<i>APOE</i> ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

Polsinelli, Angelina J.; Lane, Kathleen A.; Manchella, Mohit K.; Logan, Paige E.; Gao, Sujuan; Apostolova, Liana G.

doi:10.1002/alz.12955

Cited by 16 publications

(10 citation statements)

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“…Below age 60, however, early‐onset AD patients are equally likely to be APOE ε3/ε3 homozygotes 26,28 . Elsewhere, a recent study observed no effect of APOE ε4 on age of onset in men with early‐onset AD, but a decreased age of onset for females with early‐onset AD lacking an APOE ε4 allele 29 . That APOE ε4 plays less of a role in the earliest onset cases of AD further argues against the hypothesis that early‐onset AD is merely explained by an enrichment of late‐onset AD common genetic risk variants.…”

Section: Discussionmentioning

confidence: 99%

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

Mantyh,

Cochran,

Taylor

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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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.

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Section: Discussionmentioning

confidence: 99%

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

Mantyh,

Cochran,

Taylor

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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“…Tau‐mediated neurodegeneration may also be markedly exacerbated by APOE ε4 , leading to increased tau deposition 20,21 . APOE ε4 is associated with earlier symptom onset in LOAD and possibly a later symptom onset in EOAD, though it appears the ε4 allele has maximum impact between the onset ages of 60 to 70 years 4,22,23 . Further, Polsinelli et al 4 .…”

Section: Introductionmentioning

confidence: 96%

“…20,21 APOE ε4 is associated with earlier symptom onset in LOAD and possibly a later symptom onset in EOAD, though it appears the ε4 allele has maximum impact between the onset ages of 60 to 70 years. 4,22,23 Further, Polsinelli et al 4 found female EOAD APOE ε4 non-carriers had significantly younger symptom onset compared to female ε4 carriers and males regardless of their APOE ε4 status, suggesting a complex age-and sex-dependent relationship between APOE ε4 and AD. 24 EOnonAD patients are less likely to be APOE ε4 carriers, with a low, 14%, prevalence of the gene.…”

Section: Introductionmentioning

confidence: 97%

“…The early‐onset AD (EOAD; onset < 65 years) variant is an atypical, insidious, and aggressive form of AD with an accelerated trajectory of cognitive decline and greater pathology burden compared to late‐onset AD (LOAD) 2–5 . EOAD manifests with more extensive neurodegeneration and tau burden in regions classically correlated with AD.…”

Section: Introductionmentioning

confidence: 99%

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Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early‐onset Alzheimer's disease

Nemes,

Logan,

Manchella

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early‐onset Alzheimer's disease (EOAD).METHODSWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non‐Alzheimer's disease (EOnonAD) participants from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel‐wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.RESULTSEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non‐carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non‐carriers also had greater gray matter atrophy than female ε4 carriers.DISCUSSIONThe effects of sex and APOE ε4 must be considered when studying these populations.HIGHLIGHTS Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early‐onset Alzheimer's disease (EOAD), early‐onset non‐AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

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“…Multiple Mendelian randomization studies have indicated a causal relationship between Alzheimer's disease (AD) and COVID-19 [22,23] . Some of the same mutated genes have also been found to co-exist in both diseases, such as double mutations in the apolipoprotein E (APOE4) allele [24][25][26] . Additionally, the binding of SARS-CoV-2 viral proteins to host mitochondrial proteins may inhibit oxidative phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Identification of immune cell infiltration and biomarkers in Alzheimer's disease and COVID-19 by integrated bioinformatics analysis and machine learning

Li,

Tao,

Zhou

et al. 2024

Preprint

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Background: Since its emergence in late 2019, COVID-19 has become a global epidemic, resulting in numerous infections, including a significant number of critically ill patients. Several studies have suggested a possible link between Alzheimer's disease (AD) and COVID-19. For instance, a Mendelian randomization study has proposed a causal relationship between Alzheimer's disease and COVID-19 in the pathogenic mechanism. However, there are limited studies exploring the common pathogenic genes and immune infiltration between the two. Therefore, we conducted this study to identify key genes in COVID-19 associated with Alzheimer's disease, evaluate their correlation with immune cell characteristics and metabolic pathways, and investigate potential novel biomarkers. Methods: Transcriptome analyses were used to identify common biomolecular markers of AD and COVID-19. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on gene chip datasets (GSE213313, GSE5281, and GSE63060) from AD and COVID-19 patients to identify genes associated with both conditions. Common pathogenic molecular mechanisms were identified through Gene Ontology (GO) enrichment analyses. The core genes were then identified using machine learning methods. Subsequently, we evaluated the relationship between these core genes and common immune cells and metabolic pathways. Finally, our findings were validated through single-cell analysis. Results: The study identified 484 common differentially expressed genes (DEGs) by taking the intersection of genes between AD and COVID-19. The black module, containing 132 genes, showed the highest association between the two diseases according to WGCNA. GO enrichment analysis revealed that these genes mainly affect inflammation, cytokines, immune-related functions, and signaling pathways related to metal ions and cellular response to viruses. Additionally, a machine learning approach identified eight core genes. We identified links between these genes and immune cells and also found a strong association between EIF3H and oxidative phosphorylation. In addition, these results were further validated by single-cell analysis. Conclusion: This study identifies potential shared genes, signaling pathways, immune-related alterations, and changes in metabolic pathways that may collectively contribute to the pathogenesis of COVID-19 and Alzheimer's disease. These findings provide new targets for the diagnosis and treatment of both diseases.

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APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

Cited by 16 publications

References 16 publications

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

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

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early‐onset Alzheimer's disease

Identification of immune cell infiltration and biomarkers in Alzheimer's disease and COVID-19 by integrated bioinformatics analysis and machine learning

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