Genetic overlap between Alzheimer's disease and immune-mediated diseases: an atlas of shared genetic determinants and biological convergence.

The occurrence of immune disease comorbidities in Alzheimer's disease (AD) has been observed in both epidemiological and molecular studies, suggesting a neuroinflammatory basis in AD. However, their shared genetic components have not been systematically studied. Here, we composed an atlas of the shared genetic associations between 11 immune-mediated diseases and AD by analyzing genome-wide association studies (GWAS) summary statistics. Our results unveiled a significant genetic overlap between AD and 11 individual immune-mediated diseases despite negligible genetic correlations, suggesting a complex shared genetic architecture distributed across the genome. The shared loci between AD and immune-mediated diseases implicated several genes, including GRAMD1B, FUT2, ADAMTS4, HBEGF, WNT3, TSPAN14, DHODH, ABCB9, and TNIP1, all of which are protein-coding genes and thus potential drug targets. Top biological pathways enriched with these identified shared genes were related to the immune system and cell adhesion. In addition, in silico single-cell analyses showed enrichment of immune and brain cells, including neurons and microglia. In summary, our results suggest a genetic relationship between AD and the 11 immune-mediated diseases, pinpointing the existence of a shared however non-causal genetic basis. These identified protein-coding genes have the potential to serve as a novel path to therapeutic interventions for both AD and immune-mediated diseases and their comorbidities.

Identifying candidate genes and drug targets for Alzheimer's disease by an integrative network approach using genetic and brain region-specific proteomic data.

Genome-wide association studies (GWAS) have identified more than 75 genetic variants associated with Alzheimer's disease (ad). However, how these variants function and impact protein expression in brain regions remain elusive. Large-scale proteomic datasets of ad postmortem brain tissues have become available recently. In this study, we used these datasets to investigate brain region-specific molecular pathways underlying ad pathogenesis and explore their potential drug targets. We applied our new network-based tool, Edge-Weighted Dense Module Search of GWAS (EW_dmGWAS), to integrate ad GWAS statistics of 472 868 individuals with proteomic profiles from two brain regions from two large-scale ad cohorts [parahippocampal gyrus (PHG), sample size n = 190; dorsolateral prefrontal cortex (DLPFC), n = 192]. The resulting network modules were evaluated using a scale-free network index, followed by a cross-region consistency evaluation. Our EW_dmGWAS analyses prioritized 52 top module genes (TMGs) specific in PHG and 58 TMGs in DLPFC, of which four genes (CLU, PICALM, PRRC2A and NDUFS3) overlapped. Those four genes were significantly associated with ad (GWAS gene-level false discovery rate < 0.05). To explore the impact of these genetic components on TMGs, we further examined their differentially co-expressed genes at the proteomic level and compared them with investigational drug targets. We pinpointed three potential drug target genes, APP, SNCA and VCAM1, specifically in PHG. Gene set enrichment analyses of TMGs in PHG and DLPFC revealed region-specific biological processes, tissue-cell type signatures and enriched drug signatures, suggesting potential region-specific drug repurposing targets for ad.

Distinct effect of prenatal and postnatal brain expression across 20 brain disorders and anthropometric social traits: a systematic study of spatiotemporal modularity.

Different spatiotemporal abnormalities have been implicated in different neuropsychiatric disorders and anthropometric social traits, yet an investigation in the temporal network modularity with brain tissue transcriptomics has been lacking. We developed a supervised network approach to investigate the genome-wide association study (GWAS) results in the spatial and temporal contexts and demonstrated it in 20 brain disorders and anthropometric social traits. BrainSpan transcriptome profiles were used to discover significant modules enriched with trait susceptibility genes in a developmental stage-stratified manner. We investigated whether, and in which developmental stages, GWAS-implicated genes are coordinately expressed in brain transcriptome. We identified significant network modules for each disorder and trait at different developmental stages, providing a systematic view of network modularity at specific developmental stages for a myriad of brain disorders and traits. Specifically, we observed a strong pattern of the fetal origin for most psychiatric disorders and traits [such as schizophrenia (SCZ), bipolar disorder, obsessive-compulsive disorder and neuroticism], whereas increased co-expression activities of genes were more strongly associated with neurological diseases [such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis] and anthropometric traits (such as college completion, education and subjective well-being) in postnatal brains. Further analyses revealed enriched cell types and functional features that were supported and corroborated prior knowledge in specific brain disorders, such as clathrin-mediated endocytosis in AD, myelin sheath in multiple sclerosis and regulation of synaptic plasticity in both college completion and education. Our study provides a landscape view of the spatiotemporal features in a myriad of brain-related disorders and traits.

A cross-sectional study of cognitive performance in bipolar disorder across the lifespan: the cog-BD project.

BACKGROUND: Neuroprogressive models of the trajectory of cognitive dysfunction in patients with bipolar disorder (BD) have been proposed. However, few studies have explored the relationships among clinical characteristics of BD, cognitive dysfunction, and aging. METHODS: We conducted a cross-sectional analysis in euthymic participants with the MATRICS Cognitive Consensus Battery, the Trail Making Test B, the Stroop Test, and the Wechsler Test of Adult Reading. Age- and gender-equated control participants without a mental disorder ['Healthy Controls' - HC)] were assessed similarly. We compared cognitive performance both globally and in seven domains in four groups: younger BD (age ⩽49 years; n = 70), older BD (age ⩾50 years; n = 48), younger HC (n = 153), and older HC (n = 44). We also compared the BD and HC groups using age as a continuous measure. We controlled for relevant covariates and applied a Bonferroni correction. RESULTS: Our results support both an early impairment ('early hit') model and an accelerated aging model: impairment in attention/vigilance, processing speed, and executive function/working memory were congruent with the accelerated aging hypothesis whereas impairment in verbal memory was congruent with an early impairment model. BD and HC participants exhibited similar age-related decline in reasoning/problem solving and visuospatial memory. There were no age- or diagnosis-related differences in social cognition. CONCLUSION: Our findings support that different cognitive domains are affected differently by BD and aging. Longitudinal studies are needed to explore trajectories of cognitive performance in BD across the lifespan.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Are remitted affective disorders and familial risk of affective disorders associated with metabolic syndrome, inflammation and oxidative stress? - a monozygotic twin study.

BACKGROUND: Metabolic syndrome (MetS) is associated with reduced life expectancy in patients with affective disorders, however, whether MetS also plays a role before the onset of affective disorder is unknown. We aimed to investigate whether MetS, inflammatory markers or oxidative stress act as risk factors for affective disorders, and whether MetS is associated with increased inflammation and oxidative stress. METHODS: We conducted a high-risk study including 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). Metabolic Syndrome was ascertained according to the International Diabetes Federation (IDF) criteria. Inflammatory markers and markers of oxidative stress were analyzed from fasting blood and urine samples, respectively. RESULTS: The affected and the high-risk group had a significantly higher prevalence of MetS compared to the low-risk group (20% v. 15% v. 2.5%, p = 0.0006), even after adjusting for sex, age, smoking and alcohol consumption. No differences in inflammatory and oxidative markers were seen between the three groups. Further, MetS was associated with alterations in inflammatory markers, and oxidative stress was modestly correlated with inflammation. CONCLUSION: Metabolic syndrome is associated with low-grade inflammation and may act as a risk factor and a trait marker for affective disorders. If confirmed in longitudinal studies, this suggests the importance of early intervention and preventive approaches targeted towards unhealthy lifestyle factors that may contribute to later psychopathology.

Glucose homeostasis in major depression and schizophrenia: a comparison among drug-naïve first-episode patients.

There is evidence for insulin resistance in drug-naïve first-episode schizophrenia (Sz) patients. We have tested whether impaired insulin homeostasis is also present in first-episode patients with major depression (MD) and if this can be discerned from stress-related and medication effects. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined in a cross-sectional cohort study of acute first-episode drug-naïve patients with MD (n = 18) or Sz (n = 24), and healthy controls (C, n = 43). Morning cortisol and catecholamine metabolites were assessed to control for hormonal stress axis activation. Subjects were matched for sex, age, body mass index and waist-hip ratio to exclude the possibility that overweight and visceral adiposity were potential confounding factors. HOMA-IR did not differ between MD and controls, but was increased in Sz compared to MD (p = 0.002) and controls (p = 0.012). Catecholamine metabolites were elevated in both patient groups, indicating presence of hormonal stress axis activation. However, diagnosis-related changes of HOMA-IR were independent from this. Impaired insulin sensitivity was absent in MD, but specifically related to the early disease course of Sz. Thus, considering previous studies in this field, MD may be related to impaired glucose/insulin homeostasis in the long-term but not in early disease stages.

Aspirin and incident depressive symptoms: A longitudinal cohort study over 8 years.

OBJECTIVE: Aspirin exhibits anti-atherosclerotic and anti-inflammatory properties-two potential risk factors for depression. The relationship between aspirin use and depression, however, remains unclear. We investigated whether the aspirin use is associated with a decreased incidence of depressive symptoms in a large North American cohort. METHODS: Data from the Osteoarthritis Initiative dataset, a multicenter, longitudinal study on community-dwelling adults was analyzed. Aspirin use was defined through self-report in the past 30 days and confirmed by a trained interviewer. Incident depressive symptoms were defined as a score of ≥16 in the 20-item Center for Epidemiologic Studies-Depression scale. RESULTS: A total of 137 participants (mean age 65 y, 55.5% female) were using aspirin at baseline. Compared with 4003 participants not taking aspirin, no differences in Center for Epidemiologic Studies-Depression at baseline were evident (P = .65). After a median follow-up time of 8 years, the incidence of depressive symptoms was similar in those taking aspirin at baseline (43; 95% CI, 3-60) and in aspirin nonusers (38; 95% CI, 36-41) per 1000 y; log-rank test = 0.63). Based on Cox's regression analysis adjusted for 11 potential confounders, aspirin use was not significantly associated with the development of depressive symptoms (hazard ratio = 1.12; 95% CI, 0.78-1.62; P = .54). Adjustment for propensity scores or the use of propensity score matching did not alter the results. CONCLUSION: Our study found that prescription of aspirin offered no significant protection against incident depressive symptoms. Whether aspirin is beneficial in a subgroup of depression with high levels of inflammation remains to be investigated in future studies.

Leaky brain in neurological and psychiatric disorders: Drivers and consequences.

BACKGROUND: The blood-brain barrier acts as a highly regulated interface; its dysfunction may exacerbate, and perhaps initiate, neurological and neuropsychiatric disorders. METHODS: In this narrative review, focussing on redox, inflammatory and mitochondrial pathways and their effects on the blood-brain barrier, a model is proposed detailing mechanisms which might explain how increases in blood-brain barrier permeability occur and can be maintained with increasing inflammatory and oxidative and nitrosative stress being the initial drivers. RESULTS: Peripheral inflammation, which is causatively implicated in the pathogenesis of major psychiatric disorders, is associated with elevated peripheral pro-inflammatory cytokines, which in turn cause increased blood-brain barrier permeability. Reactive oxygen species, such as superoxide radicals and hydrogen peroxide, and reactive nitrogen species, such as nitric oxide and peroxynitrite, play essential roles in normal brain capillary endothelial cell functioning; however, chronically elevated oxidative and nitrosative stress can lead to mitochondrial dysfunction and damage to the blood-brain barrier. Activated microglia, redox control of which is mediated by nitric oxide synthases and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, secrete neurotoxic molecules such as reactive oxygen species, nitric oxide, prostaglandin, cyclooxygenase-2, quinolinic acid, several chemokines (including monocyte chemoattractant protein-1 [MCP-1], C-X-C motif chemokine ligand 1 [CXCL-1] and macrophage inflammatory protein 1α [MIP-1α]) and the pro-inflammatory cytokines interleukin-6, tumour necrosis factor-α and interleukin-1ß, which can exert a detrimental effect on blood-brain barrier integrity and function. Similarly, reactive astrocytes produce neurotoxic molecules such as prostaglandin E2 and pro-inflammatory cytokines, which can cause a 'leaky brain'. CONCLUSION: Chronic inflammatory and oxidative and nitrosative stress is associated with the development of a 'leaky gut'. The following evidence-based approaches, which address the leaky gut and blood-brain barrier dysfunction, are suggested as potential therapeutic interventions for neurological and neuropsychiatric disorders: melatonin, statins, probiotics containing Bifidobacteria and Lactobacilli, N-acetylcysteine, and prebiotics containing fructo-oligosaccharides and galacto-oligosaccharides.

Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials.

OBJECTIVE: It is unclear whether blockade of the angiotensin system has effects on mental health. Our objective was to determine the impact of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life. STUDY DESIGN: Meta-analysis of published literature. DATA SOURCES: PubMed and clinicaltrials.gov databases. The last search was conducted in January 2017. STUDY SELECTION: Randomized controlled trials comparing any angiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin converting enzyme inhibitor or non-AT1R blocker were selected. Study participants were adults without any major physical symptoms. We adhered to meta-analysis reporting methods as per PRISMA and the Cochrane Collaboration. DATA SYNTHESIS: Eleven studies were included in the analysis. When compared with placebo or other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors were associated with improved overall quality of life (standard mean difference = 0.11, 95% confidence interval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95% confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95% confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95% confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found for the depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p = 0.15). CONCLUSIONS: Use of angiotensin blockers and inhibitors for the treatment of hypertension in otherwise healthy adults is associated with improved mental health domains of quality of life. Mental health quality of life was a secondary outcome in the included studies. Research specifically designed to analyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate this novel psychiatric target.

The new field of 'precision psychiatry'.

BACKGROUND: Precision medicine is a new and important topic in psychiatry. Psychiatry has not yet benefited from the advanced diagnostic and therapeutic technologies that form an integral part of other clinical specialties. Thus, the vision of precision medicine as applied to psychiatry - 'precision psychiatry' - promises to be even more transformative than in other fields of medicine, which have already lessened the translational gap. DISCUSSION: Herein, we describe 'precision psychiatry' and how its several implications promise to transform the psychiatric landscape. We pay particular attention to biomarkers and to how the development of new technologies now makes their discovery possible and timely. The adoption of the term 'precision psychiatry' will help propel the field, since the current term 'precision medicine', as applied to psychiatry, is impractical and does not appropriately distinguish the field. Naming the field 'precision psychiatry' will help establish a stronger, unique identity to what promises to be the most important area in psychiatry in years to come. CONCLUSION: In summary, we provide a wide-angle lens overview of what this new field is, suggest how to propel the field forward, and provide a vision of the near future, with 'precision psychiatry' representing a paradigm shift that promises to change the landscape of how psychiatry is currently conceived.

The renin-angiotensin system: a possible new target for depression.

Depression remains a debilitating condition with an uncertain aetiology. Recently, attention has been given to the renin-angiotensin system. In the central nervous system, angiotensin II may be important in multiple pathways related to neurodevelopment and regulation of the stress response. Studies of drugs targeting the renin-angiotensin system have yielded promising results. Here, we review the potential beneficial effects of angiotensin blockers in depression and their mechanisms of action. Drugs blocking the angiotensin system have efficacy in several animal models of depression. While no randomised clinical trials were found, case reports and observational studies showed that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had positive effects on depression, whereas other antihypertensive agents did not. Drugs targeting the renin-angiotensin system act on inflammatory pathways implicated in depression. Both preclinical and clinical data suggest that these drugs possess antidepressant properties. In light of these results, angiotensin system-blocking agents offer new horizons in mood disorder treatment.

Cognitive remission: a novel objective for the treatment of major depression?

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.

Bias in Peripheral Depression Biomarkers.

BACKGROUND: To aid in the differentiation of individuals with major depressive disorder (MDD) from healthy controls, numerous peripheral biomarkers have been proposed. To date, no comprehensive evaluation of the existence of bias favoring the publication of significant results or inflating effect sizes has been conducted. METHODS: Here, we performed a comprehensive review of meta-analyses of peripheral nongenetic biomarkers that could discriminate individuals with MDD from nondepressed controls. PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched through April 10, 2015. RESULTS: From 15 references, we obtained 31 eligible meta-analyses evaluating biomarkers in MDD (21,201 cases and 78,363 controls). Twenty meta-analyses reported statistically significant effect size estimates. Heterogeneity was high (I2 ≥ 50%) in 29 meta-analyses. We plausibly assumed that the true effect size for a meta-analysis would equal the one of its largest study. A significant summary effect size estimate was observed for 20 biomarkers. We observed an excess of statistically significant studies in 21 meta-analyses. The summary effect size of the meta-analysis was higher than the effect of its largest study in 25 meta-analyses, while 11 meta-analyses had evidence of small-study effects. CONCLUSIONS: Our findings suggest that there is an excess of studies with statistically significant results in the literature of peripheral biomarkers for MDD. The selective publication of 'positive studies' and the selective reporting of outcomes are possible mechanisms. Effect size estimates of meta-analyses may be inflated in this literature.

Affective temperaments and emotional traits are associated with a positive screening for premenstrual dysphoric disorder.

OBJECTIVES: Preliminary evidence indicates that premenstrual dysphoric disorder (PMDD) may be frequently co-morbid with bipolar spectrum disorders. In addition, the manifestations of PMDD seem similar to a subthreshold depressive mixed state. Nevertheless, the associations between PMDD and affective temperaments and emotional traits have not been previously investigated. METHODS: A consecutive sample of 514 drug-free Brazilian women (mean age: 22.8; SD=5.4years) took part in this cross-sectional study. Screening for PMDD was obtained with the validated Brazilian Portuguese version of the Premenstrual Symptoms Screening Tool (PSST). Affective temperaments and emotional dimensions were evaluated with the Affective and Emotional Composite Temperament Scale (AFECTS). In addition, socio-demographic and data on menstrual cycle were collected. RESULTS: According to the PSST, 83 (16.1%) women screened positive for PMDD, while 216 (42.0%) women had no/mild premenstrual symptoms. The cyclothymic temperament was independently associated with PMDD (OR=4.57; 95% CI: 2.11-9.90), while the euthymic temperament had an independent association with a lower likelihood of a positive screening for PMDD (OR=0.28; 95% CI: 0.12-0.64). In addition, anger and sensitivity emerged as emotional dimensions significantly associated with PMDD. CONCLUSIONS: A positive screening for PMDD was associated with a predominant cyclothymic temperament, while an euthymic temperament was associated with a lower likelihood for a positive screening for PMDD. These data deserve replication in prospective studies.

Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies.

BACKGROUND: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. METHODS: We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. RESULTS: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. CONCLUSIONS: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.

Dissecting the shared genetic architecture between Alzheimer's disease and frailty: a cross-trait meta-analyses of genome-wide association studies.

Introduction: Frailty is the most common medical condition affecting the aging population, and its prevalence increases in the population aged 65 or more. Frailty is commonly diagnosed using the frailty index (FI) or frailty phenotype (FP) assessments. Observational studies have indicated the association of frailty with Alzheimer's disease (AD). However, the shared genetic and biological mechanism of these comorbidity has not been studied. Methods: To assess the genetic relationship between AD and frailty, we examined it at single nucleotide polymorphism (SNP), gene, and pathway levels. Results: Overall, 16 genome-wide significant loci (15 unique loci) (p meta-analysis < 5 × 10-8) and 22 genes (21 unique genes) were identified between AD and frailty using cross-trait meta-analysis. The 8 shared loci implicated 11 genes: CLRN1-AS1, CRHR1, FERMT2, GRK4, LINC01929, LRFN2, MADD, RP11-368P15.1, RP11-166N6.2, RNA5SP459, and ZNF652 between AD and FI, and 8 shared loci between AD and FFS implicated 11 genes: AFF3, C1QTNF4, CLEC16A, FAM180B, FBXL19, GRK4, LINC01104, MAD1L1, RGS12, ZDHHC5, and ZNF521. The loci 4p16.3 (GRK4) was identified in both meta-analyses. The colocalization analysis supported the results of our meta-analysis in these loci. The gene-based analysis revealed 80 genes between AD and frailty, and 4 genes were initially identified in our meta-analyses: C1QTNF4, CRHR1, MAD1L1, and RGS12. The pathway analysis showed enrichment for lipoprotein particle plasma, amyloid fibril formation, protein kinase regulator, and tau protein binding. Conclusion: Overall, our results provide new insights into the genetics of AD and frailty, suggesting the existence of non-causal shared genetic mechanisms between these conditions.

Unraveling the intercellular communication disruption and key pathways in Alzheimer's disease: an integrative study of single-nucleus transcriptomes and genetic association.

BACKGROUND: Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains. METHODS: We systematically assessed the intercellular communication networks by using a discovery snRNA-seq dataset comprising 69,499 nuclei from 48 human postmortem prefrontal cortex (PFC) samples. We replicated the findings using an independent snRNA-seq dataset of 56,440 nuclei from 18 PFC samples. By integrating genetic signals from AD genome-wide association studies (GWAS) summary statistics and whole genome sequencing (WGS) data, we prioritized AD-associated Gene Ontology (GO) terms containing dysregulated LR interactions. We further explored drug repurposing for the prioritized LR pairs using the Therapeutic Targets Database. RESULTS: We identified 190 dysregulated LR interactions across six major cell types in AD PFC, of which 107 pairs were replicated. Among the replicated LR signals, we found globally downregulated communications in the astrocytes-to-neurons signaling axis, characterized, for instance, by the downregulation of APOE-related and Calmodulin (CALM)-related LR interactions and their potential regulatory connections to target genes. Pathway analyses revealed 44 GO terms significantly linked to AD, highlighting Biological Processes such as 'amyloid precursor protein processing' and 'ion transmembrane transport,' among others. We prioritized several drug repurposing candidates, such as cromoglicate, targeting the identified dysregulated LR pairs. CONCLUSIONS: Our integrative analysis identified key dysregulated LR interactions in a cell type-specific manner and the associated GO terms in AD, offering novel insights into potential therapeutic targets involved in disrupted cell-cell communication in AD.

Disentangling Accelerated Cognitive Decline from the Normal Aging Process and Unraveling Its Genetic Components: A Neuroimaging-Based Deep Learning Approach.

Background: The progressive cognitive decline, an integral component of Alzheimer's disease (AD), unfolds in tandem with the natural aging process. Neuroimaging features have demonstrated the capacity to distinguish cognitive decline changes stemming from typical brain aging and AD between different chronological points. Objective: To disentangle the normal aging effect from the AD-related accelerated cognitive decline and unravel its genetic components using a neuroimaging-based deep learning approach. Methods: We developed a deep-learning framework based on a dual-loss Siamese ResNet network to extract fine-grained information from the longitudinal structural magnetic resonance imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. We then conducted genome-wide association studies (GWAS) and post-GWAS analyses to reveal the genetic basis of AD-related accelerated cognitive decline. Results: We used our model to process data from 1,313 individuals, training it on 414 cognitively normal people and predicting cognitive assessment for all participants. In our analysis of accelerated cognitive decline GWAS, we identified two genome-wide significant loci: APOE locus (chromosome 19 p13.32) and rs144614292 (chromosome 11 p15.1). Variant rs144614292 (G > T) has not been reported in previous AD GWA studies. It is within the intronic region of NELL1, which is expressed in neurons and plays a role in controlling cell growth and differentiation. The cell-type-specific enrichment analysis and functional enrichment of GWAS signals highlighted the microglia and immune-response pathways. Conclusions: Our deep learning model effectively extracted relevant neuroimaging features and predicted individual cognitive decline. We reported a novel variant (rs144614292) within the NELL1 gene.