Dataset Information

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

ABSTRACT: Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

SUBMITTER: Mantyh WG

PROVIDER: S-EPMC10535074 | biostudies-literature | 2023 Oct-Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Mantyh William G WG Cochran J Nicholas JN Taylor Jared W JW Broce Iris J IJ Geier Ethan G EG Bonham Luke W LW Anderson Ashlyn G AG Sirkis Daniel W DW Joie Renaud La R Iaccarino Leonardo L Chaudhary Kiran K Edwards Lauren L Strom Amelia A Grant Harli H Allen Isabel E IE Miller Zachary A ZA Gorno-Tempini Marilu L ML Kramer Joel H JH Miller Bruce L BL Desikan Rahul S RS Rabinovici Gil D GD Yokoyama Jennifer S JS

Alzheimer's & dementia (Amsterdam, Netherlands) 20230928 4

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary ...[more]

PMID: 37780862

Similar Datasets

Project description:BackgroundEvidence is lacking on the impact of alcohol consumption on colorectal cancer (CRC) risk (overall and by age at diagnosis) by polygenic risk score (PRS) levels, and it is unclear how the magnitude of CRC risk associated with alcohol consumption compares to the magnitude of genetically determined risk.MethodsMultiple logistic regression was used to assess the association between alcohol consumption and colorectal cancer (CRC) across PRS levels based on 140 CRC-related loci among 5104 CRC cases and 4131 controls from a large population-based case-control study. We compared the effects for alcohol consumption and PRS on CRC risk using the "Genetic Risk Equivalent (GRE)" for effective risk communication. Specific analyses were conducted for early-onset CRC (EOCRC, <55 years) and late-onset CRC (LOCRC, ≥55 years).FindingsHigh alcohol consumption, and to a lower extent, also alcohol abstinence were associated with increased CRC risk. Compared to low alcohol consumption (0·1-<25 g/d), lifetime average alcohol consumption ≥25 g/d was more strongly associated with EOCRC [odds ratio (OR) 1·8, 95% confidence interval (CI) 1·2-2·8] than with LOCRC risk (OR 1·3, 95% CI 1·1-1·4) (P-value for interaction with age =0·011). Interactions between alcohol consumption and PRS did not reach statistical significance for either EOCRC or LOCRC risk. The estimated impact of high lifetime alcohol consumption on EOCRC was equivalent to the effect of having 47 percentiles higher PRS (GRE 47, 95% CI 12-82), stronger than the impact on LOCRC (GRE 18, 95% CI 8-29).InterpretationExcessive alcohol use was strongly associated with EOCRC risk, independent of PRS levels. Abstaining from heavy drinking could reduce risk for CRC, in particular for EOCRC to an extent that would be equivalent to having a much lower genetically determined risk.FundingThe first author (X.C.) was supported by the Guangzhou Elite Project (GEP). The DACHS study was supported by grants from the German Research Council (BR 1704/6-1, BR1704/6-3, BR 1704/6-4, BR 1704/6-6, CH 117/1-1, BR 1704/17-1, HO 5117/2-1) and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01GL1712).

Project description:Co-pathologies play an important role in the expression of the Alzheimer's disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer's disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer's disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer's disease (median age of onset = 55 years, 44 females) and 48 with late-onset Alzheimer's disease (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer's disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer's disease pathological diagnosis in 98% of patients with early-onset Alzheimer's disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer's disease (median = 2 versus 3, Mann-Whitney Z = 3.00, P = 0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer's disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P = 0.33; Lewy body disease: 49% versus 42%, P = 0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer's disease (22% versus 6%, P = 0.02). In contrast, LATE (35% versus 8%, P < 0.001), hippocampal sclerosis (15% versus 3%, P = 0.02), argyrophilic grain disease (58% versus 41%, P = 0.052), and vascular brain injury (65% versus 39%, P = 0.004) were more common in late than in early onset Alzheimer's disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI -2.5 to -0.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-Alzheimer's disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer's disease with potentially significant implications for clinical practice and clinical trials design.

Project description:Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R2 = .77), DS and LOAD (R2 = .73), and EOAD and LOAD (R2 = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10-5) for DS, immune system regulation (p = 4.33 × 10-5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R2 = .59) and LOAD (R2 = .33) compared to the correlation between EOAD and LOAD (R2 = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

Dataset Information

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Publications

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets