Researchers have identified distinct molecular changes in the human hippocampus – a brain region critical for memory – as individuals age, and in those with Alzheimer’s disease, offering new insights into the biological processes that contribute to cognitive decline or resilience. The study, published in the journal Nature, provides a detailed “multiomic atlas” of the aging hippocampus, mapping epigenetic and transcriptional changes in neural stem cells and immature neurons.
The research builds upon decades of work in rodents, where hippocampal neurogenesis – the birth of new neurons – is well-established as a key component of learning and memory. However, the extent and functional significance of neurogenesis in the adult human brain has remained a subject of debate. While previous studies have confirmed the presence of immature neurons in the adult human hippocampus, and even in individuals with Alzheimer’s disease, the precise molecular mechanisms governing this process, and its impact on cognitive function, were largely unknown.
To address these knowledge gaps, the researchers employed single-nucleus multi-omic profiling, analyzing over 85,000 nuclei isolated from post-mortem human hippocampi. This technique, combining single-nucleus ATAC-seq (snATAC-seq) and single-nucleus RNA sequencing (snRNA-seq), allowed them to simultaneously assess both gene expression and chromatin accessibility – a measure of which genes are potentially available for activation. Analysis of samples from young adults with intact memory revealed 12 distinct cell types within the hippocampus, including neuroblasts, astrocytes, and mature neurons. Researchers identified 4,166 differentially expressed genes upregulated in neuroblasts compared to mature oligodendrocytes, and 169 associated pathways.
The study revealed a directional flow of development from neural stem cells to astrocytes and, to mature granule cells via immature neurons. Notably, neural stem cells exhibited high levels of “stemness” proxies and chromatin accessibility in regions associated with multi-lineage potential, while immature neurons showed increased accessibility in regions linked to neuronal maturation. This suggests a dynamic shift in epigenetic regulation as cells progress through the neurogenic process.
Comparing samples from healthy agers, individuals with preclinical Alzheimer’s pathology, and those diagnosed with Alzheimer’s disease, the researchers found significant differences in neurogenesis. Individuals with Alzheimer’s disease and preclinical pathology had a greater number of neural stem cells compared to healthy agers. However, the Alzheimer’s cohort exhibited a significant reduction in immature neurons and neuroblasts. Crucially, these changes were more pronounced in chromatin accessibility patterns than in gene expression levels, suggesting that epigenetic alterations may be a more reliable indicator of cognitive trajectory than transcript abundance alone.
A particularly intriguing finding emerged from the analysis of “SuperAgers” – individuals over 80 years old who maintain cognitive performance comparable to those decades younger. SuperAgers displayed a significantly higher number of immature neurons and neuroblasts compared to other groups, and exhibited distinct chromatin accessibility patterns. Researchers calculated “resilience scores” to identify consistent patterns across cohorts, revealing that chromatin and transcriptional effects remained stable in SuperAgers, young adults, and healthy agers, but were downregulated in those with Alzheimer’s disease.
Further analysis indicated that preserved excitatory synapse integrity was a hallmark of healthy cognitive aging, and that regulatory interactions involving astrocytes and CA1 pyramidal neurons distinguished successful from pathological aging. The researchers caution that the relatively little cohort sizes and inherent inter-individual variability necessitate cautious interpretation of the findings.
The study’s findings have potential therapeutic implications, suggesting that targeting epigenetic mechanisms could offer a novel approach to preserving cognitive function in aging. However, the authors emphasize the need for further research to establish causal links between the identified molecular patterns and cognitive performance. Recent research, highlighted by Harvard Medical School, has begun to explore the potential role of lithium in treating Alzheimer’s disease, suggesting a possible link between lithium deficiency and the onset of the disease, as reported in Nature. This area of investigation remains ongoing, and the precise mechanisms by which lithium might exert a protective effect are still under investigation.
