Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease.

Plasma biomarkers for Alzheimer's disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests for amyloid and tau pathology, as well as neurodegeneration and astrocytic activation. To define Alzheimer's disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer's disease instead of the risk of dementia. In a cohort of Alzheimer's disease cases [n = 1439, mean age 68 years (standard deviation = 8.2)] and screened controls [n = 508, mean age 82 years (standard deviation = 6.8)], we measured plasma concentrations of the 40 and 42 amino acid-long amyloid-ß (Aß) fragments (Aß40 and Aß42, respectively), tau phosphorylated at amino acid 181 (P-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) using state-of-the-art Single molecule array (Simoa) technology. We tested the relationships between the biomarkers and Alzheimer's disease genetic risk, age at onset and disease duration. We also conducted a genome-wide association study for association of disease risk genes with these biomarkers. The prediction accuracy of Alzheimer's disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aß40 or Aß42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (P < 4.3 × 10-5). Concentrations of the Aß-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P = 0.011-4.78 × 10-8), except NfL. No novel genome-wide significant single nucleotide polymorphisms were found in the case-control design; however, in a case-only analysis, we found two independent genome-wide significant associations between the Aß42/Aß40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aß40, Aß42, GFAP and NfL biomarkers explain additional variation over and above APOE. We identified novel plausible genome wide-significant genes associated with Aß42/Aß40 ratio in a sample which is 50 times smaller than current genome-wide association studies in Alzheimer's disease.

Association between psoriatic disease and lifestyle factors and comorbidities: cross-sectional analysis and Mendelian randomization.

OBJECTIVES: To examine associations between PsA and psoriasis vs lifestyle factors and comorbidities by triangulating observational and genetic evidence. METHODS: We analysed cross-sectional data from the UK Biobank (1836 PsA, 8995 psoriasis, 36 000 controls) to describe the association between psoriatic disease and lifestyle factors (including BMI and smoking) and 15 comorbidities [including diabetes and coronary artery disease (CAD)] using logistic models adjusted for age, sex and lifestyle factors. We applied bidirectional Mendelian randomization (MR) to genome-wide association data (3609 PsA and 7804 psoriasis cases, up to 1.2 million individuals for lifestyle factors and 757 601 for comorbidities) to examine causal direction, using the inverse-variance weighted method. RESULTS: BMI was cross-sectionally associated with risk of PsA (OR 1.31 per 5 kg/m2 increase; 95% CI 1.26, 1.37) and psoriasis (OR 1.23; 1.20, 1.26), with consistent MR estimates (PsA OR 1.38; 1.14, 1.67; psoriasis OR 1.36; 1.18, 1.58). In both designs, smoking was more strongly associated with psoriasis than PsA. PsA and psoriasis were cross-sectionally associated with diabetes (OR 1.35 and 1.39, respectively) and CAD (OR 1.56 and 1.38, respective). Genetically predicted glycated haemoglobin (surrogate for diabetes) increased PsA risk (OR 1.18 per 6.7 mmol/mol increase; 1.02, 1.36) but not psoriasis. Genetic liability to PsA (OR 1.05; 1.003, 1.09) and psoriasis (OR 1.03; 1.001, 1.06) were associated with increased risk of CAD. CONCLUSION: Observational and genetic evidence converge to suggest that BMI and glycaemic control are associated with increased psoriatic disease risk, while psoriatic disease is associated with increased CAD risk. Further research is needed to understand the mechanism of these associations.

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.

Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.

Polygenic risk and pleiotropy in neurodegenerative diseases.

In this paper we explore the phenomenon of pleiotropy in neurodegenerative diseases, focusing on Alzheimer's disease (AD). We summarize the various techniques developed to investigate pleiotropy among traits, elaborating in the polygenic risk scores (PRS) analysis. PRS was designed to assess a cumulative effect of a large number of SNPs for association with a disease and, later for disease risk prediction. Since genetic predictions rely on heritability, we discuss SNP-based heritability from genome-wide association studies and its contribution to the prediction accuracy of PRS. We review work examining pleiotropy in neurodegenerative diseases and related phenotypes and biomarkers. We conclude that the exploitation of pleiotropy may aid in the identification of novel genes and provide further insights in the disease mechanisms, and along with PRS analysis, may be advantageous for precision medicine.

Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition.

OBJECTIVE: Alzheimer disease (AD) is the most common form of dementia and is responsible for a huge and growing health care burden in the developed and developing world. The polygenic risk score (PRS) approach has shown 75 to 84% prediction accuracy of identifying individuals with AD risk. METHODS: In this study, we tested the prediction accuracy of AD, mild cognitive impairment (MCI), and amyloid deposition risks with PRS, including and excluding APOE genotypes in a large publicly available dataset with extensive phenotypic data, the Alzheimer's Disease Neuroimaging Initiative cohort. Among MCI individuals with amyloid-positive status, we examined PRS prediction accuracy in those who converted to AD. In addition, we divided polygenic risk score by biological pathways and tested them independently for distinguishing between AD, MCI, and amyloid deposition. RESULTS: We found that AD and MCI are predicted by both APOE genotype and PRS (area under the curve [AUC] = 0.82% and 68%, respectively). Amyloid deposition is predicted by APOE only (AUC = 79%). Further progression to AD of individuals with MCI and amyloid-positive status is predicted by PRS over and above APOE (AUC = 67%). In pathway-specific PRS analyses, the protein-lipid complex has the strongest association with AD and amyloid deposition even when genes in the APOE region were removed (p = 0.0055 and p = 0.0079, respectively). INTERPRETATION: The results showed different pattern of APOE contribution in PRS risk predictions of AD/MCI and amyloid deposition. Our study suggests that APOE mostly contributes to amyloid accumulation and the PRS affects risk of further conversion to AD. ANN NEUROL 2019;86:427-435.

The prevalence of co-morbidities and their impact on physical activity in people with inflammatory rheumatic diseases compared with the general population: results from the UK Biobank.

Objectives: To compare the prevalence and incidence of chronic co-morbidities in people with inflammatory rheumatic and musculoskeletal diseases (iRMDs), and to determine whether the prevalent co-morbidities are associated with physical activity levels in people with iRMDs and in those without iRMDs. Methods: Participants were recruited to the UK Biobank; a population-based cohort. Data were collected about demographics, physical activity, iRMDs (RA, PsA, AS, SLE) and other chronic conditions, including angina, myocardial infarction, stroke, hypertension, pulmonary disease, diabetes and depression. The standardized prevalence of co-morbidities in people with iRMDs was calculated. Cox regression was used to determine the relationship between the presence of an iRMD and an incident co-morbidity. The relationship between the presence (versus absence) of a (co-)morbidity and physical activity level (low, moderate, high) in people with iRMDs and in those without was assessed using multinomial logistic regression. Results: A total of 488 991 participants were included. The estimated prevalence of each co-morbidity was increased in participants with an iRMD, compared with in those without, particularly for stroke in participants with SLE (standardized morbidity ratio (95% CI), 4.9 (3.6, 6.6). Compared with people with no iRMD and no morbidity, the odds ratios (95% CI) for moderate physical activity were decreased for: no iRMD and morbidity, 0.87 (0.85, 0.89); iRMD and no co-morbidity, 0.71 (0.64, 0.80); and iRMD and co-morbidity, 0.58 (0.54, 0.63). Conclusion: Having a (co-)morbidity is associated with reduced physical activity in the general population, and to a greater extent in participants with an iRMD. Optimal management of both iRMDs and co-morbidities may help to reduce their impact on physical activity.

Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis.

OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, with a strong heritable component, affecting patients with psoriasis. Here we attempt to identify genetic variants within the major histocompatibility complex (MHC) that differentiate patients with PsA from patients with cutaneous psoriasis alone (PsC). METHODS: 2808 patients with PsC, 1945 patients with PsA and 8920 population controls were genotyped. We imputed SNPs, amino acids and classical HLA alleles across the MHC and tested for association with PsA compared to population controls and the PsC patient group. In addition we investigated the impact of the age of disease onset on associations. RESULTS: HLA-C*06:02 was protective of PsA compared to PsC (p=9.57×10-66, OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01×10-59). After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54×10-9) where the presence of asparagine or serine residue increased PsA risk. Asparagine at position 97 of HLA-B defines the HLA-B*27 alleles. CONCLUSIONS: By controlling for the age of psoriasis onset, we show, for the first time, that HLA-C*06:02 is not associated with PsA and that amino acid position 97 of HLA-B differentiates PsA from PsC. This amino acid also represents the largest genetic effect for ankylosing spondylitis, thereby refining the genetic overlap of these two spondyloarthropathies. Correcting for bias has important implications for cross-phenotype genetic studies.

Chromosome X-wide association study in case control studies of pathologically confirmed Alzheimer's disease in a European population.

Although there are several genome-wide association studies available which highlight genetic variants associated with Alzheimer's disease (AD), often the X chromosome is excluded from the analysis. We conducted an X-chromosome-wide association study (XWAS) in three independent studies with a pathologically confirmed phenotype (total 1970 cases and 1113 controls). The XWAS was performed in males and females separately, and these results were then meta-analysed. Four suggestively associated genes were identified which may be of potential interest for further study in AD, these are DDX53 (rs12006935, OR = 0.52, p = 6.9e-05), IL1RAPL1 (rs6628450, OR = 0.36, p = 4.2e-05; rs137983810, OR = 0.52, p = 0.0003), TBX22 (rs5913102, OR = 0.74, p = 0.0003) and SH3BGRL (rs186553004, OR = 0.35, p = 0.0005; rs113157993, OR = 0.52, p = 0.0003), which replicate across at least two studies. The SNP rs5913102 in TBX22 achieves chromosome-wide significance in meta-analysed data. DDX53 shows highest expression in astrocytes, IL1RAPL1 is most highly expressed in oligodendrocytes and neurons and SH3BGRL is most highly expressed in microglia. We have also identified SNPs in the NXF5 gene at chromosome-wide significance in females (rs5944989, OR = 0.62, p = 1.1e-05) but not in males (p = 0.83). The discovery of relevant AD associated genes on the X chromosome may identify AD risk differences and similarities based on sex and lead to the development of sex-stratified therapeutics.

Are Alzheimer's and coronary artery diseases genetically related to longevity?

Introduction: In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes for a particular condition or whether there are specific "longevity" genes increasing the lifespan independently of age-related conditions' risk genes. The aim of this study was to investigate the shared genetic component between longevity and two age-related conditions. Methods: We performed a cross-trait meta-analysis of publicly available genome-wide data for Alzheimer's disease, coronary artery disease and longevity using a subset-based approach provided by the R package ASSET. Results: Despite the lack of strong genetic correlation between longevity and the two diseases, we identified 38 genome-wide significant lead SNPs across 22 independent genomic loci. Of them 6 were found to be potentially shared among the three traits mapping to genes including DAB2IP, DNM2, FCHO1, CLPTM1, and SNRPD2. We also identified 19 novel genome-wide associations for the individual traits in this study. Functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants are involved in clathrin-mediated endocytosis and plasma lipoprotein and neurotransmitter clearance processes. Discussion: In summary, we have been able to advance in the knowledge of the genetic overlap existing among longevity and the two most common age-related disorders.

Age-dependent effect of APOE and polygenic component on Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant genetic heritability. Several genes have been implicated in the onset of AD with the apolipoprotein E (APOE) gene being the strongest single genetic risk loci. Evidence suggests that the effect of APOE alters with age during disease progression. Here, we aim to investigate the impact of APOE and other variants outside the APOE region on AD risk in younger and older participants. Using data from both the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, we computed the polygenic risk score of each individual informed by the latest genetic study from the International Genomics of Alzheimer's Project. Our analysis showed that the effect of APOE on the disease risk is greater in younger participants and reduces as participants' age increases. Our findings indicate the increased impact of polygenic risk score as participants' age increases. Therefore, AD in older individuals can potentially be triggered by the cumulative effect of genes which are outside the APOE region.

Genetic variability in response to amyloid beta deposition influences Alzheimer's disease risk.

Genome-wide association studies of late-onset Alzheimer's disease risk have previously identified genes primarily expressed in microglia that form a transcriptional network. Using transgenic mouse models of amyloid deposition, we previously showed that many of the mouse orthologues of these risk genes are co-expressed and associated with amyloid pathology. In this new study, we generate an improved RNA-seq-derived network that is expressed in amyloid-responsive mouse microglia and we statistically compare this with gene-level variation in previous human Alzheimer's disease genome-wide association studies to predict at least four new risk genes for the disease (OAS1, LAPTM5, ITGAM/CD11b and LILRB4). Of the mouse orthologues of these genes Oas1a is likely to respond directly to amyloid at the transcriptional level, similarly to established risk gene Trem2, because the increase in Oas1a and Trem2 transcripts in response to amyloid deposition in transgenic mice is significantly higher than both the increase of the average microglial transcript and the increase in microglial number. In contrast, the mouse orthologues of LAPTM5, ITGAM/CD11b and LILRB4 (Laptm5, Itgam/CD11b and Lilra5) show increased transcripts in the presence of amyloid plaques similar in magnitude to the increase of the average microglial transcript and the increase in microglia number, except that Laptm5 and Lilra5 transcripts increase significantly quicker than the average microglial transcript as the plaque load becomes dense. This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer's disease risk, and identification of these genes may help to predict the risk of developing Alzheimer's disease. These findings also provide further insights into the mechanisms underlying Alzheimer's disease for potential drug discovery.