Explore the vast range of titles available.

\"Learn about international soccer star Lionel Messi and all that he has had to overcome to be where he is now ... [and examine] his successes, his struggles, and how he has proven that he is a sports star who cares\"--Provided by publisher.

\"Venus and Serena Williams are two of the best tennis players in the world. They are also sisters!\" (MY FRIEND) Learn where they grew up and when their talent was discovered. Their many accomplishments are also described.

Pedro Martinez is \"the top-ranked pitcher in professional baseball, and one of the most popular athletes in the world\" (MY FRIEND). Learn when his talent was first discovered and why he is \"a shining example for youngsters to follow.\" His many accomplishments are presented.

Hockey star Anson Carter has what it takes to be a real hero. Learn more about this outstanding athlete and why what he does off the ice is just as important as his medals and trophies.

\"She may be only fourteen years old, but figure skater Sarah Hughes is taking the world by storm!\" (MY FRIEND) Learn about her many accomplishments in 1999 and her future aspirations. An address for her fans is included.

\"When figure skater Elvis Stojko takes to the ice, people expect great things.\" (MY FRIEND) Learn about his many accomplishments and the obstacles he overcame in the 1998 Winter Olympics. Discover why he never gave up. An address for his fans is included.

Background Alzheimer’s disease (AD) is clinically characterized by a progressive cognitive decline associated with stereotyped accumulation of amyloid‐beta (Aβ) plaques and hyperphosphorylated Tau (pTau) tangles across brain regions. While histopathology has revealed patterns of regional involvement, the molecular and cellular events that accompany and potentially drive this progression remain incompletely understood. Method We applied single nucleus RNA sequencing (RNAseq), ATAC‐seq, and Multiome profiling to over 7 million high‐quality nuclei from 10 brain regions—spanning medial and lateral entorhinal cortices, hippocampus, multiple temporal and frontal cortical areas, and primary visual cortex—sampled from the same cohort of 84 aged human donors across the AD spectrum (3 regions from all donors, 7 from those without severe co‐morbidities). We predicted the cell‐type for each nucleus by mapping to an expanded BRAIN initiative cell‐type taxonomy, which included AD‐associated non‐neuronal states and ∼70 brain region‐specific neuronal types. These datasets were paired with regional quantitative measurements of Aβ (6e10), pTau (AT8), and other protein pathologies, as well as cellular stains for neurons, microglia, and astrocytes. Result We inferred two distinct protein pathology accumulation patterns across brain regions: neocortical areas accumulated Aβ prior to pTau, whereas hippocampus and entorhinal cortex had early and, in some cases, substantial pTau burden independent of Aβ. Among neocortical regions, accumulation of AT8 beyond the temporal medial lobe strongly associated with dementia. In analyzing cell‐type abundance differences associated with higher levels of pTau pathology, we identified shared motifs of selective neuronal loss consistent with our previous observations from the middle temporal gyrus. These included loss of L2/3 and L5 intratelencephalic excitatory neurons and several types of inhibitory interneurons (e.g., Vip, Sst, Pvalb). These same vulnerable inhibitory types were also reduced in hippocampal and entorhinal regions, when present, and we observed parallel increases in astrocyte, microglial, and oligodendrocyte precursor cells. Additionally, we observed a decrease in specific, regionally specialized neuron subtypes in the hippocampus, entorhinal cortex, and visual cortex. Conclusion Our multimodal, multi‐region single‐cell atlas reveals common and region‐specific patterns of cellular vulnerability in AD. These cell‐types, particularly those commonly affected in distinct neural circuits, could serve as candidate therapeutic targets and biomarkers.

Aβ presence in the caudate nucleus (Ca) partially defines Thal stage III in Alzheimer's disease (AD), but little is known about AD's cellular impact on the region. Leveraging a public basal ganglia taxonomy of cellular populations, we generated a cellular resolution atlas of AD-associated pathological changes in Ca. Unlike cortex, we found that Ca AD pathology is dominated by two key features: phosphorylated tau (pTau)-containing neuropil threads enriched near oligodendrocytes in white matter tracts and amyloid-β diffuse plaques enriched in gray matter. Although AD pathology in affected cortical regions results in neuronal loss, we find no AD-driven reductions in neuron proportions in Ca. However, there were observable changes in multiple cellular populations. Protoplasmic astrocytes and FLT1+/IL1B+ microglia increased in abundance with global pTau levels. We also observe gene expression changes in fast-spiking PTHLH-PVALB interneurons indicative of disrupted signaling pathways and altered intrinsic physiological properties. This work provides a cellular-resolution framework for understanding AD pathology in Ca.

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Pseudo-progression analysis showed two major epochs corresponding with a slow early increase in pathology and a later exponential increase that correlated with cognitive decline. The early phase included inflammatory microglial and reactive astrocyte component, as well as a selective loss of Sst+ inhibitory neuron types in superficial cortical layers, loss of myelinating oligodendrocytes, and up-regulation of a re-myelination program by OPCs. The later phase involved loss of excitatory neurons and Pvalb and Vip neuron subtypes also predominantly in superficial layers. These cell vulnerabilities were also seen in prefrontal cortex and replicated by other independent studies when integrated with the BRAIN Initiative reference. Study data and exploratory tools are freely available to accelerate progress in AD research at SEA-AD.org.Competing Interest StatementThe authors have declared no competing interest.Footnotes* The revised manuscript now features: 1) Description of a single nucleus RNA sequencing dataset generated from a new cortical region, the dorsolateral prefrontal cortex (DLPFC) 2) An integrated atlas across 10 publicly available single cell studies that also profiled the DLPFC in AD donors 3) New data and analysis of MERFISH spatial analyses 4) Additional analyses on non-neuronal cells* http://sea-ad.org* https://adknowledgeportal.synapse.org/Explore/Studies/DetailsPage?Study=syn26223298* https://registry.opendata.aws/allen-sea-ad-atlas/