The Brain That Renews Itself: Super-Age Individuals Continue Forming New Neurons Every Day

The study demonstrates that the adult human hippocampus continues to produce new neurons, even in old age. This capacity diminishes and undergoes significant alterations in Alzheimer's disease, with changes detectable even in pre-clinical stages. On the other hand, individuals with exceptional memory in old age present a distinct molecular profile that may represent a protective or resilience mechanism. The research also mapped, in detail, the genetic mechanisms that regulate this process in the human brain.

For many years, scientists believed that the adult human brain was incapable of producing new neurons. Studies in rodents, such as mice and rats, clearly showed that there is continuous neuron formation in a region called the hippocampus, fundamental for memory and learning. In these animals, it is known that this process decreases with aging and is also affected in models of Alzheimer's disease.

However, in the human brain, the existence of this cellular renewal has been the subject of intense debate, mainly due to technical difficulties in accurately identifying truly new cells and differentiating them from other similar cell types.

One of the main difficulties lay in the methods used to identify young neurons. Researchers use "markers," which are molecules characteristic of certain cell types. The problem is that some markers of immature neurons also appear in other cell types, which has raised doubts about previous results.

Furthermore, the way brain tissue is collected and preserved after death can affect the quality of the analyses. Therefore, it was necessary to employ more precise techniques and multiple complementary approaches to obtain more reliable answers.

In this study, researchers analyzed samples of the human hippocampus obtained after death from different groups of people: young adults with preserved cognition, elderly individuals with age-appropriate performance, individuals with early brain changes related to Alzheimer's disease, patients with diagnosed Alzheimer's, and a special group called "SuperAgers," elderly individuals with memory performance comparable to that of much younger adults. The goal was to compare how the production of new neurons behaved in each group.

To this end, modern techniques called "multiomics" analyses were used, which allow the study of different layers of biological information simultaneously. One of these was single-core RNA sequencing, which identifies which genes are active in each individual cell by analyzing RNA, the molecule that indicates which genetic instructions are being used.

The other technique was single-nucleus accessible chromatin sequencing, which reveals which parts of the DNA are “open” and available for activation. Chromatin is the set of DNA and proteins that forms chromosomes, and its organization directly influences which genes can be switched on or off. By combining these two approaches, scientists were able to understand not only which genes were active, but also how their regulation was organized.

With these tools, researchers identified different stages in the development of new neurons. They found neural stem cells, which are cells capable of generating new neurons; neuroblasts, which are cells in an intermediate stage; immature neurons; and mature neurons fully integrated into brain circuits.

Using advanced computational analyses, it was possible to reconstruct a “developmental trajectory,” that is, a sequence showing how a stem cell gradually transforms into a functional neuron. This directional flow reinforces the idea that the formation of new neurons actually occurs in the adult human hippocampus.

Another central point was the study of so-called gene regulatory networks, which are sets of genes and proteins that control when and how other genes are activated. Researchers identified progressive changes in these control systems throughout the development of neural cells.

In stem cells, factors that maintain the capacity for multiplication predominate; while in immature neurons, factors that promote maturation and integration into memory circuits predominate. This demonstrates that there is an organized biological program guiding the formation of these new cells.

When comparing the different groups, scientists observed that individuals with Alzheimer's disease showed a reduction in immature neurons and significant alterations in chromatin organization, suggesting failures in the regulation of neurogenesis.

Interestingly, people in the pre-clinical phase, before evident symptoms, already showed initial alterations in these mechanisms. In contrast, the SuperAgers presented a distinct profile, with characteristics suggesting greater preservation or efficiency in the process of forming new neurons, which may be related to their exceptional memory.

These findings indicate that the human brain maintains, throughout life, a capacity to generate new neurons, although this process is influenced by aging and neurodegenerative diseases. Furthermore, differences in genetic regulation and DNA organization may explain both the vulnerability and cognitive resilience observed in different individuals.

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Human hippocampal neurogenesis in adulthood, ageing and Alzheimer’s disease

Ahmed Disouky, Mark A. Sanborn, K. R. Sabitha, Mostafa M. Mostafa, Ivan Alejandro Ayala, David A. Bennett, Yisha Lu, Yi Zhou, C. Dirk Keene, Sandra Weintraub, Tamar Gefen, M.-Marsel Mesulam, Changiz Geula, Mark Maienschein-Cline, Jalees Rehman, and Orly Lazarov

Nature. 25 February 2026

DOI:10.1038/s441586-026-10169-4

Abstract:

The existence of human hippocampal neurogenesis has long been disputed1,2,3,4,5,6,7,8,9,10,11,12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer’s disease (AD)11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a ‘resilience signature’. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.