Associations of risk genes with onset age and plasma biomarkers of Alzheimer's disease: a large case-control study in mainland China.

Background/Objectives: Studies have shown that higher polygenic risk scores (PRSs) for Alzheimer’s disease (AD) are associated with smaller volumes in temporal brain regions typically affected by this disease. These effects have also been found in cognitively unimpaired (CU) older adults. This study aimed to investigate the relationship between PRSs and brain volumes in specific areas associated with early AD. Methods: 342 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative and stratified into three groups: 114 amyloid-positive atrophic (A+N+), 114 amyloid-negative non-atrophic (A−N−), and 114 amyloid-positive non-atrophic (A+N−) people. Linear regressions were performed within each group to investigate associations between PRSs and regional grey matter volumes. Analyses were also repeated after stratifying groups by APOE status and clinical diagnosis. Two sensitivity analyses were run to investigate the impact of APOE and amyloid status and concordance across biomarkers. Multiplicity was controlled for using the Benjamini–Hochberg false discovery rate (FDR) approach. Results: Negative associations were observed between PRSs and volumes of the left amygdala and hippocampus in A+N+, right hippocampus in A+N−, and right posterior cingulate cortex in A−N− participants. Associations were found especially in A−N− participants, both ε4 allele carriers and non-carriers, and mostly confirmed in sensitivity analyses. Associations emerged only in CU and AD participants, but not in people with MCI. None of these findings survived correction for FDR. Conclusions: These findings highlight the potential of PRSs as novel biological indicators for a deeper characterisation of AD-related neural alterations.

BackgroundPolygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans.MethodsIn this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.ResultsThe PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results.ConclusionsWe showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Background: Due to the availability of effective lipid-lowering therapies, familial hypercholesterolemia (FH) case finding is adopted by many healthcare systems. In parallel, polygenic risk scores (PRS) have emerged as a powerful tool for capturing the effect of common genetic variants associated with CAD. Research Question: What proportion of individuals at high PRS for CAD exhibit equivalent risk compared to FH variant carriers, and what are the potential clinical benefits of treating these individuals with statins. Methods: We analyzed data from the UK Biobank, identifying FH carriers via whole-exome sequencing and defining polygenic risk using a CAD PRS. Incident CAD events in statin-naive individuals were compared between FH carriers and individuals with high PRS. Number-needed-to-treat (NNT) with statins and number needed to screen (NNS) were calculated to assess therapeutic impact in high PRS individuals. Results: The top 8% of the PRS distribution exhibited comparable or higher CAD risk than FH carriers. This high-PRS group accounted for between 18 and 29 times more CAD events than FH carriers, depending on age. In the untreated high PRS group the rate of CAD events was 10.28 per 1000 person years (9.01 - 11.67) compared to 6.78 per 1000 person years (5.39 - 8.42) in the treated high PRS group, representing a relative risk reduction (RRR) of 0.34 (0.15 - 0.49). In the median PRS group, the rate of CAD events was 5.28 per 1000 persons (4.67 - 5.94) compared to 3.93 per 1000 person years (3.21 - 4.75) in the treated group, representing a RRR of 0.26 (0.07 - 0.41). The NNT in the high PRS group was 286 compared to 741 in the median PRS group, indicating that statins were roughly 2.6 fold more effective, after matching on clinical risk factors. The NNT (286) for statins in the high PRS group is similar to literature based estimates for statin treatment in FH (222) but the number needed to screen is approximately 21 fold higher for FH than for high PRS. Conclusion: In the population, screening for high CAD PRS individuals will prevent more CAD cases than screening for FH. This is because high PRS individuals are much more prevalent than FH individuals and have enhanced therapeutic benefit from statin treatment (compared to those without high PRS). The polygenic component of CAD is a major, treatable risk factor that is not routinely evaluated in prevention programs, despite a growing body of evidence that this can be implemented easily into clinical practice.

The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study

BackgroundAPOE e4 has been used to evaluate the risk for Alzheimer’s diseases (AD) but there exist other AD risk genes, and their effects can be collectively measured by polygenic risk scores (PRS). In this study, we sought to use both PRS (APOE excluded) and APOE e4 to evaluate the AD risk.MethodThe discovery dataset was meta‐analysis of three large‐scale European ancestry AD GWAS (Kunkle et al, 2019, the UK Biobank, and the FinnGen consortium). SNPs within 500Kb from transcript starting and ending sites of APOE were excluded. PRS‐CS was used to calculate PRS. Target datasets were European ancestry samples from NIA Alzheimer’s disease centers (ADC, 2,413 cases and 3,423 controls) and All of Us research program (AOU, 1,177 cases and 60,607 controls). Participants having age at onset (cases) or age at the last interview (controls) <60 were excluded. The prevalence of AD were higher in ADC (41.35%) and lower in AOU (1.91%) than those in general populations; therefore, we combined ADC and AOU samples to approximate the PRS distribution in general populations. Then we dichotomized PRS as high (highest 10%) and other (the remaining 90%) based on the PRS distribution of combined sample. Cox proportional hazard model was used to test the effects of dichotomized PRS and e4 genotypes (0, 1, and 2 copies of e4 alleles) by adjusting for sex. Additionally, we performed sex stratified analyses in ADC only as numbers of high PRS and e4/e4 carriers in AOU in either sex were <5.ResultResults are summarized in Table 1. We used those having other PRS and no e4 as the reference group. In both ADC and AOU, high PRS or e4 were significantly associated with the AD risk (PRS hazard ratios (HRs): 1.31‐1.74, P‐values≤0.01; e4 HRs: 1.39‐8.68, P‐values≤2.80E‐06) but having both substantially increased the AD risk (HRs: 2.07‐14.26, P‐values≤6.80E‐05). In ADC, both high PRS and e4 had larger effects in females than in males.ConclusionThe effects of PRS were modest and cannot be used alone to evaluate the AD risk; however, PRS can potentially be used with APOE e4 to evaluate the AD risk.

Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile; P<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46-0.86]; P=0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78-0.98]; P=0.022; interaction P=0.04). A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.

BackgroundGenetics plays a significant role in Alzheimer's disease (AD) biomarker traits. However, the underlying genetic underpinnings remain poorly understood.MethodsA total of 3,707 individuals were enrolled, including 1,697 AD patients and 2,010 controls, all of whom underwent whole genome sequencing. Cerebrospinal fluid (CSF) biomarkers were available in 226 AD patients, while plasma biomarkers were measured in 302 samples (184 AD patients and 118 controls). We performed association analysis for common variants (MAF ≥ 0.05) and gene‐based association studies for rare variants (MAF < 0.05) with AD biomarker traits. Additionally, we constructed a polygenic risk score (PRS) to evaluate its association with AD risk and biomarkers.ResultPRS was significantly associated with higher AD risk, lower MMSE scores, and elevated levels of plasma p‐tau217 and GFAP. Gene‐based rare variant association studies revealed that three novel genes reached genome‐wide significance, including ABCA7 rare damaging variants for MMSE score, an ECSIT rare damaging missense variant for CSF Aβ42, and an ADPRHL1 rare LoF variant for plasma GFAP, respectively (all p <0.05).ConclusionsOur study highlights the contribution of both PRS and rare variants in ABCA7, ECSIT, and ADPRHL1 to AD biomarker traits. These findings provide insights into the pathophysiology of AD and may lead to novel targets for diagnosis and therapy.

Polygenic Risk Score Reveals Genetic Heterogeneity of Alzheimer's Disease between the Chinese and European Populations.

BackgroundEarly identification of individuals at risk for Alzheimer's disease (AD) is critical for effective intervention. Amyloid deposition, a hallmark of AD pathology, offers insights into genetic factors driving disease progression. While the APOE genotype is a major contributor, the role of other risk variants in amyloid deposition and early AD endophenotypes remains unclear. This study aims to (1) identify amyloid polygenic risk scores (PRS) that best predict amyloid burden in Europeans and Hispanics beyond APOE, (2) compare the amyloid PRS with APOE, an AD risk PRS, and a tau PET PRS, and (3) validate these PRSs against AD endophenotypes in non‐demented older adults.MethodAmong Europeans, amyloid PRSs were developed using GWAS of amyloid PET, plasma p‐tau181, and CSF p‐tau181, along with separate PRSs for AD risk and tau PET burden. For Hispanics, amyloid PRSs were derived using GWAS of plasma p‐tau181 and the GAUDI method, which incorporates individual‐level plasma p‐tau181 and local ancestry among admixed population. Multi‐ancestry PRSs were constructed using PRS‐CSx from GWAS of plasma p‐tau181 and AD across ancestries. After parameter tunning, all PRSs were tested in two datasets (515 Hispanics and 1,120 Europeans) using linear and mixed‐effects models to evaluate cross‐sectional and longitudinal associations with plasma p‐tau181, p‐tau217, Aβ42, Aβ42/Aβ40, GFAP, NfL, and global cognition.ResultAmong Europeans, the APOE‐ε4 allele explains 3.6%–6% of the variance in p‐tau181 (β=0.071, 95%CI: 0.034–0.108) and p‐tau217 (β=0.127, 95%CI: 0.101–0.152). PRSs derived from amyloid‐PET GWAS explain 3%–4% of the variance in p‐tau181 (β=0.039, 95%CI:0.018–0.060) and p‐tau217 (β=0.036, 95%CI: 0.022–0.051). Among Hispanics, the APOE‐ε4 allele explains 1% of the variance in p‐tau181 (β=0.057, 95%CI: 0.004–0.109), while GAUDI PRSs explain 1.5% (β=0.032, 95%CI: 0.009–0.054). Among non‐demented older adults, in Europeans, amyloid‐PET PRSs are associated with plasma Aβ42, Aβ42/Aβ40, GFAP, NfL, and global cognition, while GAUDI PRSs show similar associations in Hispanics. Other PRSs derived from AD or tau GWAS or multi‐ancestry PRS show weaker or no associations in both ancestries.ConclusionAmyloid PRSs show promise as predictive tools for early AD pathology in asymptomatic individuals among Europeans and Caribbean Hispanics.

Polygenic risk scores (PRS) are measures of an individual's aggregate genetic risk of disease and are typically calculated using common variants. Rare variants (RV), though not captured by PRS, have been shown to play an important role in AD. We utilized an AD PRS to discover associations with novel RVs. PRS for non-Hispanic white (NHW) samples (n=11,409; AD=6630, controls=4779) from the Alzheimer's Disease Sequencing Project (ADSP) R4 dataset were calculated using published GWAS summary statistics of NHW subjects, excluding the APOE region. Participants were classified into high (n=5,442) and low (n=5,967) PRS groups based on the median PRS. After quality control, 11,485,531 low frequency variants (LV) (1% < MAF < 5%) and RVs with a MAC>5 were included in the analysis. The association of each variant was evaluated in low and high PRS groups separately using a regression model including covariates for age, sex, and principal components of ancestry implemented in GENESIS. Genome-wide significant (GWS) associations of RVs and LVs with AD were identified in both the low and high PRS groups. Risk variants were disproportionately enriched in the low group while protective ones were disproportionately enriched in the high group. Among the GWS, RVs in the coding region of NYNRIN (rs570910195) (β=4.06, p=4.37x10-10) and 52 kb upstream of LOC105373398 (rs572619714, β=1.67, p=2.20x10-8) increased AD risk in the low PRS group. A rare deletion located 27 kb downstream of SDHC (chr1:161390036) was associated with decreased AD risk (β=-2.33, p=7.45x10-9) and a low frequency variant 20 kb downstream of SMNDC1 (rs150913764, MAF=0.02) was associated with increased AD risk (β=0.96, p=3.13x10-8) in the high PRS group. These variants were not associated with AD in the other respective PRS group. Stratifying individuals into those with lower and higher risk for AD based on aggregated effects of common variants enhanced the detection of RV and LV associations. Our results suggest that a PRS calculated from common variants may not necessarily correspond to an individual's genetic relative risk for AD. These findings also provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.

The Promise and Limits of Suicide Genetics.

BackgroundRecent single‐cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia‐centred pathological mechanism may be considered one of the pathologies of Alzheimer’s disease (AD). However, a single gene mutation, such as a TREM2 mutation, can rarely explain the pathology of AD. Therefore, polygenic effects involving multiple gene mutations have been proposed. In this study, we propose a polygenic risk score (PRS) to quantify the microglial polygenic effect. We stratified patient groups by this PRS and examined differences in pathogenesis based on omics analysis using postmortem brains.MethodWhole‐genome sequencing and bulk brain tissue RNA‐seq of the frontal cortex were performed using postmortem brain samples from 100 subjects with Braak senile plaque (SP) and neurofibrillary tangle (NFT) staging information. In addition, single‐nuclei RNA‐seq (snRNA‐seq) was performed on 15 of these subjects (healthy subjects: 8 subjects, AD patients: 7 subjects).ResultWe divided AD patients into low and high groups by microglial PRS and performed bulk brain tissue RNA‐seq analysis. We identified 112 differentially expressed genes and found that those genes were related to autophagy and inflammation. To further validate these findings at the single‐cell level, we identified cell clusters containing microglia based on snRNA‐seq. Gene expression analysis of microglia in 3 AD patients with low PRS and 4 AD patients with high PRS suggested altered transcriptional profiles of immune cells and phagocytosis. The expression of APOE and TYROBP, signature genes of reactive microglia, was significantly upregulated in the AD patients with low PRS compared to the AD patients with high PRS and healthy subjects. In contrast, CX3CR1 and P2RY12, signature genes of homeostatic microglia, were downregulated.ConclusionThe stratification analysis of AD by PRS suggests that microglial reactivity differs among AD patient groups. Future detailed microglial observations in postmortem brains from AD patients with low PRS and those with high PRS will further elaborate our results.

&lt;div&gt;Abstract&lt;p&gt;Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in &lt;i&gt;ATM, BRCA2, PALB2,&lt;/i&gt; and &lt;i&gt;NBN&lt;/i&gt; with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%–66% of PRS), men with low (0%–33%) and high (66%–100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31–0.95) and 3.22 (95% CI = 2.20–4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status.&lt;/p&gt;Significance:&lt;p&gt;These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in &lt;i&gt;ATM, BRCA2, PALB2,&lt;/i&gt; and &lt;i&gt;NBN&lt;/i&gt; with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%–66% of PRS), men with low (0%–33%) and high (66%–100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31–0.95) and 3.22 (95% CI = 2.20–4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status.&lt;/p&gt;Significance:&lt;p&gt;These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.&lt;/p&gt;&lt;/div&gt;

BackgroundNeuropathological changes in late‐onset Alzheimer's disease (LOAD) precede symptoms by years, underscoring the need for early detection. While the APOE ε4 allele is the strongest genetic risk factor, it does not fully explain LOAD risk. Polygenic risk scores (PRS), which aggregate multiple genetic variants, show promise in predicting Alzheimer's risk and age at onset (AAO). However, most PRS models are based on European‐ancestry populations, limiting applicability to other ancestries. Furthermore, the relationship between PRS and AAO remains unclear, particularly across diverse populations. This study evaluates whether higher PRS is associated with earlier AAO in a multi‐ancestry cohort from the Alzheimer's Disease Sequencing Project (ADSP).MethodData were collected from three ADSP cohorts, comprising 1261 participants (466 LOAD cases, 795 controls) of European, African American, and Hispanic ancestry. PRS scores were derived from 40 variants identified in a multi‐ancestry genome‐wide association study (GWAS). Participants were categorized into quintiles based on their PRS score. A Cox proportional hazards model, with age as the timescale, was used to estimate hazard ratios (HRs), adjusting for sex and APOE score.ResultHigher PRS was associated with earlier AAO. Participants in the highest PRS quintile (80–100%) had a 45% higher hazard of developing LOAD compared to the lowest quintile (0–20%) (HR = 1.45, 95% CI: 1.08–1.94, p = 0.013). APOE score was strongly predictive of LOAD (HR = 1.76, 95% CI: 1.58–1.96, p < 0.001), while female sex had a modest protective effect (HR = 0.81, 95% CI: 0.67–0.99, p = 0.038). Violin plots showed a stepwise decline in median AAO with increasing PRS categories, from 83 years in the lowest quintile to 77 in the highest.ConclusionHigher PRS is associated with earlier AAO, supporting its utility in identifying high‐risk individuals. PRS models based on the first multi‐ancestry GWAS represent progress but could improve with larger datasets. Incorporating genetic, environmental, and lifestyle factors may further enhance the accuracy of PRS in diverse populations. Analyses are underway with the new ADSP Release 5.