Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
APOE4 homozygosity: a unique genetic variant of Alzheimer disease
August 2024—Alzheimer disease is genetically intricate and involves rare and common genetic variants. Early-onset autosomal dominant Alzheimer disease (ADAD) is caused by mutations in the APP, PSEN1, and PSEN2 genes, while variants in numerous other genes contribute to the risk of developing late-onset Alzheimer disease, with APOE considered the most significant risk factor. APOE4 homozygotes face a lifetime risk of Alzheimer disease dementia of up to 60 percent by age 85, significantly higher than that of heterozygotes or noncarriers of the gene. The predictability of outcomes in APOE4 homozygotes has not been previously studied, limiting the application of statistical methods used in ADAD for APOE4 research. The predictable sequence of pathological, biomarker, and clinical changes in ADAD and Down syndrome has offered insights into Alzheimer disease pathophysiology. However, the impact of APOE4 on these changes has not been explored to the same degree, and sample-size constraints have made it particularly difficult to study the differences between APOE4 heterozygotes and homozygotes. Leveraging the National Alzheimer’s Coordinating Center (NACC) data set and data from five large multicenter cohorts, the authors conducted a study in which they examined clinical, pathological, and biomarker changes in APOE4 homozygotes. They hypothesized that the changes could represent a form of genetically determined dementia. The authors analyzed data from 3,297 brain donors in the NACC cohort and 10,039 people in clinical cohorts. The data indicated that nearly all APOE4 homozygotes exhibited high or intermediate Alzheimer disease neuropathological change scores. In vivo biomarker analysis indicated that APOE4 homozygotes consistently showed higher levels of abnormal biomarkers than APOE3 homozygotes starting at age 55, with almost all APOE4 homozygotes having abnormal amyloid and tau biomarkers by age 65. The predictability of symptom onset in APOE4 homozygotes was comparable to that found in those with ADAD and Down syndrome and in PSEN1 mutation carriers. Furthermore, neurodegeneration biomarkers, including neurofilament light chain and hippocampal atrophy, showed early divergence in APOE4 homozygotes. Comparing APOE4 homozygotes to those with ADAD and Down syndrome, the authors constructed an integrated model of biomarker changes, revealing similar temporal patterns across these genetic conditions. The primary difference was less hippocampal atrophy at all ages, suggesting a unique neurodevelopmental impact of APOE4. The study findings indicate a need to reconceptualize the genetic architecture of Alzheimer disease by considering APOE4 homozygotes to be a distinct genetically determined form of Alzheimer disease, akin to ADAD and Down syndrome. This has implications for clinical practice, including genetic counseling and APOE screening, and suggests that APOE4 homozygotes should be considered separately from heterozygotes due to their distinct risk profiles. Future research should include diverse populations to fully understand the effects of APOE4 across ethnicities. This study highlights the need for new research and clinical trials focused on APOE4 homozygotes.
Fortea J, Pegueroles J, Alcolea D, et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nat Med. 2024;30:1284–1291.
Correspondence: Dr. Juan Fortea at jfortea@santpau.cat
Multiomics study of renal cell carcinoma subtypes and a new treatment option
Renal cell carcinoma is one of the 10 most common cancers worldwide, and the most common subtype is clear cell renal cell carcinoma. Advances in single-cell and spatial sequencing technologies have enhanced the medical community’s understanding of the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). Yet correlating these findings with genomic and epigenomic data has been challenging due to limited sample sizes. The authors conducted a study in which they analyzed subtypes of ccRCC to shed light on outcomes and treatment of the disease. They used such advanced methods as exome sequencing, RNA sequencing, and mass spectrometry-based proteome and metabolomic profiling to analyze 100 ccRCC samples from an RCC cohort of patients at Tongji Hospital, Wuhan, China, who had not had any treatment. An analysis of tumor data and clinical data, as well as multiomic profiling of paired normal adjacent tissue from 50 patients, unveiled four distinct genetic subgroups of ccRCC. These subgroups displayed distinct immune and tumor microenvironment characteristics. Analysis of gene expression and protein levels revealed a strong association with changes in the number of copies of DNA in human cells. This allowed the authors to differentiate between cancerous tumors and healthy tissue and emphasized the increased activity of such processes as blood vessel formation, glucose metabolism, and immune response in ccRCC tissues. The findings were supported by metabolomic analysis that revealed an integrated map of metabolites and enzymes indicating plausible reasons for lipid droplets to form in tumor tissue. The authors categorized the malignancies into the four immune subtypes of IM1 through IM4. IM1 was characterized by a lack of immune cell signatures suggestive of immune exclusion, IM2 by enriched endothelial signatures, IM3 by increased T cells and tumor-associated macrophages (TAMs), and IM4 by the highest stromal and TAM scores. Kaplan-Meier analysis showed that patients in the IM2 group had the most favorable survival results and those in the IM4 group had the least favorable outcomes. Further analysis using single-nucleus RNA-sequencing and ATAC-sequencing (assay for transposable-accessible chromatin with sequencing) techniques identified variations in immune cell populations and metabolic pathways between the subtypes. Notably, IM4 tumors exhibited unique metabolic characteristics and were associated with a negative prognosis. The authors then correlated those immune subtypes with clinical trial data, which suggested that combination therapies, such as PD-L1 and VEGF inhibitors, may benefit IM3 and IM4 groups. The study also proposed a dynamic ccRCC progression model (de-clear cell differentiation, DCCD), in which tumors progress from non-DCCD (IM1–IM3) to DCCD (IM4) characterized by somatic copy number alteration events. This multiomic study highlights the complex interplay between genomic, transcriptomic, proteomic, and metabolomic alterations in ccRCC and proposes new insights into tumor classification, progression, and potential therapeutic strategies. Further validation and exploration of these findings could improve personalized treatment for ccRCC patients.
Hu J, Wang SG, Hou Y, et al. Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression. Nat Genet. 2024;56:442–457.
Correspondence: Ke Chen at shenke@hust.edu.cn