate gyrus, and right TP. The direction of the associations between verbal memory and brain volumes was positive in non‐carriers and negative in carriers.

Conclusion

In cognitively normal midlife women, APOE4 carrier status may influence the extent to which the hippocampal, temporal, and frontal lobe structures support verbal memory performance. This subtle effect may emerge before the main effect of this genetic risk factor on brain volume and memory.
The evaluation of translated neuropsychological assessments tools for the early detection of mild cognitive impairment (MCI) in low‐ and middle‐income countries (LMICs)
Authors: Ghosheh Mohammad , Ghosheh Ghadeer , Ghosheh Jamal
Published: December 2023

Background

The incidence of mild cognitive impairment (MCI), particularly in low and middle‐income countries (LMICs) has been noticeably on the rise. With the high cost of dementia care, the need for tools that aid with the early detection of MCI is becoming of high importance, especially in LMICs. As a part of screening for MCI, many tests have been proposed evaluating for impairments in cognitive, behavioral, and functional domains, which are important for ruling out and evaluating for any reversible causes. While useful, most of these tests were developed in the west, limited works exist reporting the appropriateness and experience of using such tests for patients from LMICs.

Method

In this work, we aim to evaluate the use of translated digital assessment for detecting MCI in an Arabic‐speaking population in Palestine. For this purpose, we developed a digital test covering three cognitive, behavioral, and functional domains, where MMSE and the Neuropsychiatric Inventory ‐ Questionnaire (NPI‐Q) together with two functional assessment questionnaires were translated to Modern Standard Arabic (MSA) and presented in a digital interface. Upon the development and translation of the digital tests, field testing was conducted to check for use experience and appropriate patient comprehension of the questions to match their intended use.

Result

Following the implementation of the digital assessment tools, quantitative and qualitative data was collected summarizing the user experience, where numerous limitations were noted. Despite being asked in their native language, several patients expressed the need for more clarifying questions. While all patients were Arabic speakers, some patients required the use of simpler terminology that matches their local dialects. Other patients reported the lack of relevance of certain questions, regarding the activities of daily living in the functional assessments. Overall, the patient’s experience and comprehension of questions varied with their age and literacy level.

Conclusion

Despite the high prevalence of dementia in LMICs, there are limited available neuropsychological assessment tools that are fit for the local cultural and linguistic. The findings suggest the need for the development of culturally and linguistically appropriate assessments to ensure appropriate patient comprehension, and avoid misdiagnosis of patients.
Working memory binding failures and abnormal alpha power in Alzheimer’s disease
Authors: Mallas Emma‐Jane , David Michael CB , Karakoc Hanim , Tsoi Chris ML , Malhotra Paresh A , Scott Gregory , Sharp David J
Published: December 2023

Background

Associative binding is key to normal memory function and is selectively impaired in Alzheimer’s disease (AD).1 Electrophysiological abnormalities are frequently reported in AD including during tasks requiring associative binding.2 We use a precision spatial working memory test to investigate the binding of distinct visual features (object and location) in working memory in AD patients and test the hypothesis that misbinding is related to electrophysiological abnormalities.

Methods

36 AD patients and 29 healthy age‐matched controls (HC) were tested with a precision working memory paradigm that required the association of object and location information (Fig 1A). Participants were excluded if they were unable to perform the identification element of the task significantly above chance level (p>0.05). High‐density eyes‐closed resting‐state EEG was used to assess changes in electrophysiological power across frequency bands.

Results

25 AD and all HC performed above chance level (Fig 1C). AD patients showed abnormalities in working memory function and made significantly more misbinding errors (p<0.001) than HC (Fig1E) indicating that working memory recall was abnormally biased by the spatial locations of distractor items (Fig 1F). AD patients demonstrated significant reductions in global alpha and increases in global theta (Fig 2A). Channel‐wise analysis revealed significant clusters of decreased power in AD across occipital‐parietal channels in alpha and beta bands (p<0.05; Fig 2C). Misbinding errors significantly correlated with alpha power in AD but not HC (p<0.05; Fig 2D).

Conclusions

These results offer further support for a deficit in working memory binding being a sensitive cognitive biomarker of AD. Pathologically reduced alpha power may offer mechanistic insight into the profound working memory binding impairments seen in AD.

References:

1. Della Sala S, Parra MA, Fabi K, Luzzi S, Abrahams S. Short‐term memory binding is impaired in AD but not in non‐AD dementias. Neuropsychologia. 2012;50(5):833‐840. https://doi.org/10.1016/j.neuropsychologia.2012.01.018

2. Han Y, Wang K, Jia J, Wu W. Changes of EEG Spectra and Functional Connectivity during an Object‐Location Memory Task in Alzheimer’s Disease. Front Behav Neurosci. 2017;11:107. https://doi.org/10.3389/fnbeh.2017.00107
Late‐onset behavioural change is enriched with C9orf72 repeat expansion regardless of family history or diagnosis
Authors: Boer Sterre C.M. , Krudop Welmoed A. , Gossink Flora T , Oudega Mardien L , Kerssens Cora J. , Dols Annemiek , van Ruissen Red , Lee Sven J , Pijnenburg Yolande A.L.
Published: December 2023

Background

The C9orf72‐repeat expansion (C9RE) is the most prevalent genetic cause of frontotemporal dementia (FTD). Since its discovery, studies have shown that both family history (FH) and medical history of FTD patients carrying a C9RE are often not only positive for dementia, but also for psychiatric disorders and late‐onset behavioural change. Conversely, finding a C9RE carrier in a primary psychiatric disorder (PPD) cohort is rare. These findings justify clinicians to test for the C9RE, regardless of FH, when diagnosing a patient with FTD but not to screen for C9REs in PPD cohorts. It is unknown what the frequency is of C9RE in cases presenting with late‐onset behavioural change. Therefore, we investigated the diagnostic value of screening for C9RE in cases with late‐onset behavioural change.

Method

Patients with late‐onset (>45years) behavioural change referred to the Alzheimer Center Amsterdam between 2011 and 2023, that received a baseline diagnosis of FTD or non‐FTD were included. Genetic screening was performed and mutation carriers other than C9RE were excluded. The cohort was devided in C9RE‐carriers and non‐carriers. FH data was retrieved. Positive FH (FH+) was defined as having a first‐degree relative with dementia or psychiatry, negative FH (FH‐) without a first‐degree relative with dementia or psychiatry. Distribution of FH(+/‐) between C9RE‐carriers and non‐carriers was studied. Within the C9RE‐carriers, distribution of FH between FTD and non‐FTD diagnosis was measured. Distributions were compared using chi‐squared tests.

Result

A total of n = 344, of which 16,2% C9RE‐carriers, were included. Of the C9RE‐carriers, 66.7% had a FH+ versus 35.7% of the non‐carriers (p = 4.36e‐05). Within the C9RE‐carriers group, n = 34 cases received a FTD diagnosis of which n = 20 had a FH‐ (58.5%) versus n = 20 cases receiving a non‐FTD diagnosis of which n = 14 (70%) having a FH‐ (p‐value = 0.596, table 1).

Conclusion

Within a cohort of late‐onset behavioural change, 14 cases (4.2% of total cohort) received a non‐FTD diagnosis, had a negative FH for dementia and psychiatry but turned out to have a C9RE. This shows late‐onset behavioural change is enriched with C9RE, regardless of FH or baseline diagnosis, and suggests that screening for C9RE is of both diagnostic and prognostic value in late‐onset behavioural disorders.
Investigating the Role of APOE Genotype in Human Microglia
Authors: Ulm Brittany , Amin Najaf , Bahnassawy Lamiaa , Reinhardt Peter , Curado Marco Rocha , Peitz Michael , Fliessbach Klaus , Ramirez Alfredo , Ruiz Agustin , Ried Janina S , Bakker Margot H.M. , Van Duijn Cornelia M ,   IMI ADAPTED Consortium
Published: December 2023

Background

Although the pivotal role of apolipoprotein E () in AD has been recognized for three decades, its function in different brain cells is far from understood. Knockout studies of the APOE gene may shed light of the function of ApoE. The aim of the present study was to unravel its function in induced pluripotent stem cell (iPSC) derived microglia.

Method

We studied two human iPSC‐derived microglia cell cultures, one derived from a healthy control (Bioni010‐C – endogenous genotype apolipoprotein E34 (APOE34)) and one from an AD patient (UKBi011‐A – endogenous genotype APOE44) and their edited isogenic cell‐lines (for UKBi011‐A, APOE22 and APOE33 and for Bioni010‐C, hemizygous due to gene editing, APOE2‐ and APOE3‐ (32971461, 29753274)). Additionally, APOE KO lines were generated from both backgrounds. We performed whole genome transcriptomic (IlluminaTruSequencing) and proteomic (TMT‐labelled Nano‐LC peptidomic MS) analysis (n = six per genotype). For transcriptomic data, log2‐normalized intensities were analysed with (in R); there were 13115 unique transcripts. For proteomics analysis, after global normalization, the data were locally normalized (by protein), the limma package was used to calculate FDR‐corrected p‐values (1% cut off); there were 3975 (Bioni010 samples) and 4349 (UKBi011 samples) proteins. In the quality control analysis for the proteomics, we excluded one outlier of the six per line based on principle component/Euclidean distance analysis. We extracted pairwise comparisons to APOE KO in transcriptomic (|logFC|>0.5, FDR <0.05) and proteomic (|logFC|>0 and FDR <0.05) data.

Result

Twenty transcripts (including APOE) were concordantly differentially expressed across all comparisons between APOE‐expressing and KO. These are broadly involved in processes related to mitochondrial function/organization, apoptosis, transcriptional regulation, immune functions, extracellular matrix, and energy metabolism among others. Seven proteins were concordantly differentially expressed across all pairwise comparisons with APOE KO, involved in extracellular matrix, immune signalling, energy metabolism, and cytoskeletal structure.

Conclusion

Our study finds APOE knockout leads to a number of changes related to immune, mitochondrial, and extracellular matrix genes, suggesting that APOE in human iPSC‐derived microglia cells influences immune and mitochondrial functions.
Fine semantic segmentation of hands for human functional pattern recognition in IADLs using deep learning
Authors: Babatope Eyitomilayo Yemisi , Acosta‐Franco Jesus Alejandro , García‐Vázquez Mireya Saraí , Ramírez‐Acosta Alejandro Álvaro
Published: December 2023

Background

Alzheimer’s Disease (AD) is an irreversible degenerative brain disease and the most common cause of dementia, in the elderly population (age 65 and above) although people younger may develop the disease (Clemmensen, 2020). AD is characterized by impairment in behavior and cognition which eventually obstruct the Instrumental Activities of Daily Living (IADL) (Kumar, 2022). Researchers have predicted functional capacity by assessing IADL as they are strongly associated with cognitive impairment. With the availability of big data and public repositories of multimedia data such as images and videos, artificial intelligence algorithms have been used in classifying and making informed decisions that could help in disease prediction and monitoring. In the context of early diagnosis of Alzheimer, researchers have worked with machine learning techniques applied to neuroimaging for AD classification (Lama, 2021). Researchers and practitioners often use Activity of Daily Living to monitor independent‐living senior citizens’ self‐care ability, wellness status, and disease progression (Zhu, 2021). Automating the assessments of IADL will ease the evaluation of functional and cognitive function and strengthen the prediction of AD.

Method

Our work approaches the timely detection and diagnosis of AD by exploring the deficiency in hand dexterity and visuospatial skills while performing IADL using egocentric videos. Therefore, in this work, we propose a fine semantic segmentation of hands, optimizing the predictions at the level of the relationship between pixels in a deep learning method. We trained the optimized RefineNet‐Pix convolutional neural network, obtaining a higher accuracy in the segmentation of semantic maps of hands.

Results

With the optimization of RefineNet‐Pix we obtained an accuracy higher than 87.9% (Urooj, 2018) in the semantic segmentation of hands. By integrating the RefineNet‐Pix results to the base model for human functional pattern recognition, we obtain an accuracy higher than 74% with respect to the base model (Yemisi, 2022).

Conclusion

The optimized RefineNet‐Pix model segments pixel‐wise the hand regions in egocentric videos, providing hand motion information that can be used to classify impairment based on human functional patterns. Optimization of these models is a way forward in building a technological device for the support of Alzheimer’s diagnosis.
Area Deprivation Index is associated with biomarkers of inflammation cross‐sectionally and longitudinally over a 9‐year follow‐up period
Authors: Gogniat Marissa A. , Khan Omair A. , Bolton Corey J , Ratangee Brina A. , Liu Dandan , Pechman Kimberly R. , Yates Alexis , Eaton James , Houston Michelle L , Gifford Katherine A. , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L.
Published: December 2023

Background

Living in a socioeconomically disadvantaged neighborhood has a negative impact on health outcomes, including increased risk for Alzheimer’s disease (AD). The biological mechanisms underlying this risk are poorly understood. We examined how neighborhood disadvantage relates to core AD pathology, neurodegeneration, and inflammatory biomarkers in community‐dwelling older adults

Method

Vanderbilt Memory and Aging Project participants (n = 327, 73±8 years, 41% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.8 years). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline based on 17 components [e.g., housing, income, education, and household characteristics (Kind & Buckingham, 2018)]. Ordinary least squares regressions cross‐sectionally related ADI to plasma and CSF biomarkers adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, apolipoprotein E‐e4 status, and cognitive status. Linear mixed‐effects regression models related baseline ADI to longitudinal biomarkers with identical baseline covariates plus follow‐up time. Outcomes included CSF chitinase‐3‐like protein 1 (YKL‐40), CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2), CSF amyloid‐b40 (Ab40), CSF amyloid‐b42 (Ab42), CSF Ab40/Ab42 ratio, CSF tau, CSF phosphorylated tau (ptau), plasma high sensitivity C‐reactive protein (CRP), and plasma and CSF neurofilament light chain (NfL).

Result

On average, the sample was from relatively less disadvantaged neighborhoods (ADI national decile = 35.4±25.0, range = 1‐98). Greater neighborhood disadvantage at study entry was cross‐sectionally associated with elevated CSF YKL‐40 (β = ‐0.733, p = 0.003), sTREM2 (β = 19.74, p = 0.04), Aβ40 (β = 35.96, p = 0.01), tau (β = 2.31, p = 0.02), and ptau (β = 0.33, p = 0.03). Greater neighborhood disadvantage at study entry related to longitudinal increases in CRP (β = 0.012, p<0.001) and decreases in plasma NfL (β = ‐0.025, p = 0.04) over the follow‐up period.

Conclusion

Among community‐dwelling older adults, greater neighborhood disadvantage was associated with elevated inflammatory and AD CSF biomarkers cross‐sectionally, and longitudinal increases in a non‐specific inflammatory blood biomarker. Collectively, findings suggest that neighborhood disadvantage confers immediate risk for systemic neuroinflammation and AD and future risk for non‐specific inflammation, providing valuable evidence of a sociobiological mechanism underlying health disparities in aging adults based on geographic location.

Funding. R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082
Association between plasma inflammatory biomarkers and [18F]FDG‐PET signal in a transgenic amyloid rat model
Authors: Lazzarotto Gabriela , Machado Luiza Santos , da Rocha Andreia Silva , Siebert Marina , Limberger Christian , Soares Carolina , Schlickmann Thomas , Ferreira Pamela C.L. , Pascoal Tharick A. , Souza Diogo O. , Rosa‐Neto Pedro , Zimmer Eduardo R
Published: December 2023

Background

Neuroinflammation is thought to play an important role in the pathogenesis of Alzheimer’s disease (AD). It has recently been demonstrated that [18F]FDG positron emission tomography (PET) signal is sensitive to central inflammatory changes in AD. However, it is unknown whether blood cytokines, which are important signaling molecules that regulate the peripheral inflammatory process, are associated with the cerebral [18F]FDG‐PET signal. In this work, we aimed to investigate whether plasma cytokines are associated with brain glucose metabolism in a transgenic amyloid rat model.

Method

Brain metabolism of 4‐ and 10‐month‐old wild‐type (WT) and APP/PS1 rats (TgF344‐AD) were assessed with [18F]FDG‐PET imaging. Plasma inflammatory markers (IFN‐γ, IL‐1α, IL‐1β, IL‐6, IL‐10 and TNF‐α) were measured by multiplex immunoassay. [18F]FDG‐SUVr was calculated with pons as the reference region. Correlation between inflammatory markers and [18F]FDG‐PET signal was conducted at the voxel level (RMINC; p<0.05 and t>2).

Result

At 4 months, IL‐10 levels significantly associate with [18F]FDG‐PET signal in the frontal and temporoparietal cortices (FCx and TPCx) and hippocampus (Fig1A), whereas other biomarkers present only small clusters associated with [18F]FDG‐PET signal (Fig1A). At 10 months, a positive association with [18F]FDG‐PET was found between IL‐1α and IL‐1β at FCx and TPCx, while IL‐10 showed a positive correlation at the TPCx (Fig1B). Additionality, IFN‐γ and TNF‐α presented small correlation clusters at the TPCx, and IL‐6 at the TPCx and CxF (Fig1B).

Conclusion

At the pre‐amyloid plaque stage, only an anti‐inflammatory cytokine, IL‐10, presented positive associations with brain glucose metabolism. However, multiple pro‐inflammatory cytokines correlated with brain glucose metabolism at the amyloid plaque stage. These findings suggest a dual peripheral inflammatory response impacting brain metabolism, which can be associated with amyloid species and deposition.
Detecting Protective Rare Variants for Alzheimer’s Disease from Whole‐Genome Sequencing in the Amish
Authors: Song Yeunjoo E. , Wang Weihuan , Miskimen Kristy L. , Laux Renee A. , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Main Leighanne R. , Osterman Michael D. , Lynn Audrey , Prough Michael B. , Slifer Susan H. , Adams Larry D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Dorfsman Daniel A. , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: December 2023

Background

A shift in focus from risk to resilience for Alzheimer’s disease (AD) encourages efforts to uncover novel AD biological mechanisms. Rare variants identified through whole genome sequencing (WGS) may represent an important and understudied component of complex trait genetics. While population‐based studies are powered to discover associations with common genetic variants, founder populations are better powered for discovery of previously unknown rare alleles that have risen to higher frequency due to genetic drift.

Method

We examined WGS data from the Mid‐Western Amish population in a genome‐wide search for rare coding variants shared only among cognitively‐unimpaired (CU) individuals. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. Allele frequencies were calculated across all samples and for CU and cognitively‐impaired (CI) groups separately. We defined rare variants as having an allele frequency <0.05 across all samples. Variants with a minor allele count (MAC)>10 in the CU group, and 0 in the CI group were annotated to determine likely loss of function.

Result

After extensive QC, 1,048 samples were available to estimate overall allele frequency. Allele frequencies of rare variants (n = 11,854,817) within 634 CU (mean age = 81.53±6.10, 60% female) and within 184 CI (mean age = 84.77±6.60, 62% female) individuals were compared and 51,616 variants with MAC >10 were found only in CU. There were 316 unique coding variants (288 missense, 4 inframe_insertion, 6 inframe_deletion, 11 frameshift, 4 stop_gained, 3 splice_donor) and 180 synonymous variants located within 425 unique genes. Among them, 7 missense variants and 7 synonymous variants had MAC >20 and the remaining variants had MAC of 11‐20. The mean allele frequency of the 7 missense variants was 0.0038 in TOPMed compared to 0.0154 in our data. Two synonymous variants were located within proposed AD genes (NYAP1 and ZNF423). Additionally, several untranslated region or nonsense‐mediated decay transcript variants existed within 26 known AD gene regions, among which 8 of them are reported to harbor protective variants for AD.

Conclusion

Numerous rare variants potentially impacting gene function were found only in CU individuals, providing a rich resource for further investigation of genes that may provide protection from cognitive impairment.
Anterior and posterior default mode network functional connectivity and segregation in aging
Authors: Taylor Lisa M. , Adams Jenna N. , Kim Soyun , Harris Alyssa L. , McMillan Liv , Keator David B. , Yassa Michael A.
Published: December 2023

Background

The default mode network (DMN) supports memory performance and has been shown to be vulnerable to the effects of aging. The posterior DMN (pDMN) is an early region of amyloid‐β (Aβ) accumulation, which may lead to disrupted communication within/between subnetworks of the DMN. Using resting state functional connectivity (FC), we tested whether communication within and between the pDMN and anterior DMN (aDMN) were altered by aging and Aβ pathology and related to memory performance. We also tested segregation FC between the aDMN and pDMN.

Method

Data from 27 cognitively normal adults (69.6 years, 59% females) with resting state fMRI (rsfMRI), 18F‐florbetapir (FBP) PET to measure Aβ, and the Rey Auditory Verbal LearningTest (RAVLT) delayed recall to assess memory were analyzed. The rsfMRI data were preprocessed using CONN toolbox. ROI‐to‐ROI FC matrices were constructed for regions included in the aDMN and pDMN. We calculated: (1) the average FC within each network (Zw), (2) average FC between the aDMN and pDMN (Zb), and (3) network segregation [(Zw‐Zb)/Zw] for each DMN network. Global FBP SUVR was calculated as the mean across association cortical regions, and a cutoff of 1.11 was used to determine Aβ positivity. Analyses included the FC variables and their associations with age, Aβ, and memory.

Result

Older age was associated with reduced network segregation of the pDMN (r = ‐0.53, p = 0.004), and a trend level association for reduced within‐pDMN FC (r = ‐0.37, p = 0.057). Global FBP SUVR was not associated with FC or network segregation, and there was no significant difference in FC between Aβ groups (controlling for age). There was a trend‐level association between better memory performance and stronger FC between aDMN and pDMN (r = 0.37, p = 0.066; controlling for age and education).

Conclusion

Results demonstrated that aging is associated with specific FC disruptions of pDMN, leading to reduced specialization of processing as indexed by network segregation. Moreover, increased communication between DMN subnetworks may support memory in aging. Future analyses in a larger sample will further test the association between Alzheimer’s pathology and functional changes to DMN subnetworks.
Semantic cognition as an early cognitive marker of Alzheimer’s disease: importance of executive processes mediation
Authors: Guinea Sara Fernández , Rivera‐Fernandez Claudia , Soto‐Añari Marcio F. , Marqués Javier González
Published: December 2023

Background

Impaired semantic memory is one of the earliest characteristic features of Alzheimer’s disease. Its assessment is crucial to accurately predict conversion to Alzheimer disease related disorders (ADRD). Recent evidence supports the necessity to differentiate between subprocesses of semantic cognition: a) activation in the semantic representation system; b) executive processes to control or select relevant aspects of semantic knowledge. In this study we compare semantic memory tests that differ in these subprocesses to find out which of them are the best predictors of conversion of MCI to ACD in two years. We also want to identify which semantic memory tests have more sensitivity and specificity at the baseline in the differentiation MCI‐no converters and MCI converters after two years

Method

We assessed 130 amnestic MCI patients. Semantic memory tests more based on integrity of semantic knowledge (Similarities, ACE‐language) and more executive determined (verbal fluency – phonemic and categories, Boston Naming Test) were administered at baseline and at 2‐years follow‐up, together with cognitive screening tools and IADL measures. A binary regression model was used to examine which semantic memory tests predict MCI progression to Alzheimer’s Clinical Syndrome (ACS) in two years. ROC curves were used to study early clinical diagnosis differentiating MCI converters and MCI non converters

Result

Only semantic category fluency test significantly explained the conversion to ACS (p<.01). Baseline score semantic categories fluency were significantly lower in MCI patients who develop ACS after two years (p<.001). ROC curves showed that semantic categories fluency and Boston Naming tests were the best tests to differentiate at baseline between MCI converter and non‐converter (AUC = 0.768, p<0,0001 and AUC = 0.712, p<0,01, respectively)

Conclusion

Semantic category fluency test was the best predictor from MCI to ACS conversion in two years. Semantic category fluency and Boston Naming tests clearly identify people with high risk to develop ACS in two years. Semantic memory tests including executive contributions could detect and characterize prodromal Alzheimer’s disease