bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing genetic overlap of Alzheimer’s disease with type 2 diabetes
Authors: Adewuyi Emmanuel O , Porter Tenielle , Verdile Giuseppe , Laws Simon M.
Published: January 2025

Background

Whilst numerous studies have explored the relationship between Alzheimer’s disease (AD) and diabetes, there remains significant conflicting evidence as to their relationship. Some studies suggest an increased likelihood of developing AD in individuals with diabetes, especially type 2 diabetes (T2D) and that both diseases share pathological features. In contrast, other studies indicate that T2D is more aligned with vascular cognitive impairment and dementia and associated cerebrovascular/white matter pathology. Moreover, there is evidence showing no significant genetic correlation between the two disorders. Understanding the genetic relationship between these potentially comorbid conditions could offer insights into AD’s poorly understood biological mechanisms. This study used two complementary methods to evaluate the genetic relationship between AD and T2D. We hypothesise that both disorders are, to an extent, genetically correlated.

Method

We performed an extensive analysis of large‐scale genome‐wide association summary data using the ‘linkage disequilibrium score regression’ analysis (for global correlation) and ‘single nucleotide polymorphism (SNP) effect concordance analysis’ (SECA, for genetic overlap) methods. We performed several analyses testing our findings’ potential (partial) replications, using several GWAS data for AD (with and without the APOE region) and T2D.

Result

We found a highly significant positive genome‐wide (global) genetic correlation between AD (clinically diagnosed with proxy cases) and all T2D GWAS assessed, with or without the APOE region. We largely replicated the positive and significant results using clinically diagnosed AD GWAS. Utilising SECA, we found robust SNP overlap and strong effect concordance with low permutation p‐value and significant Fisher’s exact test—underscoring the strong association between SNP sets (and association in effect direction) for both disorders. Our SECA results were consistently significant irrespective of whether AD or T2D was dataset 1 or dataset 2. We replicated SECA’s results across clinically diagnosed AD and other T2D GWAS data (with or without the APOE region included).

Conclusion

Our analyses reveal a notable genetic correlation and overlap between AD and T2D, indicating shared genetic factors (shared genetic foundation) and biological pathways influencing the risk or susceptibility to both conditions.
Unraveling the dysregulation of Frizzled receptors in Alzheimer’s disease: Critical contributor for synapse loss
Authors: Basavaraju Nimisha , Kommaddi Reddy Peera
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by early synapse loss, which is further associated with deficits in memory and cognition. The loss of synapses could be mediated by dysregulation of molecular mechanisms crucial for maintaining synaptic structure and function. Among these mechanisms, the Wnt signaling pathway holds significant importance in regulating synaptic assembly. Specifically, Frizzled receptors have been identified as necessary and/or sufficient to recruit synaptic proteins at both the pre‐ and post‐synapse. Despite the pivotal role of frizzled receptors at the synapse, their contribution to synapse loss in AD remains relatively unclear. This lack of clarity persists as existing research on dysregulation of Wnt signaling in AD has predominantly focused on antagonist (Dkk1), kinase (Gsk3β), and co‐receptor (Lrp6). So, the goal of our study is to unravel how frizzled receptors are regulated and how they affect the phosphorylation and ubiquitination of β‐catenin at the synapse in AD.

Method

Post nuclear supernatant and synaptosomes were isolated from brain cortex of nine‐month‐old male wild type and APP/PS1 mice. The samples were subjected to immunoblotting against Frizzled receptor 7 (Fzd7) and phosphorylation of β‐catenin. β‐catenin immunoprecipitated samples of synaptosomes were immunoblotted and probed for β‐catenin ubiquitination. Statistical comparisons between wild type and APP/PS1 group were conducted using two tailed, unpaired Mann‐Whitney U test.

Result

Protein levels of Fzd7 are significantly decreased in synaptosomes of nine‐month‐old APP/PS1 mice compared to that of control mice. Decrease in the levels of receptor, Fzd7 implies an increase in β‐catenin phosphorylation and ubiquitination at the synaptosomes as a result of decreased Wnt signaling. Intriguingly, our observations reveal a significant decrease in both phosphorylation and ubiquitination of β‐catenin in synaptosomes of nine‐month‐old APP/PS1 mice.

Conclusion

Decreased phosphorylation and ubiquitination of β‐catenin is observed in nine‐ month‐old APP/PS1 mice compared to wild type suggesting an elevated Wnt signaling at the synapse. Our study provides novel insight into how elevated Wnt signaling could contribute to the synapse loss in AD.
How Does Increased Human Astrocyte‐Derived α‐Synuclein Affect Trophic Factor Release and Neurodegeneration in Neuron‐Astrocyte Synaptic Components?
Authors: Şengül Büşra , Dursun Erdinc , Gezen‐Ak Duygu
Published: January 2025

Background

Astrocytes secrete neuromodulators, neurohormones, trophic factors, and synaptogenesis modulators. Trophic factors regulate various cellular processes including synaptic transmission. Astrocytes have critical roles in synaptic development and plasticity. They are involved in synapse formation and their absence leads to loss of synaptic connections and, neurodegeneration. Our previous study reported that α‐synuclein overexpression in human astrocytes alters the production and release of trophic factors. In the present study, we investigated the potential of astrocyte‐derived α‐synuclein increment to trigger the degeneration of synaptic connections and promote neurodegeneration by affecting the release of growth factors required for synapse formation.

Method

A co‐culture system containing LUHMES cells which are human precursor neural cells, and human primary astrocyte cells was established. The plasmid carrying the human SNCA gene was transferred only to astrocytes using a lipid‐based transfection agent and then, SNCA overexpressing astrocytes were co‐cultured with neurons. We investigated whether the transfected α‐synuclein in astrocytes transffered to neurons or not by live cell imaging. The levels of synaptic proteins such as thrombospondin, synaptophysin, PSD‐95, and NGF were determined by western blot.

Result

Our data showed that astrocyte‐derived α‐synuclein migrated to LUHMES cells, α‐synuclein pathology increased neuronal cytotoxicity and decreased NGF expression. We found that astrocyte‐derived α‐synuclein increased the production and release of astrocyte‐derived thrombospondin, the production of synaptophysin and PSD‐95 proteins that are all involved in synapse formation in neurons.

Conclusion

Our results indicate that α‐synuclein may affect synapse formation by increasing the thrombospondin levels. Evaluating this result with the increased membrane damage, we may speculate that these increments in synaptic proteins may be considered as a cellular response to reverse the damaged cell structures.
Multiregional neuropathological changes and cellular correlates of Alzheimer’s disease
Authors: Gabitto Mariano I
Published: January 2025

Background

Alzheimer’s Disease is marked by the gradual aggregation of pathological proteins, Tau and beta‐amyloid, throughout various areas of the brain. The progression of these pathologies follows a consistent pattern, impacting various cellular populations as it advances through each brain region. Previously, we used Bayesian algorithms to create a continuous progression score to mathematically capture the collective aggregation of multiple pathological variables within a specific brain region. This score allowed us to discern the cellular and molecular alterations associated with the disease, offering valuable insights into the etiology of these changes within a single brain region.

Method

As part of The Seattle Alzheimer’s Disease Cell Atlas (SEA‐AD, https://sea‐ad.org), we stained and quantified multiple neuropathological proteins (a‐Syn, pTDP43, pTau and beta‐amyloid) and cellular populations (neurons, astrocytes and microglia) in several brain regions (middle temporal gyrus, the middle frontal gyrus, hippocampus, and medial entorhinal cortex). Next, we profiled multiple brain regions using single nucleus RNA‐seq and a subset of donors and regions were profiled with ATAC‐seq or multiome in each SEA‐AD brain donor. We integrated these single nucleus datasets into a common latent representation, and mapped cellular types to our MTG taxonomy, adding additional cell types occurring in specific brain regions.

Result

We mapped the progression of pathology using our Bayesian algorithms in each individual region. Next, we identified the order of the successive regions affected sequentially by disease. Additionally, we segmented the hippocampal formation and characterized the progression of pathology within it and linked it to synaptic connectivity across regions. Next, we used our scale of disease progression to identify the vulnerable populations in each region. After comparing populations with the known burden of pTAU and beta‐amyloid, we repeated the test to associate affected populations with the burden of each individual pathology, controlling for covariates such as sex, age and race.

Conclusion

The Bayesian algorithms we developed permitted to create a continuous axis of disease progression across multiple brain regions and stage these regions given the progressive accumulation of pathology. By combining single‐nucleus experiments with detailed disease pathologies we identified a common set of affected populations in disease.
Trans‐ancestry GWAS for Alzheimer’s Disease Reveals a Novel Locus interacting with APOE*4
Authors: Belloy Michael E. , Reid Danielle M. , Guen Yann Le , Napolioni Valerio , Greicius Michael D
Published: January 2025

Background

APOE*4 is the strongest genetic risk for late‐onset Alzheimer’s disease (AD), but other genetic loci may counter its detrimental effect, providing therapeutic avenues. Expanding beyond non‐Hispanic White subjects, we sought to additionally leverage genetic data from non‐Hispanic and Hispanic subjects of admixed African ancestry to perform trans‐ancestry APOE*4‐stratified GWAS, anticipating that allele frequency differences across populations would boost power for gene discovery.

Method

Participants were ages 60+, of European (EU; ≥75%) or admixed African (AFR; ≥25%) ancestry, and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed or whole genome sequencing (WGS). Genome‐wide association studies (GWAS) were performed per data type, APOE*4 status, and Hispanic/non‐Hispanic status (Figure‐1A), requiring genotyping rate ≥80% and minor allele frequency ≥0.1% in EU and ≥1% in AFR, followed by random effects meta‐analysis (Plink v2.0; GWAMA v2.2.2). An APOE*4‐by‐SNP interaction model was also evaluated. GWAS performed multiple linear regression on an AD‐age score (Le Guen & Belloy et al. 2021; Figure‐1B), adjusting for APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Variants were filtered to be covered on at least half of the individuals per stratum and on both EU as well as AFR ancestry datasets.

Result

We found 1 novel genome‐wide significant locus in the APOE*4‐by‐SNP interaction GWAS (Figure‐2), with lead variant rs17042744 located intronic on a long non‐coding RNA (ENSG00000233005) and 558kb away from APOB. This variant showed disparate allele frequencies across the studied populations, yet was consistently protective in APOE*4 carriers and risk‐increasing in APOE*4 non‐carriers (Figure‐3).

Conclusion

We show the relevance of expanding beyond non‐Hispanic white samples to identify genetic risk variants that may modulate the effect of APOE*4 on AD risk, identifying a risk locus with substantially elevated frequencies in African compared to European ancestry. The locus harbored APOB, a ligand for the LDL receptor, regulator of plasma cholesterol levels, and known to have mutations in its regulatory region that cause hypobetalipoproteinemia and hypercholesterolemia. Ongoing work is exploring replication and computational functional genomics follow‐up work.
Deciphering the molecular and cellular underpinnings of cognitive resilience in Alzheimer’s disease
Authors: Castanho Isabel , Yeganeh Pourya Naderi , Boix Carles A , Mathys Hansruedi , Prokopenko Dmitry , White Bartholomew , Morgan Sarah , Lange Christoph , Bennett David A. , Bertram Lars , Tanzi Rudolph E. , Tsai Li‐Huei , Kellis Manolis , Hide Winston
Published: January 2025

Background

A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer’s disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD.

Method

We integrated multi‐modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi‐regional single nucleus (n = 48) RNA sequencing. Subjects were categorized into AD, Resilient, and Control based on Aβ and tau pathologies, and cognitive status. We investigated genetic risk and transcriptomic changes in resilience and prioritized protected cell populations using genetic enrichment and cellular distribution estimation. We further characterized these populations using multiplex immunofluorescence.

Result

Resilient individuals exhibited an intermediate genetic risk profile between AD and Control. Remarkably, only GFAP and KLF4 were differentially expressed between Resilient and Control subjects in bulk tissue. GFAP was upregulated in Resilient astrocytes in the dorsolateral prefrontal cortex compared to AD and Control. Inhibitory and excitatory neurons displayed distinct brain region‐specific phenotypes in cognitive resilience. Somatostatin‐positive interneurons were enriched for genes linked to protective rare genetic variants and showed vulnerability in AD but not in Resilient individuals. Specific excitatory neuronal populations in the entorhinal cortex exhibited resilience‐like behavior and expressed genes previously associated with cognitive resilience.

Conclusion

Our findings suggest that at the bulk tissue transcriptome level, cognitive resilience does not exhibit marked gene expression differences from healthy aging, despite significant Aβ and tau neuropathology. At the cellular level, specialized excitatory neuronal populations may drive cognitive resilience, while a specific subset of interneurons may play a crucial role in other forms of protection against AD‐associated neuronal vulnerability. This systematic study provides direct insight into the molecular basis of cognitive resilience, yielding targets offering the potential to convert natural protective systems into effective therapeutic interventions for AD.
“I feel happy, I can remember things because my family is supportive of me.” Patient’s experiences of Alzheimer’s disease in Nairobi, Kenya
Authors: Bosire Edna N , Kamau Lucy Wambui
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common type of dementia globally and is the fifth leading cause of death and disability. About half of all people suffering from the disease are living in sub‐Saharan African Countries including Kenya. However, research on dementia has been almost exclusively focused on the Global North societies. In Kenya, little is known about patients’ lived experiences with AD. Objective: To explore patient’s experiences living with and managing Alzheimer’s disease in Kenya.

Method

We employed ethnographic methods encompassing clinical and home observations and lengthy interviews among people with early‐stage Alzheimer’s disease (n = 30) in Kenya. Patients were purposively recruited from the neurology clinic at the Aga Khan University Hospital in Nairobi. We also conducted 10 home visits to understand existing social support systems and self‐management practices. Field notes and qualitative interviews were transcribed and analyzed verbatim with use of QSR NVivo 12 software.

Result

Two‐thirds of the patients were aged 50 years and above, had low education levels and fully depended on close family members for support. Patients experienced challenges such as higher cost of hospital care and treatment, comorbidities (e.g., depression, diabetes and hypertension), language barrier, forgetfulness, being misunderstood and conflicts with loved ones. These challenges made managing their AD difficult. Social connectedness – which entailed: (i) Self‐connectedness – including active participation in self‐care, relaxation and having personal time; and (ii) Connectedness with others (e.g., relationships with family, friends to prevent loneliness and isolation) were found to be key on how patients managed and coped with their Alzheimer’s disease.

Conclusion

People living with AD in Kenya cannot be understood without knowing about their inner lives, other people around them and the background where they belong. Alzheimer’s disease can transform people’s self‐identities but with good social support system, patients can live quality lives. There is a need to train family members and other informal caregivers to improve care and foster a sense of belonging amongst the patients. More research on Alzheimer’s disease in Kenya is needed as well as increased public awareness and community sensitization regarding dementias.
The effect of estrogen signaling modulation on female‐specific microglial heterogeneity in the mouse hippocampus
Authors: Ko Sunghwan
Published: January 2025

Background

Estrogens, such as 17β‐estradiol, are the primary female sex hormones predominantly synthesized by mature ovarian follicular cells. The natural exhaustion of ovarian follicular cells during menopause causes a rapid decline in endogenous estrogen levels. This decline in estrogen levels is associated with an increase in chronic, age‐related pathologies, including inflammation in the brain. Studies suggest that estrogens can temper inflammatory processes in the brain by activating estrogen receptor α (ERα), a nuclear transcription factor expressed by microglia, the brain’s primary resident macrophage. However, the pathways responsible for estrogens’ anti‐inflammatory effects in microglia remain unresolved. Here, we hypothesize that estrogen signaling through microglial ERα suppresses pro‐inflammatory signaling pathways. We believe that ablation of endogenous estrogens during menopause induces neuroinflammation and promotes the transition of microglia to activated phenotypes, contributing to various brain diseases, including Alzheimer’s disease (AD).

Method

To test the effect of estrogenic depletion on microglial heterogeneity in mice, we: 1) knocked out ERα, 2) depleted endogenous estrogens with 4‐vinylcyclohexene diepoxide (VCD) treatment, and 3) compared to untreated female C57BL/6 controls. We then examined the changes in hippocampal microglial phenotypic states using 10X single‐cell transcriptomic sequencing (scRNA‐seq).

Result

scRNA‐seq data were quality filtered, and unbiased clustering analyses (i.e., UMAP) identified five hippocampal microglial subtypes. Interestingly, the expression of specific microglial phenotypic state (stage 1 disease‐associated microglia) was increased upon ablation of endogenous estrogen production by VCD or knockout of ERα.

Conclusion

Such skewing of microglia towards reactive phenotype suggests that loss of estrogen‐ ERα signaling may encourage “priming” of microglia to transition to the stage 1 DAM phenotype, which is then more susceptible to becoming “reactive” DAMs (stage 2 DAMs).
A Transport Vehicle‐enabled TREM2 agonist antibody induces putative transcription factor activation in microglia
Authors: Monroe Kathryn M.
Published: January 2025

Background

Loss‐of‐function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. We’ve previously described a high‐affinity mouse TREM2‐activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), ATV:4D9. Single‐cell RNA sequencing and morphometry revealed that ATV:4D9 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. However, the factors mediating ATV:4D9‐induced transcriptional responses in microglia is not known.

Method

We performed fluorescence‐activated nuclei sorting (FANS) to isolate PU.1+ microglial nuclei from frozen brain tissue followed by assaying for transposase‐accessible chromatin with sequencing (ATAC‐Seq) to determine regions of accessible chromatin in the microglial genome.

Result

We identified changes in chromatin accessibility that are observed in microglia dosed with ATV:4D9 compared to isotype control antibody. Bioinformatic analysis identified motifs for putative regulatory transcription factors in ATV:4D9‐activated enhancers.

Conclusion

Our data provide insights into putative transcription factors that mediate microglial state changes in response to ATV:4D9, which further elucidates mechanisms of TREM2 agonism.
Genetic Risks of AD and Associated Health Conditions are Linked with the Dynamic Patterns of AD’s Clinical and Physiological Course
Authors: Fournier Nemo , Durrleman Stanley
Published: January 2025

Background

Over‐representation of several health conditions (such as diabetes, hearing loss, etc) have been identified up to 15 years before Alzheimer’s Disease (AD) diagnosis through the study of electronic health records [1]. Mechanisms underlying these associations remain elusive. We propose to study the associations between these co‐pathologies (proxied by genetic risk scores), and the physiological and clinical evolution of AD patients.

Method

Longitudinal and genetic data was obtained on 1120 AD patients from the ADNI cohort. Genetic risks for AD and selected health conditions (type 2 diabetes, hypertension, hearing loss, depression, ldl cholesterol, and colon cancer) are computed using state‐of‐the‐art Polygenic Risk Scores. We utilize a non‐linear mixed‐effects model [2] to estimate a multimodal progression profile of the disease (jointly modelling structural and PET imaging biomarkers as well as cognitive scores — fig. 1). Interpretable parameters describing each patient’s progression are estimated (Fig. 2). Pearson correlations between random‐effects and genetic risk scores were computed, with presented P‐values Bonferroni‐corrected for multiple testing. Conditioning the fixed‐effects of the model by the genetic risk scores (as introduced in [2]) allows studying associations between these genetic risks and the disease dynamics at a biomarker‐by‐biomarker level.

Result

Higher AD genetic risk is associated with all longitudinal aspects of the disease: earlier onset (P<0.001), faster disease pace (P<0.001), and inter‐marker patterns (P = 0.042). Elevated type‐II diabetes genetic risk is associated with earlier onset of AD (p = 0.031). Increased hypertension genetic risk is associated with a faster progression pace (P = 0.012). We then exhibit (Fig. 3) finer links between these genetic risks and the progression patterns of the disease.

Conclusion

This study unveils the relationship between genetic risk scores for health conditions and nuanced aspects of AD progression. We show that despite being established on case/control cohorts, these genetic risk scores offer valuable insights into the finer dynamics of disease progression.

References:

[1] Nedelec et al., Identifying health conditions associated with Alzheimer’s disease up to 15 years before diagnosis: an agnostic study of French and British health records, in Lancet Digital Health, 2022

[2] Fournier and Durrleman, A Multimodal Disease Progression Model for Genetic Associations with Disease Dynamics, in MICCAI 2023
Phenotypic characterization of a novel Spi1*rs1377416 mouse model of Alzheimer’s Disease
Authors: Milinkeviciute Giedre , Da Cunha Celia , Mendoza‐Arvilla Adrian , Butler Claire Ann , Kawauchi Shimako , Neumann Jonathan , Walker Amber , Tenner Andrea J , LaFerla Frank M , MacGregor Grant R , Green Kim N.
Published: January 2025

Background

Genome‐Wide Association Studies (GWAS) implicate SPI1 (PU.1) as a risk factor for late‐onset Alzheimer’s Disease (LOAD). Within the brain, SPI1 encodes a microglia‐specific transcription factor, necessary for microglial proliferation and activation. SPI1 rs1377416 has been identified as a non‐coding GWAS risk variant for AD. We have developed a novel mouse model with the SPI1 rs1377416 variant to explore its impacts on AD pathogenesis.

Method

By using CRISPR/Cas9, we have generated SPI1*rs1377416 mice that carry a non‐coding mutation corresponding to the rs1377416 SNP found in human SPI1. We crossed the SPI1 mice with the 5xFAD mouse model of AD and aged them to 4 and 12 months of age. Coronal brain sections were then obtained and immunolabeled with several markers to visualize amyloid plaques, glial cells and assess axonal and neuritic damage. Confocal images were then obtained and quantified in subiculum and cortex.

Result

We found an age‐related increase in dense core plaque number and size in the subiculum of 5xFAD;SPI1 mice. Microglial volume as well as astrocytic activation were reduced in 5xFAD;SPI1 compared to 5xFAD mice in both brain areas at 12 months. Correspondingly, neuritic dystrophy and axonal damage were also diminished. Significant sex difference was observed in different analyses with males being affected less than females (with the exception of plaque deposition), and mainly detected in subiculum.

Conclusion

Our results indicate that the rs1377416 variant of SPI1 induces an age‐dependent increase in amyloid deposition in the 5xFAD model of AD. Moreover, this SPI1 variant exerts a protective effect by suppressing astrocytic response and preventing neuritic and axonal damage. There is a strong sex difference observed between males and females when the variant is present and requires further investigation.
Sex Modulates the Influence of APOE Genotype on Sleep and Sleep‐Dependent Memory Consolidation in Older Adults
Authors: Sattari Negin , Mander Bryce A , Dave Abhishek , Lui Kitty K. , Sprecher Kate E , Chappel‐Farley Miranda G. , Riedner Brady A , Bendlin Barbara B. , Benca Ruth M
Published: January 2025

Background

Alzheimer’s disease (AD) is a world‐wide healthcare crisis among older adults. Sex, aging, and apolipoprotein E (APOE) genotype are among the most impactful risk factors for AD. Sleep is beneficial for memory and changes with age. We aimed to test whether sex and APOE (ε4‐carriers/non‐carriers) interact to impact sleep‐dependent memory consolidation (SDMC).

Methods

We tested 67 older adults (41 women, 25 ε4‐carriers, mean±SD; 61.8±6.1 years). Participants encoded word‐pairs in the evening, were tested immediately, then underwent overnight in‐lab polysomnography, and performed a delayed test in the morning. SDMC was computed as a difference score (morning‐evening). Time spent in non‐rapid eye movement (NREM) sleep stages, and electroencephalography (EEG) spectral power in frontal canonical frequency bands during NREM sleep, were quantified. ANOVA, independent t‐tests, and bivariate correlation analyses were employed in the study.

Results

A sex × APOE interaction predicted SDMC (p = 0.02). Post hoc analysis revealed no difference between male ε4‐carriers and non‐carriers (p = 0.36), but among women, ε4‐non‐carriers exhibited increased deterioration (more forgetting) compared to ε4‐carriers (p = 0.02). Additionally, male ε4‐carriers had worse memory retention than female ε4‐carriers (p = 0.01). Further analysis showed that female ε4‐carriers spent more time in N3 sleep (p = 0.01), correlating with better SDMC (r = 0.72, p = 0.02), while male ε4‐carriers spent more time in N2 sleep (p = 0.04), also linked to better SDMC (r = 0.68, p = 0.03). Fisher r‐to‐z transformation indicated significant differences in these associations (p = 0.01). Regardless of sex, among ε4 non‐carriers, no significant associations were found between theta, alpha, slow‐sigma, fast‐sigma during NREM sleep and memory (all ps>0.17). Among ε4‐carriers, male participants showed no significant associations (all ps>0.54), whereas females exhibited positive associations between memory and theta (r = 0.80, p = 0.005), alpha (r = 0.82, p = 0.004), slow‐sigma (r = 0.85, p = 0.002), and fast‐sigma (r = 0.77, p = 0.009).

Conclusion

Our study reveals that the interplay of sex and APOE affects sleep patterns and memory consolidation in older adults. Notably, distinct non‐rapid eye movement (NREM) sleep stages impact Slow Delta and Theta Modulation (SDMC) differently in male and female APOE ε4‐carriers. While enhanced sleep quality may mitigate APOE and sex‐related cognitive decline in later life, considering sex‐related differences in memory benefits from sleep is crucial for older adults at high risk for AD.
Functional Connectivity of the Affective Blindsight Pathway in Atypical Alzheimer’s Disease
Authors: Yi Hae Young H , Li Joyce S , Trainer Anne E , Ficek‐Tani Bronte , Constable Todd , Fredericks Carolyn
Published: January 2025

Background

Affective cognition and emotion processing is impaired in amnestic Alzheimer’s disease (AD), although less is known about atypical (AT) variants such as logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). The affective blindsight pathway bypasses V1 via the superior colliculus‐pulvinar route to activate the amygdala in cases of occipital lesioning and may explain maintenance of emotion identification and visual information processing in non‐amnestic AD despite atrophy in visuospatial regions. We sought to characterize functional connectivity from key regions along the affective blindsight pathway in a clinically heterogeneous AD cohort.

Method

We collected structural, resting‐state, and task functional MRI scans where participants viewed affective face and neutral scene images, and neuropsychological data in individuals with clinically heterogeneous AD (8 lvPPA, 9 PCA) and age‐matched healthy controls (24 HC). We assessed connectivity from 4mm radius seeds located along the affective blindsight pathway (superior colliculus, medial pulvinar, and amygdala) using CONN toolbox. Two‐sample t‐tests were used to compute group‐level differences (AT > HC; p < 0.05/0.05), using w‐scores to correct for atrophy.

Result

As expected, AT participants performed significantly worse on visuospatial tasks outside the scanner (WAIS‐III Blocks Design, Benson Complex Figure Copy immediate recall; p < 0.01). During resting state scans, the AT group had relatively lower connectivity to visuospatial regions including the lateral occipital cortex, angular gyrus, and precuneus from the superior colliculus and medial pulvinar seeds. During the scenes/faces task, they displayed relatively higher connectivity to those same visuospatial regions. From the amygdala seed, the AT group had higher connectivity to area V1 during the resting state scan and lower connectivity to frontal lobe regions during scenes/faces.

Conclusion

We explored functional connectivity of the affective blindsight pathway in a clinically heterogeneous AD cohort. Connectivity was relatively higher in the AT group from the superior colliculus, medial pulvinar, and amygdala to occipital lobe regions commonly atrophied in PCA and lvPPA, suggesting a function of this pathway may be to compensate for disease‐related atrophy. While preliminary, these findings hint that the blindsight pathway may serve a compensatory function in atypical AD.
A weakly‐supervised, MRI‐guided clustering of cognitive decline: A post‐hoc analysis of the EXPEDITION‐3 clinical trial
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Demirsoy Idris , Lipton Richard B. , Davatzikos Christos , Rabin Laura , Sajjadi S. Ahmad , Ezzati Ali
Published: January 2025

Background

Alzheimer’s disease exhibits heterogeneity through varied phenotypic and pathological manifestations. Here, we aimed to investigate the potential of semi‐supervised pattern classification applied to volumetric MRI data in identifying relatively homogeneous subgroups of individuals exhibiting cognitive decline (CD) throughout the study period.

Method

We used data from the placebo arm of trial of Solanezumab for mild dementia due to AD (EXPEDITION‐3 trial). Participants were classified as showing CD if there was any increase in Clinical Dementia Rating (CDR, Sum of Boxes) from baseline to the 80 weeks of follow‐up, and as stable cognition (SC) otherwise. We applied a non‐linear, semi‐supervised clustering algorithm, HYDRA, that captures subtypes within the decliner group accounting for the heterogeneous variations that are also present in the stable group. Two models with different feature‐sets were developed: model I used only baseline volumetric MRI measures, while the model II included both baseline volumetric MRI measures and longitudinal changes observed after 80 weeks.

Result

Participants were 710 individuals with longitudinal MRI and CDR measures (mean age: 72.57[±7.69] years, 60.1% Female). Models I and II each produced two distinct subgroups of CD with notable differences in their baseline MRI volumes, and different rates of change in cognitive outcomes over the course of trial (Table 1). In both the models, one of the subgroups (Slow Decliner) had significantly lower change in scores than the other (Fast Decliner) on the 11‐item version of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS‐Cog) at the end of Week 80 (Figure 1). In Model‐I, both the decliner subgroups had smaller temporal and parietal lobe volumes at baseline compared to the Stable group (Figure 2). In Model‐II, the Slow Decliner group had higher baseline MRI volumes than the stable group and significantly lower change in ADAS‐Cog compared to that of the Fast Decliner group (Figure 2).

Conclusion

Heterogeneity in brain atrophy is linked to distinct patterns of cognitive decline. Using longitudinal changes in MRI measures revealed decliner subgroups with greater difference in ADAS‐cog scores compared to those obtained by baseline measures only.
Tau pathology increases α‐synuclein spreading from the periphery to the CNS
Authors: Soto‐Faguás Carlos M , Bowman Anna , Woltjer Randall , Unni Vivek K
Published: January 2025

Background

Dementia with Lewy Bodies (DLB) is one of the most common Alzheimer’s Disease (AD)‐related dementias and it is defined by the presence of abnormal cytoplasmic inclusions composed of aggregated α‐synuclein (αsyn) in neuronal soma, known as Lewy bodies (LB). LB often coexists with AD type pathology such as amyloid‐β (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau in several LB dementias, including Parkinson’s Disease Dementia and Lewy Body variant AD. These co‐pathologies likely represent a spectrum of various contributions of shared mechanisms that underlie these diseases. However, the mechanisms of the interaction of these pathological proteins is still poorly understood. Furthermore, there is a lack of mammalian model systems demonstrating robust generation of both Lewy with Aβ and/or tau pathology in the field. Unraveling the mechanistic link between αsyn and AD‐related pathologies might be useful for the treatment of DLB.

Method

We have recently developed a brand‐new transgenic mouse line that expresses A53T αsyn tagged with GFP (A53T Syn‐GFP, AA) that forms LB pathology ∼10x faster than previous models after intracortical/peripheral PFF injection. To investigate the role of tau in αsyn spreading from the periphery to the CNS we crossed the AA mice with the P301S tau transgenic mice (PS19). We have performed monomeric/PPF injection in the gastrocnemius muscle of single and double transgenic mice and carried out a histological analysis of the αsyn and tau pathologies through the spinal cord and the brain.

Result

We found an increase in the number of αsyn+ inclusion induced by PFF injection in the spinal cord and the brain of PS19/AA mice compared to single AA mice. Interestingly, we found sex differences in αsyn pathology being higher in females than males. Furthermore, monomeric αsyn caused reduced but some αsyn inclusions in the spinal cord after muscle injection.

Conclusion

Our preliminary data shows an increase in αsyn pathology and spreading from the periphery to the brain in the presence of tau pathology suggesting a link between αsyn and tau pathologies that could represent potential treatment target for the treatment of DLB patients.
SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation
Authors: Balcomb Kaleah , Johnston Caitlin , Kavanagh Tomas , Halliday Glenda M , Wisniewski Thomas , Sunde Margaret , Drummond Eleanor
Published: January 2025

Background

SMOC1 has recently emerged as one of the most significant and consistent new biomarkers of early Alzheimer’s disease (AD). SMOC1 is one of the earliest changing proteins in AD, with SMOC1 cerebrospinal fluid levels increasing 29 years before symptom onset in autosomal dominant AD. Despite this clear association with disease, very little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to study the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced Aβ aggregation.

Methods

The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, frontal cortex) using immunohistochemistry in a cohort of 74 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD and cognitively normal controls. The Aβ‐SMOC1 interaction was assessed in advanced AD human brain tissue (n = 6) using co‐immunoprecipitation and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin T assays and electron microscopy.

Results

SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (44.0±2.6%), MCI (33.0±5.9%) and preclinical AD (28.5±6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. Confocal imaging confirmed that SMOC1 consistently colocalized with Aβ fibrils within plaques and CAA, suggesting a possible direct interaction. SMOC1 also colocalized with a subpopulation of pTau aggregates in AD (13.2±3.1%), albeit at a much lower intensity than observed for plaques or CAA. A SMOC1‐Aβ interaction was confirmed in human AD brain tissue using co‐immunoprecipitation. Thioflavin T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose‐dependent manner. Electron microscopy confirmed that the Aβ aggregates generated in the presence of SMOC1 had a different morphology; fibrils were thinner and more twisted and many small, spherical, oligomeric structures were present.

Conclusions

SMOC1 colocalizes with amyloid plaques, CAA and tau pathology. SMOC1 interacts with Aβ and delays Aβ aggregation in vitro, making it a key candidate for future drug development studies.
Neuropathology in the LifeAfter90 Study: 2024 update on an Ethnically Diverse Cohort Study of Oldest‐Old
Authors: Dugger Brittany N , Jin Lee‐Way , Patel Viharkumar , Pamatz Madely Martinez , Luu Melanie , Decarli Charles , Gilsanz Paola , Mungas Dan M. , Kawas Claudia H. , Corrada María M. M. , Whitmer Rachel A.
Published: January 2025

Background

Examining the neuropathology of the oldest‐old has significantly advanced our understanding of the multiple etiologies in very late life. Most studies have included exclusively White decedents with limited ethnoracial diversity. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old decedents.

Method

The LifeAfter90 study is an ongoing cohort study of Kaiser Permanente Northern California members, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Interviews and cognitive assessments occur approximately every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using National Alzheimer’s Coordinating Center Neuropathology forms and NIA‐AA guidelines diagnoses.

Result

As of January 2024, 340 participants (39%) have enrolled in autopsy (22% Asian, 18% African American, 17% Latino, 9% Multiracial/Other, and 34% White). Of the 340 participants, 91 had died and neuropathological evaluations were completed. The mean age of death was 95 years (range 90‐105), 51 (56%) were female, 12 Asian, 10 Black, 16 Latino, 44 White, and 8 Multiracial/Other. At final clinical exam, 25 participants had dementia (28%), 24 had cognitive impairment no dementia (CIND, 42%), and 41 had normal cognition (45%) (Table 1). Alzheimer disease (AD) and vascular pathologies were the most frequent findings (Figure & Table 2). Nineteen percent of participants did not have AD, one lacked neurofibrillary tangles (NFT). The most severe distributions/densities of NFTs and plaques were infrequent, with high likelihood of AD in only four participants. For vascular pathologies, 54% had moderate/severe white matter rarefaction and 76% had moderate/severe arteriolosclerosis. Thirty‐three percent had Lewy bodies, with six cases having diffuse type. Two cases had hippocampal sclerosis. One case had pathologic evidence of progressive supranuclear palsy and had dementia at last diagnosis.

Conclusion

This ethnoracially diverse cohort of over 90 oldest‐old individuals reveal numerous brain pathologies are present with advanced age, with AD and select vascular pathologies being the most common. This confirms previous findings that with increases in cognitive impairment there is increasing pathology severity especially for AD pathologies.
Isomerized Aβ in the brains can distinguish the status of amyloidosis in the Alzheimer’s Disease continuum
Authors: Mukherjee Soumya , Dubois Celine , Perez Keyla , Birchall Ian , Hinton Fairlie , McLean Catriona , Masters Colin L , Roberts Blaine Russell
Published: January 2025

Background

The extracellular amyloid plaques, one of the pathological hallmarks of Alzheimers Disease (AD), are frequently also observed in the cortex of cognitively unimpaired subjects or as co‐pathology in other neurodegenerative diseases. Progressive deposition of fibrillar amyloid‐β (Aβ) as amyloid plaques for two decades prior disease onset leads to extensive isomerization of Aβ N‐terminus. Quantifying the extent of isomerized Aβ can be provide insight into the different stages of amyloidosis in the brain.

Methods

We measured Aβ isoforms using mass spectrometry. We analysed postmortem brains (frontal cortex) from patient with AD (n = 59), Parkinson disease (n = 57) and age matched control brains (61). We also measured Asp residue isomerization at Aβ N‐terminus.

Results

We observed a significant increase in isomerization of Aβ N‐terminus in AD compared to age‐matched control brains in the soluble and insoluble pool.1‐3 While AD brains contain significant amount of Asp‐1 and Asp‐7 isomerized Aβ1‐15, cognitively unimpaired patients with amyloid deposits (CU‐AP) also have minor isomerized species. We further demonstrate that ratio of isomerized N‐terminus Aβ (Aβ1‐15) species in the brain soluble pool differentiates amyloid deposits in AD brain compared to CU‐AP individuals and patients with co‐morbidities.

Conclusions

Isomerized N‐terminus Aβ (Aβ1‐15) is a common feature of parenchymal amyloid deposits in the brain. Our results suggest Aβ deposits associated with early AD neuropathologic changes are distinct to the mature plaques found in AD, a consequence of prolonged deposition in the later. Our results have implications for early therapeutic targeting of these modified species as well potential for better biofluids biomarker development to track drug efficacy.

References

1. Mukherjee S, Perez KA, Lago LC, et al. Quantification of N‐terminal amyloid‐β isoforms reveals isomers are the most abundant form of the amyloid‐β peptide in sporadic Alzheimer’s disease. Brain Commun. 2021;3(2). https://doi.org/10.1093/braincomms/fcab028

2. Mukherjee S, Perez KA, Dubois C, et al. Citrullination of Amyloid‐β Peptides in Alzheimer’s Disease. ACS Chem Neurosci. 2021;12(19):3719‐3732. https://doi.org/10.1021/acschemneuro.1c00474

3. Mukherjee S, Fjeldsted JC, Masters CL, Roberts BR. Enhanced ion mobility resolution of Abeta isomers from human brain using high‐resolution demultiplexing software. Anal Bioanal Chem. Published online April 15, 2022. https://doi.org/10.1007/s00216‐022‐04055‐x
Performance of the Amsterdam IADL scale in Assessing Functional Decline among Older People in Primary Health Care
Authors: Fawad Ayesha , Nilsson Maria H , Sikkes Sietske A.M , Postema Merel C. , Stomrud Erik , Tideman Pontus , Hansson Oskar , Palmqvist Sebastian
Published: January 2025

Background

The Amsterdam Instrumental ADL Questionnaire (A‐IADL‐Q) has shown promising performance in detecting subtle impairment in IADL independency. Importantly, it has not been validated in older people in a primary care setting, i.e., where the initial work‐up and triaging of cognitive impairment occurs. The main aim was to examine the accuracy of the A‐IADL‐Q for estimating the cognitive stage in a primary care sample, both in the whole population and within the Alzheimer’s disease (AD) continuum. Secondary aims were to examine associations with the clinical dementia rating (CDR) scale and global cognition (MMSE), including the effects of non‐cognitive co‐morbidities and medications.

Method

This cross‐sectional study includes informants of 362 participants from the BioFINDER‐Primary care study. They completed the A‐IADL‐Q (higher scores = “better”) either on an iPad or at home on a computer. Cognitive stage was assessed by a dementia expert (blinded to A‐IADL‐Q scores). Amyloid status was determined using FDA‐approved CSF or PET measures. The main outcome was cognitive stage according to the NIA‐AA scale. Secondary outcomes were CDR‐sum of the boxes (CDR‐SOB) and MMSE. Receiver Operating Curves (ROC) analyses were used to calculate the area under the curves (AUCs).

Result

The mean age of participants (44.9% female) was 76.1 (SD 7.2) years. Out of which, 83 (23%) had subjective cognitive decline (SCD), 169 (47%) mild cognitive impairment (MCI), and 110 (30%) dementia. The AUC (95% CI) for differentiating between SCD versus MCI/dementia was 0.89 (0.85‐0.92), and it was 0.89 (0.85‐0.93) for SCD/MCI versus dementia. In amyloid positive participants (n = 303), AUCs were similar. Better A‐IADL‐Q scores were associated with worse results on CDR‐SOB (r = ‐0.73, p<0.001) and better global cognition (MMSE, r = 0.361, p<0.001). The effects of different co‐morbidities on the A‐IADL score, adjusted for cognitive stage, will be presented at AAIC.

Conclusion

Our findings suggest that the A‐IADL‐Q accurately estimates the cognitive stage among cognitively impaired older people (with high prevalence of comorbidities) in a primary care setting. This can aid primary care physicians in the diagnosis of cognitive impairment, clinical management/support, and as part of the work‐up for identifying eligible participants for anti‐amyloid treatment.