This paper describes the creation of a massive molecular and cellular atlas of middle temporal gyrus to better frame and understand how Alzheimer’s disease progresses. By analyzing the genetic activity of millions of individual cells, the researchers discovered that the disease actually unfolds in two distinct phases: an early, slow-moving stage where specific Sst+ interneurons are lost and inflammation begins, followed by a later stage of accelerated neuropathology and loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in prefrontal cortex in SEA-AD and other major AD studies.

This commentary on Gabitto, Travaglini, et al 2024 presents SEA-AD as a multifaceted open community resource designed to identify cellular and molecular pathologies that underlie Alzheimer’s disease. Integrating neuropathology, single cell and spatial genomics, and longitudinal clinical metadata, SEA-AD is a unique resource for studying the pathogenesis of Alzheimer’s and related dementias.

This paper introduces B-BIND, a new mathematical framework designed to track how Alzheimer’s disease progresses by analyzing the buildup of various pathological proteins. Because researchers often only have "snapshots" of the brain from different individuals, this model uses a "pseudotime" scale to rank patients along a continuous timeline of disease severity. Ultimately, this framework lays the groundwork for identifying the hidden biological stages of neurodegeneration and the specific cellular changes that drive the disease over time.

This paper introduces TabVI, a lightweight AI model designed to analyze single-cell genomic data more effectively than standard language-based AI. By adapting "transformer" technology—the same tech behind ChatGPT—to better fit the non-sequential, hierarchical nature of genes, TabVI can more accurately identify cell types and biological patterns. This tool provides a more efficient and interpretable way for researchers to study how diseases like Alzheimer’s affect individual cells across large datasets.

This paper introduces Annotation Comparison Explorer (ACE), a web-based tool developed by the Allen Institute to address the challenge of comparing cell-type classifications across different brain studies. ACE allows researchers to map their own single-cell data to established taxonomies, such as the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD), and compare annotations like donor demographics and disease-related changes. By applying ACE to multiple published Alzheimer's datasets, the authors identified consistent signatures of the disease, such as a decrease in specific somatostatin interneurons, demonstrating the tool's utility in unifying diverse datasets to advance the understanding of brain health and neurodegeneration.

Using transcriptomic datasets (including SEA-AD), this study reveals that somatic mutations—genetic changes occurring after birth—are twice as common in Alzheimer’s brains than in healthy, age-matched controls. These mutations are concentrated in the brain's immune cells (microglia) and often affect "cancer driver" genes, causing the cells to multiply and trigger inflammation. This suggests that Alzheimer's may be driven by a tumor-like process where mutated immune cells expand throughout the brain and accelerate neurodegeneration.

This study analyzed single nucleus transcriptomics data (including from SEA-AD) to understand how Alzheimer's disease affects men and women differently at a genetic level. Researchers found female-specific gene associations providing "protective" effects in neurons of dorsolateral prefrontal cortex, while specific inflammatory signals in microglia may increase risk for protein buildup in women. These findings highlight that the molecular path to cognitive decline is sex-specific, pointing toward new, targeted genes for future treatment research.

This study utilizes genome-wide CRISPRi screens in human iPSC-derived neurons to identify cellular factors regulating the accumulation of tau aggregates, a primary driver of Alzheimer’s disease. The researchers identified the ubiquitin ligase CUL5-SOCS4, alongside pathways such as UFMylation and mitochondrial function, as critical modifiers of tau stability and potential therapeutic targets. Furthermore, the team leveraged SEA-AD data to validate these findings, demonstrating that these tau-regulating genes exhibit altered expression within the specific cell types most vulnerable to Alzheimer’s in human donors.