Awakening Silent Memories: What Alzheimer’s Research Reveals About Engrams

One of the most captivating points from this semester’s talk with Stephanie Grella of the idea that memories in Alzheimer’s disease may not be gone forever, in contrast would be locked away in what are called silent engrams. “An engram is portrayed as a set of neurons that undergoes many chemical or even physical changes during any experience which allows the memory to be stored in the brain.” These engrams are the physical traces of memories that are encoded in the human brain. When a particular situation arises when a patient can’t recall an event, the engram in the brain could still exist–like a file saved on a hard drive, yet hidden behind a forgotten password. This particular perspective reforms memory loss as a problem of access rather than as a complete erasure of the memory. 

A study that includes a very fascinating example in relation of engrams is from Perusini et al. (2017). This specific study explored memory recovery in an Alzheimer’s disease mouse model. The researchers that took part of this research, investigated that mice with Alzheimer’s–like symptoms performed very defectively on memory exams. This has led to the suggestion that mice had “forgotten” the information that they acquired. Yet, when scientists use optogenetics–a technique that uses light to activate the specific neurons in the brain–to restore the dentate gyrus engrams cells that are tied to those specific memories, which lead to the mice suddenly remembered. This overall proposes that memories were stored in the brain, just not easily accessed through the normal route.  

This finding deeply connects to Stephanie Grella’s focus on engram theory and how its fundamental role in such disorders and conditions like Alzheimer's disease. If there are memories that are not truly destroyed yet instead are silenced, then upcoming treatments might aim to “awaken” those silent engrams. As said in the research, engrams cannot be retrieved by the natural way of retrieval but therefore could be recaptured with “direct optogenetic stimulation”. While optogenetics is not currently a practice for humans, the proposition behind it opens the door for other therapeutic strategies. This could include the usage of drugs, stimulation techniques, or other targeted behavioral therapies that could help restore memory retrieval.

Considering memory loss in this particular way, does bring a difference on how we understand late-life illnesses. Instead of analyzing Alzheimer’s as an unbeatable deletion of self, such research like this proposes that the brain retains much more than we realize. The challenge lies in finding such pathways to reconnect the patients with their own memories that shape who they are. Memory may be hidden, yet not fully disappeared. 

References

Josselyn, S. A., & Tonegawa, S. (2020). Memory engrams: Recalling the past and imagining the future. Science, 367(6473), eaaw4325. https://doi.org/10.1126/science.aaw4325 

Perusini, J. N., Cuevas, J. S., Shin, J., Yaeger, J. D. W., Goldberg, A. R., Koivisto, M., …Tanaka, K. Z. (2017). Optogenetic reactivation of memory engrams restores memory in mouse models of early Alzheimer’s disease. Nature, 531(7595), 508-512. https://doi.org/10.1038/nature17172

Why Global Representation in Parkinson’s Genetics Matters

    This semester, Dr. Mary Makarious shared her research with the Global Parkinson's Genetics Program (GP2). She uses data analytics and genetics in this program to investigate Parkinson's disease in various populations. Her discussion stood out for its emphasis on diversity. Treatments and risk assessments may not be applicable to the rest of the globe because most of our current genetic research is conducted on individuals of European heritage. Their goal in creating larger databases is to ensure that they represent the diversity of human communities and empower local researchers (Saffie-Awad et al., 2025).  
    This is supported by a recent study by Flores-Ocampo et al. (2025) titled "Population-Specific Differences in Pathogenic Variants of Genes Associated with Monogenic Parkinson's Disease." After examining several well-known Parkinson's genes, the researchers discovered that some ancestry groups had a high frequency of pathogenic mutations, while others had very few or none. For instance, new risk variants appear in underrepresented areas, while a mutation deemed "classic" for Parkinson's disease in European populations may be nearly undetectable in other groups. Their results demonstrate how risky it would be to presume that findings in one population would inevitably apply to others. 
    A larger question emerges when comparing the Flores-Ocampo study and Dr. Makarious's talk: In what ways may precision medicine offer customized care without escalating health inequalities around the world? On the one hand, identifying population-specific differences may revolutionize the treatment of Parkinson's disease by enabling more accurate diagnosis and potentially more effective therapies. However, if funds and resources for research are not distributed equitably, patients in understudied areas may still be left behind. The evident challenge is to build a future in which precision medicine implies not only "individualization," but also equitable. Studies like Flores-Ocampo et al. and initiatives like GP2 show that inclusion in research is essential and cannot be ignored. 

References 

Flores-Ocampo, V., Lim, A. W., Ogonowski, N. S., García-Marín, L. M., Ong, J. S., Yeow, D., Gonzaga-Jauregui, C., Kumar, K. R., & Rentería, M. E. (2025). Population-Specific Differences in Pathogenic Variants of Genes Associated with Monogenic Parkinson's Disease. Genes, 16(4), 454. https://doi.org/10.3390/genes16040454 

Saffie-Awad, P., Grant, S. M., Makarious, M. B., Elsayed, I., Sanyaolu, A. O., Wild Crea, P., Schumacher Schuh, A. F., … Bandrés-Ciga, S. (2025). Insights into ancestral diversity in Parkinson’s disease risk: A comparative assessment of polygenic risk scores. npj Parkinson’s Disease. https://doi.org/10.1038/s41531-025-00967-4 

Engrams, Alzheimer's, and Chronic Stress

The first week of this semester, we had the pleasure of listening to Stephanie Grella present her research on the formation and retrieval of memories involving the engram. Her studies aimed to identify engram cells and discover how information is stored and retrieved in the engram, as well as learn how the structure of an engram can affect the quality of memory functions, how engrams interact with one another, and how engrams can change over time.

To find answers to these questions, the results of observational studies, loss-of-function studies, gain-of-function studies, and mimicry experiments were compiled and analyzed. Most, if not all, of these studies look at the memory function of mice. One finding that I found interesting is the synaptic plasticity and strengthening of the engram during fear conditioning experiments. Some characteristics of these engrams include increased dendritic spine density and neuronal excitability. Both of these characteristics correlate with functioning memory retrieval and storage. Another interesting finding is the effects of damaging engrams and the evidence of silent engrams. Damaged engrams may result in memories that can no longer be retrieved, but silent engrams are engrams that contain memories that can only be retrieved through artificial means. In the study discussed, researchers were able to induce amnesia in mice by disrupting protein synthesis and discovered that silent engram cells showed less of an increase in synaptic strength and dendritic spine density than other engrams. A decrease in synaptic activity and dendritic spine density is related to the silencing of an engram, decreasing its overall function. In an experiment where researchers gave rats an LTP-like optogenetic stimulation, it was discovered that the stimulation impaired their memory function and silenced specific engrams. However, it was also found that the same stimulation could allow memories from these silenced engrams to be retrieved. I think that a lot of the findings discussed by Grella have many implications for future possible cures, treatments, and preventions of neurodegenerative diseases, including Dementia and Alzheimer's. I believe these findings have great potential to influence new research regarding these diseases, and most likely already have. Now that researchers better understand engrams and how they relate to memory function and decline, the next step could be applying these findings to medical research.

 

            The research that Stephanie Grella presented to our class made me wonder what further research on engrams might have been done recently. A research article by Freddy Jeanneteau investigates the effect that stress has on the risk of Alzheimer’s Dementia. In his article, Jeanneteau asks the question of whether deconstructed engrams can be rebuilt to restore memory functions. In this article, the many biochemical effects of stress and stress-related hormones and their similarities to mechanisms of underlying neurodegenerative diseases are discussed in detail. One thing about Jeanneteau’s research that stood out most to me is the effect that chronic stress has on engram functions. Experiments similar to those discussed in Grella’s research (administering experimental LTP to mice to induce amnesia) are correlated in this article to chronic stress and the body’s release of glucocorticoid, a stress response hormone. It is also noted that dendritic spine clustering, a characteristic related to functioning engrams in Grella’s research, is impaired in Alzheimer’s Dementia. Jeanneteau explains that this might happen because of the destruction that chronic stress hormones cause to the mechanisms of neuron and synapse maintenance. The maintenance of these synapses between engrams could potentially retrieve a pathway of connected neurons and retrieve lost memories. However, plaques like amyloid-β prevent these networks from excitability and are usually found near silent neurons and engrams. This research takes the findings from Grella’s presentation and applies them to a medical context. I believe that the findings discussed by Grella and Jeanneteau could potentially be developed further into effective solutions to diseases like Alzheimer’s Dementia. Learning the biological mechanisms of memory and memory decline is imperative to developing methods of prevention, treatment, and possibly a cure.

 

References

 

Jeanneteau, F. (2023). *Stress and the risk of Alzheimer's dementia: Can deconstructed engrams be rebuilt?* *Journal of Neuroendocrinology*. Advance online publication. [https://doi.org/10.1111/jne.13235](https://doi.org/10.1111/jne.13235)

 

 

Josselyn, S. A., & Tonegawa, S. (2020). *Memory engrams: Recalling the past and imagining the future.* *Science, 367*(6473), eaaw4325. [https://doi.org/10.1126/science.aaw4325](https://doi.org/10.1126/science.aaw4325)