Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

Traffic-related air pollution, APOE ∊4 status, and neurodevelopmental outcomes among school children enrolled in the BREATHE project (Catalonia, spain)

BACKGROUND: Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the e4 allele of Apolipoprotein E (APOE) gene, the primary genetic risk factor for AD. OBJECTIVE: We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOE e4 status in children. METHODS: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2–4 times during January 2012–March 2013), and APOE genotypes were obtained for 1,667 children age 7–11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012–April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO ) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012). RESULTS: APOE e4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO were stronger or limited to e4 carriers for behavior problem scores (P-interaction 0.03 and 0.04), caudate volume (P-interaction 0.04 and 0.03), and inattentiveness trajectories (P-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC. CONCLUSION: PAHs, EC, and NO were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOE e4 allele carriers in our study population, and corresponding associations were weak or absent among e4 noncarriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

BACKGROUND: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer's disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. METHODS: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database ( www.oasis-brains.org ). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. RESULTS: Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). CONCLUSION: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

BACKGROUND: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer's disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. METHODS: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database ( www.oasis-brains.org ). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. RESULTS: Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). CONCLUSION: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development

Cross-sectional and longitudinal association of sleep and Alzheimer biomarkers in cognitively unimpaired adults

Sleep abnormalities are prevalent in Alzheimer's disease, with sleep quality already impaired at its preclinical stage. Epidemiological and experimental data point to sleep abnormalities contributing to the risk of Alzheimer's disease. However, previous studies are limited by either a lack of Alzheimer's disease biomarkers, reduced sample size or cross-sectional design. Understanding if, when, and how poor sleep contributes to Alzheimer's disease progression is important so that therapies can be targeted to the right phase of the disease. Using the largest cohort to date, the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, we test the hypotheses that poor sleep is associated with core Alzheimer's disease CSF biomarkers cross-sectionally and predicts future increments of Alzheimer's disease pathology in people without identifiable symptoms of Alzheimer's disease at baseline. This study included 1168 adults aged over 50 years with CSF core Alzheimer's disease biomarkers (total tau, phosphorylated tau and amyloid-beta), cognitive performance, and sleep quality (Pittsburgh sleep quality index questionnaire) data. We used multivariate linear regressions to analyse associations between core Alzheimer's disease biomarkers and the following Pittsburgh sleep quality index measures: total score of sleep quality, binarized score (poor sleep categorized as Pittsburgh sleep quality index > 5), sleep latency, duration, efficiency and disturbance. On a subsample of 332 participants with CSF taken at baseline and after an average period of 1.5 years, we assessed the effect of baseline sleep quality on change in Alzheimer's disease biomarkers over time. Cross-sectional analyses revealed that poor sleep quality (Pittsburgh sleep quality index total > 5) was significantly associated with higher CSF t-tau; shorter sleep duration (9 versus 0) was associated with lower CSF amyloid-beta. Longitudinal analyses showed that greater sleep disturbances (1-9 versus 0 and >9 versus 0) were associated with a decrease in CSF Aβ42 over time. This study demonstrates that self-reported poor sleep quality is associated with greater Alzheimer's disease-related pathology in cognitively unimpaired individuals, with longitudinal results further strengthening the hypothesis that disrupted sleep may represent a risk factor for Alzheimer's disease. This highlights the need for future work to test the efficacy of preventive practices, designed to improve sleep at pre-symptomatic stages of disease, on reducing Alzheimer's disease pathology

Polygenic pathways shape white matter vulnerability to Alzheimer's disease-related pathophysiological changes

BACKGROUND: The accumulation of amyloid-β 1-42 (Aβ 1-42) peptides and phosphorylated-Tau 181 (p-Tau 181) tangles from the preclinical stages of Alzheimer's disease (AD) has led to a biological definition of the disease. However, among Aβ 1-42-positive individuals, cognitive decline onset varies, and some never develop symptoms. Genetic influences on molecular pathways and their interactions with proteinopathy may underlie this heterogeneity. Leveraging data from a large sample of cognitively intact older adults in the European Prevention of Alzheimer Dementia (EPAD) cohort, we examined how AD-related pathophysiological changes (i.e., Aβ 1-42 and p-Tau 181), polygenic pathways and their interaction are associated with WM micro- and macrostructural properties. METHODS: We selected 803 individuals (mean age = 64.7 ± 7.3 years, 458 [57.0%] females, 275 [34.2%] APOE-ε4 carriers) with CSF-Aβ 1-42 and p-Tau 181 measurements available, full genotyping, and structural and diffusion MRI. Polygenic risk scores (PRSs) were computed using 85 AD-related genetic variants. These were mapped to their corresponding genes and, after excluding those belonging to the APOE locus, clustered by function into six pathway-specific PRSs (i.e., immune activation, signal transduction, inflammation, lipid, amyloid, and clearance pathways). Diffusion MRIs were processed through the fixel-based analysis framework to derive fiber density (FD) and fiber cross-section (FC) metrics, which were averaged within WM tracts. Linear models assessed the effects of AD-related pathophysiological changes, global and pathway-specific PRSs, and their interactions on FD and FC at both the tract and fixel levels. Models were corrected for multiple comparisons. RESULTS: P-Tau 181 was primarily associated with greater FD. The lipid pathway was associated with greater FD and FC, with these effects predominantly occurring in the left hemisphere, consistent with evidence of hemispheric dominance. The clearance pathway moderated the effect of Aβ 1-42 on FD, with a positive slope in A + compared to A- individuals. The immune activation pathway moderated the effect of p-Tau 181 on FD, with a negative slope in T + compared to T- individuals. CONCLUSIONS: Pathway-specific genetic vulnerability to AD is associated with alterations in WM tracts both directly and by moderating the effects of AD-related pathophysiological changes. AD-associated genetic risk should be integrated into the AD diagnostic framework to enable targeted screening and intervention for future preclinical trials aimed at specific biological pathways.</p

Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer’s disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer’s continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer’s continuum

Polygenic pathways shape white matter vulnerability to Alzheimer's disease-related pathophysiological changes

Background: The accumulation of amyloid-β1−42 (Aβ1−42) peptides and phosphorylated-Tau181 (p-Tau181) tangles from the preclinical stages of Alzheimer’s disease (AD) has led to a biological definition of the disease. However, among Aβ1−42-positive individuals, cognitive decline onset varies, and some never develop symptoms. Genetic influences on molecular pathways and their interactions with proteinopathy may underlie this heterogeneity. Leveraging data from a large sample of cognitively intact older adults in the European Prevention of Alzheimer Dementia (EPAD) cohort, we examined how AD-related pathophysiological changes (i.e., Aβ1−42 and p-Tau181), polygenic pathways and their interaction are associated with WM micro- and macrostructural properties. / Methods: We selected 803 individuals (mean age = 64.7 ± 7.3 years, 458 [57.0%] females, 275 [34.2%] APOE-ε4 carriers) with CSF-Aβ1−42 and p-Tau181 measurements available, full genotyping, and structural and diffusion MRI. Polygenic risk scores (PRSs) were computed using 85 AD-related genetic variants. These were mapped to their corresponding genes and, after excluding those belonging to the APOE locus, clustered by function into six pathway-specific PRSs (i.e., immune activation, signal transduction, inflammation, lipid, amyloid, and clearance pathways). Diffusion MRIs were processed through the fixel-based analysis framework to derive fiber density (FD) and fiber cross-section (FC) metrics, which were averaged within WM tracts. Linear models assessed the effects of AD-related pathophysiological changes, global and pathway-specific PRSs, and their interactions on FD and FC at both the tract and fixel levels. Models were corrected for multiple comparisons. / Results: P-Tau181 was primarily associated with greater FD. The lipid pathway was associated with greater FD and FC, with these effects predominantly occurring in the left hemisphere, consistent with evidence of hemispheric dominance. The clearance pathway moderated the effect of Aβ1−42 on FD, with a positive slope in A + compared to A- individuals. The immune activation pathway moderated the effect of p-Tau181 on FD, with a negative slope in T + compared to T- individuals. / Conclusions: Pathway-specific genetic vulnerability to AD is associated with alterations in WM tracts both directly and by moderating the effects of AD-related pathophysiological changes. AD-associated genetic risk should be integrated into the AD diagnostic framework to enable targeted screening and intervention for future preclinical trials aimed at specific biological pathways

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. // METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. // RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. // DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. // Highlights: . Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. . Inflammatory pathways are mostly related to cerebrovascular burden. . White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. Highlights Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways