Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and they have been shown to predict lifetime risk of Alzheimer's disease (AD) development. ...However, the relationship between PRS and AD pathogenesis is largely unknown. To this end, we performed a differential gene-expression and associated disrupted biological pathway analyses of AD PRS vs. case/controls in human brain-derived cohort sample (cerebellum/temporal cortex; MayoRNAseq). The results highlighted already implicated mechanisms: immune and stress response, lipids, fatty acids and cholesterol metabolisms, endosome and cellular/neuronal death, being disrupted biological pathways in both case/controls and PRS, as well as previously less well characterised processes such as cellular structures, mitochondrial respiration and secretion. Despite heterogeneity in terms of differentially expressed genes in case/controls vs. PRS, there was a consensus of commonly disrupted biological mechanisms. Glia and microglia-related terms were also significantly disrupted, albeit not being the top disrupted Gene Ontology terms. GWAS implicated genes were significantly and in their majority, up-regulated in response to different PRS among the temporal cortex samples, suggesting potential common regulatory mechanisms. Tissue specificity in terms of disrupted biological pathways in temporal cortex vs. cerebellum was observed in relation to PRS, but limited tissue specificity when the datasets were analysed as case/controls. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.
The APOE-ε4 allele is known to predispose to amyloid deposition and consequently is strongly associated with Alzheimer's disease (AD) risk. There is debate as to whether the APOE gene accounts for ...all genetic variation of the APOE locus. Another question which remains is whether APOE-ε4 carriers have other genetic factors influencing the progression of amyloid positive individuals to AD. We conducted a genome-wide association study in a sample of 5,390 APOE-ε4 homozygous (ε4ε4) individuals (288 cases and 5102 controls) aged 65 or over in the UK Biobank. We found no significant associations of SNPs in the APOE locus with AD in the sample of ε4ε4 individuals. However, we identified a novel genome-wide significant locus associated to AD, mapping to DAB1 (rs112437613, OR = 2.28, CI = 1.73–3.01, p = 5.4 × 10−9). This identification of DAB1 led us to investigate other components of the DAB1-RELN pathway for association. Analysis of the DAB1-RELN pathway indicated that the pathway itself was associated with AD, therefore suggesting an epistatic interaction between the APOE locus and the DAB1-RELN pathway.
OBJECTIVE:To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial ...volume ratio HpVR) across AD stages.
METHODS:The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimerʼs Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status.
RESULTS:Across groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001).
CONCLUSION:Women showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages.
Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or ...around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10−14), two common variants, GCH1 (rs72713460, P = 4.36 × 10−5) and KCNJ15 (rs928771, P = 3.60 × 10−6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
Increasing evidence supports a role for deficient Wnt signaling in Alzheimer’s disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD ...patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPP
NL-G-F/NL-G-F
mouse AD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3β signaling with a concomitant increase in inhibitory synapses via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.
Alzheimer’s disease is the most common form of dementia worldwide. The cognitive decline typically observed in this condition is associated with the weakening and eventually the loss of synapses, the structures that allow neurons to communicate. Increasing evidence points to this deterioration being linked to deficiency in the Wnt signalling pathway, a cascade of molecular events crucial for brain function and development.
The DKK protein family helps to tightly regulate the Wnt pathway by dampening its activity. Previous work suggests that DKK proteins could also be connected to Alzheimer’s disease. For example, an elevated amount of DKK1 leads to synapse and memory defects in mice, while brain production of DKK1 is increased in individuals with late Alzheimer’s.
More recent studies show high levels of another DKK protein, DKK3, in Alzheimer’s patients. This protein is also present in the harmful amyloid-β aggregates, named ‘plaques’, that typically form in the brain in this condition. Despite these findings, how DKK3 participates in synaptic health remains unclear.
To address this question, Martin-Flores, Podpolny et al. tracked DKK3 levels in the brains of Alzheimer’s patients, revealing that they increase early in the disease. Additional experiments in Alzheimer’s mouse models suggested that DKK3 secretion rise before amyloid-β plaques form, with the protein then accumulating in abnormal neuronal structures present in the surroundings of these toxic deposits.
Martin-Flores, Podpolny et al. then examined the impact of DKK3 on the Wnt pathway, and ultimately, on the balance between synapses that control neuronal activity. These experiments showed that elevated DKK3 levels are linked to a loss of synapses which are excitatory, with a concomitant increase in those that are inhibitory. Crucially, reducing DKK3 levels in a mouse model of Alzheimer’s restored this synaptic balance and improved memory, highlighting DKK3 as a potential driver of cognitive impairment.
Overall, these findings help to refine our understanding of the molecular mechanisms that contribute to synaptic impairment in Alzheimer’s disease. They may also be relevant for researchers studying other conditions that involve aberrant activity of the Wnt pathway, such as cancer.
Abstract
In 2011, a randomized controlled trial (RCT) of a mental health intervention for families with children under the age of 5 years coming into the Scottish care system was launched, called the ...Best Services Trial (BeST). When attempts were made to expand the study to English sites, the local leadership Judge objected, concerned that randomization in family proceedings was unfair, potentially discriminatory, and unlawful. Considerations about parental consent, fairness of randomization, and an understanding that the new intervention might be no better, or even harmful, compared to current best practices were crucial in addressing these concerns. In 2017, BeST was launched in England utilizing a randomized methodology. Significant input into the design of BeST came from the leadership Judge who had previously considered randomization unlawful. In July 2021, 383 families with 488 children had been recruited across both Scottish and English sites. Follow-up continues and 76 per cent of families continue to participate at 2.5 years after entering the study. Although there were undoubted challenges in designing and implementing BeST, with hindsight, the objections raised to the testing of interventions randomly were demonstrably resolvable and the process of randomization encountered no legal challenges. This is the first time an RCT has been accommodated within live proceedings in the family justice arena in England and Wales and one of a relatively few such RCTs conducted internationally.
Accumulating evidence suggests that Alzheimer's disease (AD) is heterogenous and can be classified into several subtypes. Here, we propose a robust subtyping method for AD based on cortical atrophy ...patterns and graph theory. We calculated similarities between subjects in their atrophy patterns throughout the whole brain, and clustered subjects with similar atrophy patterns using the Louvain method for modular organization extraction. We applied our method to AD patients recruited at Samsung Medical Center and externally validated our method by using the AD Neuroimaging Initiative (ADNI) dataset. Our method categorized very mild AD into three clinically distinct subtypes with high reproducibility (>90%); the parietal-predominant (P), medial temporal-predominant (MT), and diffuse (D) atrophy subtype. The P subtype showed the worst clinical presentation throughout the cognitive domains, while the MT and D subtypes exhibited relatively mild presentation. The MT subtype revealed more impaired language and executive function compared to the D subtype.
Background
Large‐scale multi‐study analyses are required to ensure reproducibility, reliability and generalizability in mapping neurodegeneration and risk for ADRD. However, the heterogeneity in data ...collection paradigms can complicate and confound data pooling; data harmonization is essential. Longitudinal studies add to the complexity of harmonization as a variety of follow‐up time points and time encoding schemes are used. Here, we pool data from 8 publicly available longitudinal neuroimaging studies on neurodegeneration and dementia to highlight differences in: 1) diagnostic categorization of controls, and people with mild cognitive impairment, and dementia; 2) the extent of follow‐up visits across neuroimaging and clinical assessments; and 3) encodings of various meta‐data elements including scanner manufacturer, sex, and handedness. To allow a systematic approach to multi‐study dementia research, we propose an initial ontological framework for longitudinal data archival and retrieval, capable of capturing similar data elements within given themes while ensuring that unique differences across studies are retained.
Method
AIBL, ADNI‐1, ADNI2/GO, ADNI‐3, OASIS‐2, OASIS‐3, PREVENT‐AD, and MIRIAD, were accessed. Study designs, inclusion and exclusion criteria, and downloaded data elements were used to describe diagnostic criteria, imaging data, demographic features, and longitudinal data collection schemes. We create common terms to map data elements across studies, and a consistent naming scheme for longitudinal data.
Result
Figure 1 shows the breakdown of diagnostic labels per cohort, and highlights how different cognitive labels may be assigned to people with the same performance scores, for example, on the Mini Mental State Examination (MMSE). Figure 2 highlights the differences in longitudinal data collection schemes across cohorts, and in labels of commonly collected elements. Using common terms provided an easy way to simultaneously query data across all studies, while retaining a map back to the original terms. Figure 3 showcases our proposed naming scheme for capturing longitudinal data elements using a relational ontological framework. This framework successfully harmonized data across study demographics, timepoints, and imaging properties.
Conclusion
Multi‐study data analyses are becoming common practice thanks to large scale efforts such as ENIGMA and GAAIN. Harmonization of meta‐data across studies will allow for efficient pooling of data for tracking disease progression and related risk over time.
Grafting a piece of mature skin over the surface of a freshly amputated amphibian limb inhibits regeneration. In striking contrast, when a more distal level blastema (the bud of tissue that forms ...following amputation) is grafted to a more proximal limb stump it induces intercalary regeneration from the host and a proximodistally complete limb is restored (Pescitelli and Stocum, 1980). Interestingly, when a mature hand is grafted to a more proximal level stump, intercalary regeneration is inhibited. These experiments create a unique opportunity to decipher the signals responsible for normal intercalary regeneration and possibly regeneration itself. Through juxtaposition of beads charged with growth factors between a mature hand graft and more proximal level stump it may be possible to induce intercalary regeneration and by doing so, begin to identify the early molecular cues that initiate and drive intercalary regeneration in salamanders. Preliminary results employing this approach will be presented.
Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker ...of inflammation with potential as a prognostic biomarker after TBI. The
ransforming
esearch and
linical
nowledge in
raumatic
rain
njury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (
< 0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC = 0.892). Combining hsCRP and GFAP at 2 weeks produced AUC = 0.939 for prediction of disability. Serum hsCRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.
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